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Hugh, Farida, i K. R. Dumbell. "Virulence of variola viruses for suckling mice". Transactions of the Royal Society of Tropical Medicine and Hygiene 97, nr 1 (styczeń 2003): 97–99. http://dx.doi.org/10.1016/s0035-9203(03)90036-8.
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Joseph, Tomy, Josephine McAuliffe, Bin Lu, Hong Jin, George Kemble i Kanta Subbarao. "Evaluation of Replication and Pathogenicity of Avian Influenza A H7 Subtype Viruses in a Mouse Model". Journal of Virology 81, nr 19 (18.07.2007): 10558–66. http://dx.doi.org/10.1128/jvi.00970-07.
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ABSTRACT Avian influenza A H7 subtype viruses pose a significant threat to human health because of their ability to transmit directly from domestic poultry to humans and to cause disease and, sometimes, death. Although it is important to develop vaccines against viruses of this subtype, very limited information is available on the immune response and pathogenesis of H7 viruses in animal models such as mice and ferrets. Ten H7 viruses were selected for possible vaccine development on the basis of their phylogenetic relationships and geographical locations. The virulence of the 10 viruses for mice and the immunogenicity of the viruses in mice and ferrets were evaluated to study the extent of antigenic relatedness and the level of cross-reactivity of antibodies. Most of the viruses showed similar patterns of cross-reactivity with mouse and ferret antisera. The Eurasian viruses elicited broadly cross-reactive antibodies that neutralized viruses from both Eurasian and North American lineages, but the converse was not true. A subset of the viruses was also evaluated for the ability to replicate and cause disease in BALB/c mice following intranasal administration. H7 subtype viruses were able to infect mice without adaptation and manifested different levels of lethality and kinetics of replication. On the basis of phylogenetic data, induction of broadly cross-neutralizing antibodies in mouse and ferret antisera, and their ability to replicate in mice, we have selected A/Netherlands/219/03 (subtype H7N7) and A/chicken/BC/CN-7/04 (subtype H7N3) viruses for vaccine development. The mouse model can be used for the preclinical evaluation of these vaccines against H7 subtype viruses.
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Song, Yafen, Weiqiang Li, Wenbo Wu, Zhiting Liu, Zhuoliang He, Zuxian Chen, Bingbing Zhao i in. "Phylogeny, Pathogenicity, Transmission, and Host Immune Responses of Four H5N6 Avian Influenza Viruses in Chickens and Mice". Viruses 11, nr 11 (10.11.2019): 1048. http://dx.doi.org/10.3390/v11111048.
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H5Nx viruses have continuously emerged in the world, causing poultry industry losses and posing a potential public health risk. Here, we studied the phylogeny, pathogenicity, transmission, and immune response of four H5N6 avian influenza viruses in chickens and mice, which were isolated from waterfowl between 2013 and 2014. Their HA genes belong to Clade 2.3.4.4, circulated in China since 2008. Their NA genes fall into N6-like/Eurasian sublineage. Their internal genes originated from different H5N1 viruses. The results suggested that the four H5N6 viruses were reassortants of the H5N1 and H6N6 viruses. They cause lethal infection with high transmission capability in chickens. They also cause mild to severe pathogenicity in mice and can spread to the brain through the blood–brain barrier. During the infection, the viruses result in the up-regulation of PRRs and cytokine in brains and lungs of chickens and mice. Our results suggested that the high viral loads of several organs may result in disease severity in chickens and mice; there were varying levels of cytokines induced by the H5N6 viruses with different pathogenicity in chickens and mice.
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Lu, Xiuhua, Terrence M. Tumpey, Timothy Morken, Sherif R. Zaki, Nancy J. Cox i Jacqueline M. Katz. "A Mouse Model for the Evaluation of Pathogenesis and Immunity to Influenza A (H5N1) Viruses Isolated from Humans". Journal of Virology 73, nr 7 (1.07.1999): 5903–11. http://dx.doi.org/10.1128/jvi.73.7.5903-5911.1999.
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ABSTRACT During 1997 in Hong Kong, 18 human cases of respiratory illness, including 6 fatalities, were caused by highly pathogenic avian influenza A (H5N1) viruses. Since H5 viruses had previously been isolated only from avian species, the outbreak raised questions about the ability of these viruses to cause severe disease and death in humans. To better understand the pathogenesis and immunity to these viruses, we have used the BALB/c mouse model. Four H5N1 viruses replicated equally well in the lungs of mice without prior adaptation but differed in lethality for mice. H5N1 viruses that were highly lethal for mice were detected in multiple organs, including the brain. This is the first demonstration of an influenza A virus that replicates systemically in a mammalian species and is neurotropic without prior adaptation. The mouse model was also used to evaluate a strategy of vaccination against the highly pathogenic avian H5N1 viruses, using an inactivated vaccine prepared from nonpathogenic A/Duck/Singapore-Q/F119-3/97 (H5N3) virus that was antigenically related to the human H5N1 viruses. Mice administered vaccine intramuscularly, with or without alum, were completely protected from lethal challenge with H5N1 virus. Protection from infection was also observed in 70% of animals administered vaccine alone and 100% of mice administered vaccine with alum. The protective effect of vaccination correlated with the level of virus-specific serum antibody. These results suggests a strategy of vaccine preparedness for rapid intervention in future influenza pandemics that uses antigenically related nonpathogenic viruses as vaccine candidates.
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Williams, Simon H., Xiaoyu Che, Joel A. Garcia, John D. Klena, Bohyun Lee, Dorothy Muller, Werner Ulrich i in. "Viral Diversity of House Mice in New York City". mBio 9, nr 2 (17.04.2018): e01354-17. http://dx.doi.org/10.1128/mbio.01354-17.
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ABSTRACTThe microbiome of wildMus musculus(house mouse), a globally distributed invasive pest that resides in close contact with humans in urban centers, is largely unexplored. Here, we report analysis of the fecal virome of house mice in residential buildings in New York City, NY. Mice were collected at seven sites in Manhattan, Queens, Brooklyn, and the Bronx over a period of 1 year. Unbiased high-throughput sequencing of feces revealed 36 viruses from 18 families and 21 genera, including at least 6 novel viruses and 3 novel genera. A representative screen of 15 viruses by PCR confirmed the presence of 13 of these viruses in liver. We identified an uneven distribution of diversity, with several viruses being associated with specific locations. Higher mouse weight was associated with an increase in the number of viruses detected per mouse, after adjusting for site, sex, and length. We found neither genetic footprints to known human viral pathogens nor antibodies to lymphocytic choriomeningitis virus.IMPORTANCEMice carry a wide range of infectious agents with zoonotic potential. Their proximity to humans in the built environment is therefore a concern for public health. Laboratory mice are also the most common experimental model for investigating the pathobiology of infectious diseases. In this survey of mice trapped in multiple locations within New York City over a period of 1 year, we found a diverse collection of viruses that includes some previously not associated with house mice and others that appear to be novel. Although we found no known human pathogens, our findings provide insights into viral ecology and may yield models that have utility for clinical microbiology.
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Beck, Melinda A. "Selenium and host defence towards viruses". Proceedings of the Nutrition Society 58, nr 3 (sierpień 1999): 707–11. http://dx.doi.org/10.1017/s0029665199000920.
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The association between viral disease and nutrition has long been thought to be due to effects on the host immune system. This theory suggests that when a host is malnourished, the immune system is compromised, and thus increased susceptibility to viral infection will occur. However, the virus itself may also be affected by the nutritional status of the host. We have demonstrated that a normally-benign strain of coxsackievirus B3 (CVB3/0) becomes virulent in either Se-deficient or vitamin E-deficient mice. Although the deficient animals are immunosuppressed, the virus itself is also altered. Six nucleotide changes were found in the virus that replicated in the deficient mice, and once these mutations occurred, even mice with normal nutrition became susceptible to disease. Thus, the nutritional status of the host was able to transform an avirulent virus into a virulent one due to genomic changes in the virus. We believe that a common mechanism of oxidative stress is the underlying cause of the genetic changes. Both vitamin E and Se act as antioxidants, and benign virus inoculated into GSH peroxidase (EC 1.11.1.9)-knockout mice will also convert to virulence due to genomic changes. Our work points to the importance of host nutrition during a viral disease, not only from the perspective of the host, but from the perspective of the viral pathogen as well.
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Ilyushina, Natalia A., Alexey M. Khalenkov, Jon P. Seiler, Heather L. Forrest, Nicolai V. Bovin, Henju Marjuki, Subrata Barman, Robert G. Webster i Richard J. Webby. "Adaptation of Pandemic H1N1 Influenza Viruses in Mice". Journal of Virology 84, nr 17 (30.06.2010): 8607–16. http://dx.doi.org/10.1128/jvi.00159-10.
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ABSTRACT The molecular mechanism by which pandemic 2009 influenza A viruses were able to sufficiently adapt to humans is largely unknown. Subsequent human infections with novel H1N1 influenza viruses prompted an investigation of the molecular determinants of the host range and pathogenicity of pandemic influenza viruses in mammals. To address this problem, we assessed the genetic basis for increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09 (H1N1) isolates, which are not lethal for mice, in a new mammalian host by promoting their mouse adaptation. The resulting mouse lung-adapted variants showed significantly enhanced growth characteristics in eggs, extended extrapulmonary tissue tropism, and pathogenicity in mice. All mouse-adapted viruses except A/TN/1-560/09-MA2 grew faster and to higher titers in cells than the original strains. We found that 10 amino acid changes in the ribonucleoprotein (RNP) complex (PB2 E158G/A, PA L295P, NP D101G, and NP H289Y) and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K, and D222G) controlled enhanced mouse virulence of pandemic isolates. HA mutations acquired during adaptation affected viral receptor specificity by enhancing binding to α2,3 together with decreasing binding to α2,6 sialyl receptors. PB2 E158G/A and PA L295P amino acid substitutions were responsible for the significant enhancement of transcription and replication activity of the mouse-adapted H1N1 variants. Taken together, our findings suggest that changes optimizing receptor specificity and interaction of viral polymerase components with host cellular factors are the major mechanisms that contribute to the optimal competitive advantage of pandemic influenza viruses in mice. These modulators of virulence, therefore, may have been the driving components of early evolution, which paved the way for novel 2009 viruses in mammals.
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Bocharov, E. F., Yu P. Shorin, I. A. Solodovnikova, L. S. Kazaryan, V. G. Selyatitskaya i N. A. Pal'chikova. "Experimental diabetes in mice infected with coxsackie viruses". Bulletin of Experimental Biology and Medicine 103, nr 2 (luty 1987): 182–86. http://dx.doi.org/10.1007/bf00840326.
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Tan, Mingming, Wenkui Sun, Chunlai Feng, Di Xia, Xiaoyue Shen, Yuan Ding, Zhicheng Liu, Zheng Xing, Xin Su i Yi Shi. "The microRNA-let-7b-mediated attenuated strain of influenza A (H1N1) virus in a mouse model". Journal of Infection in Developing Countries 10, nr 09 (30.09.2016): 973–81. http://dx.doi.org/10.3855/jidc.6861.
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Introduction: Evaluating the attenuation of influenza viruses in animal studies is important in developing safe and effective vaccines. This study aimed to demonstrate that the microRNA (miRNA)-let-7b-mediated attenuated influenza viruses (miRT-H1N1) are sufficiently attenuated and safe in mice. Methodology: The pathogenicity of the miRT-H1N1virus was investigated in a mouse model, evaluated with median lethal dose (LD50). The replicative dynamics of the miRT-H1N1, wild type (wt)-H1N1, and scramble (scbl)-H1N1 viruses in the lungs of infected mice were compared. The degrees of lesions and the expression levels of IL-6, TNF-α, and IFN-β in the lungs of mice infected with different viruses were also analyzed. Results: In miRT-H1N1 virus-infected mice, 100% of mice survived, and a lower pathogenicity was characterized with non-significant weight loss when compared to mice infected with the control wt virus. The miRT-H1N1 virus was not fatal for mice, even at the highest dose administered. The viral load in the lungs of miRT-H1N1-infected mice was significantly lower than that of the wild-type virus-infected mice. Fewer pulmonary lesions and lower levels of selected pro-inflammatory cytokines in the lungs of the mice infected with the miRT-H1N1 virus were also observed. The virulence of the miRT-H1N1 virus reduced significantly, suggesting that the miRT-H1N1 virus was safe for mice. Conclusions: Our study demonstrated that the miRNA-mediated gene silencing is an alternative approach to attenuating the pathogenicity of wt influenza viruses that have potential in the development of influenza vaccines.
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Gillim-Ross, Laura, Celia Santos, Zhongying Chen, Amy Aspelund, Chin-Fen Yang, Dan Ye, Hong Jin, George Kemble i Kanta Subbarao. "Avian Influenza H6 Viruses Productively Infect and Cause Illness in Mice and Ferrets". Journal of Virology 82, nr 21 (20.08.2008): 10854–63. http://dx.doi.org/10.1128/jvi.01206-08.
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ABSTRACT Influenza pandemic preparedness has focused on influenza virus H5 and H7 subtypes. However, it is not possible to predict with certainty which subtype of avian influenza virus will cause the next pandemic, and it is prudent to include other avian influenza virus subtypes in pandemic preparedness efforts. An H6 influenza virus was identified as a potential progenitor of the H5N1 viruses that emerged in Hong Kong in 1997. This virus continues to circulate in the bird population in Asia, and other H6 viruses are prevalent in birds in North America and Asia. The high rate of reassortment observed in influenza viruses and the prevalence of H6 viruses in birds suggest that this subtype may pose a pandemic risk. Very little is known about the replicative capacity, immunogenicity, and correlates of protective immunity for low-pathogenicity H6 influenza viruses in mammals. We evaluated the antigenic and genetic relatedness of 14 H6 influenza viruses and their abilities to replicate and induce a cross-reactive immune response in two animal models: mice and ferrets. The different H6 viruses replicated to different levels in the respiratory tracts of mice and ferrets, causing varied degrees of morbidity and mortality in these two models. H6 virus infection induced similar patterns of neutralizing antibody responses in mice and ferrets; however, species-specific differences in the cross-reactivity of the antibody responses were observed. Overall, cross-reactivity of neutralizing antibodies in H6 virus-infected mice did not correlate well with protection against heterologous wild-type H6 viruses. However, we have identified an H6 virus that induces protective immunity against viruses in the North American and Eurasian lineages.
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Hughes, Mark T., Mikhail Matrosovich, M. Elizabeth Rodgers, Martha McGregor i Yoshihiro Kawaoka. "Influenza A Viruses Lacking Sialidase Activity Can Undergo Multiple Cycles of Replication in Cell Culture, Eggs, or Mice". Journal of Virology 74, nr 11 (1.06.2000): 5206–12. http://dx.doi.org/10.1128/jvi.74.11.5206-5212.2000.
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ABSTRACT Influenza A viruses possess both hemagglutinin (HA), which is responsible for binding to the terminal sialic acid of sialyloligosaccharides on the cell surface, and neuraminidase (NA), which contains sialidase activity that removes sialic acid from sialyloligosaccharides. Interplay between HA receptor-binding and NA receptor-destroying sialidase activity appears to be important for replication of the virus. Previous studies by others have shown that influenza A viruses lacking sialidase activity can undergo multiple cycles of replication if sialidase activity is provided exogenously. To investigate the sialidase requirement of influenza viruses further, we generated a series of sialidase-deficient mutants. Although their growth was less efficient than that of the parental NA-dependent virus, these viruses underwent multiple cycles of replication in cell culture, eggs, and mice. To understand the molecular basis of this viral growth adaptation in the absence of sialidase activity, we investigated changes in the HA receptor-binding affinity of the sialidase-deficient mutants. The results show that mutations around the HA receptor-binding pocket reduce the virus's affinity for cellular receptors, compensating for the loss of sialidase. Thus, sialidase activity is not absolutely required in the influenza A virus life cycle but appears to be necessary for efficient virus replication.
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Liu, Liling, Xianying Zeng, Pucheng Chen, Guohua Deng, Yanbing Li, Jianzhong Shi, Chunyang Gu i in. "Characterization of Clade 7.2 H5 Avian Influenza Viruses That Continue To Circulate in Chickens in China". Journal of Virology 90, nr 21 (24.08.2016): 9797–805. http://dx.doi.org/10.1128/jvi.00855-16.
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ABSTRACTThe H5N1 avian influenza viruses emerged in Southeast Asia in the late 20th century and have evolved into multiple phylogenetic clades based on their hemagglutinin (HA)-encoding genes. The clade 7.2 viruses were first detected in chickens in northern China in 2006, and vaccines specifically targeted to the clade were developed and have been used in poultry in China since 2006. During routine surveillance and disease diagnosis, we isolated seven H5 viruses between 2011 and 2014 that bear the clade 7.2 HA genes. Here, we performed extensive studies to understand how the clade 7.2 H5 viruses have evolved in chickens in China. Full genome sequence analysis revealed that the seven viruses formed two subtypes (four H5N1 viruses and three H5N2 viruses) and four genotypes by deriving genes from other influenza viruses. All of the viruses had antigenically drifted from the clade 7.2 viruses that were isolated in 2006. Pathogenicity studies of four viruses, one from each genotype, revealed that all of the viruses are highly pathogenic in chickens, but none of them could replicate in ducks. The four viruses exclusively bound to avian-type receptors and replicated only in the turbinates and/or lungs of mice; none of them were lethal to mice at a dosage of 10650% egg infective doses (EID50). Our study indicates that although the clade 7.2 viruses have not been eradicated from poultry through vaccination, they have not become more dangerous to other animals (e.g., ducks and mice) and humans.IMPORTANCEAnimal influenza viruses can acquire the ability to infect and kill humans. The H5N1 viruses have been a concern in recent decades because of their clear pandemic potential. We sorted H5N1 influenza viruses into different phylogenetic clades based on their HA genes. The clade 7.2 viruses were detected in chickens in several provinces of northern China in 2006. Vaccines for these viruses were subsequently developed and have been used ever since to control infection of poultry. Here, we analyzed the genetic and biologic properties of seven clade 7.2 viruses that were isolated from chickens between 2011 and 2014. We found that after nearly 9 years of circulation in chickens, the clade 7.2 viruses still exclusively bind to avian-type receptors and are of low pathogenicity to mice, suggesting that these H5 viruses pose a low risk to human public health.
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Chambers, Thomas J., Yan Liang, Deborah A. Droll, Jacob J. Schlesinger, Andrew D. Davidson, Peter J. Wright i Xiaoshan Jiang. "Yellow Fever Virus/Dengue-2 Virus and Yellow Fever Virus/Dengue-4 Virus Chimeras: Biological Characterization, Immunogenicity, and Protection against Dengue Encephalitis in the Mouse Model". Journal of Virology 77, nr 6 (15.03.2003): 3655–68. http://dx.doi.org/10.1128/jvi.77.6.3655-3668.2003.
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ABSTRACT Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 105 PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.
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Lu, Xiuhua, Mary Renshaw, Terrence M. Tumpey, Gloria D. Kelly, Jean Hu-Primmer i Jacqueline M. Katz. "Immunity to Influenza A H9N2 Viruses Induced by Infection and Vaccination". Journal of Virology 75, nr 10 (15.05.2001): 4896–901. http://dx.doi.org/10.1128/jvi.75.10.4896-4901.2001.
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ABSTRACT Avian influenza A H9N2 viruses are widespread among domestic poultry and were recently isolated from humans with respiratory illness in China. Two antigenically and genetically distinct groups of H9N2 viruses (G1 and G9) are prevalent in China. To evaluate a strategy for vaccination, we compared G1 and G9 viruses for their relative immunogenicity and cross-protective efficacy. Infection of BALB/c mice with representative viruses of either group protected against subsequent challenge with the homologous or heterologous H9N2 virus in the absence of detectable cross-reactive serum hemagglutination inhibition antibody. Mice injected intramuscularly with inactivated G1 whole virus vaccine were completely protected from challenge with either H9N2 virus. In contrast, mice administered inactivated G9 vaccine were only partially protected against heterologous challenge with the G1 virus. These results have implications for the development of human vaccines against H9N2 viruses, a priority for pandemic preparedness.
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Kane, Melissa, i Tatyana V. Golovkina. "Mapping Viral Susceptibility Loci in Mice". Annual Review of Virology 6, nr 1 (29.09.2019): 525–46. http://dx.doi.org/10.1146/annurev-virology-092818-015544.
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Genetic alleles that contribute to enhanced susceptibility or resistance to viral infections and virally induced diseases have often been first identified in mice before humans due to the significant advantages of the murine system for genetic studies. Herein we review multiple discoveries that have revealed significant insights into virus-host interactions, all made using genetic mapping tools in mice. Factors that have been identified include innate and adaptive immunity genes that contribute to host defense against pathogenic viruses such as herpes viruses, flaviviruses, retroviruses, and coronaviruses. Understanding the genetic mechanisms that affect infectious disease outcomes will aid the development of personalized treatment and preventive strategies for pathogenic infections.
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Hui, Eric Ka-Wai, Donald F. Smee, Min-Hui Wong i Debi P. Nayak. "Mutations in Influenza Virus M1 CCHH, the Putative Zinc Finger Motif, Cause Attenuation in Mice and Protect Mice against Lethal Influenza Virus Infection". Journal of Virology 80, nr 12 (15.06.2006): 5697–707. http://dx.doi.org/10.1128/jvi.02729-05.
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ABSTRACT Mutations in CCHH, the putative zinc finger motif, apparently do not play an important role in virus replication in MDCK cells in culture (E. K.-W. Hui, K. Ralston, A. K. Judd, and D. P. Nayak, J. Gen. Virol. 84:3105-3113, 2003). In this report, however, we demonstrate that the CCHH motif plays a critical role in virulence in mice and that some CCHH mutants are highly attenuated in BALB/c mice. Some of the mutant viruses replicated the least in mice lungs, induced little or no lung lesions, and caused highly reduced morbidity and mortality. Furthermore, growth patterns of mutant viruses in different cell lines (MDCK, MLE12, 3LL, A549, and 293T) varied. Mutant viruses that were attenuated in mice also grew poorly in mouse and human cells in culture. However, wild-type (WT) and all mutant viruses replicated to the same titer in MDCK (canine) cells or embryonated chicken eggs. Attenuation in mice correlated with reduced growth in mouse cells in culture, suggesting that potential attenuation in a given host can be predicted from the growth characteristics of the virus in cultured cells (preferably lung cells) from the same species. In challenge experiments, mice immunized by infection with attenuated mutant viruses were fully protected from lethal challenge with WT virus. In summary, the replication and attenuating properties of these mutants suggest that the CCHH motif provides a critical determinant for virulence in mouse and that mutations in the CCHH motif yield potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines.
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Maines, Taronna R., Xui Hua Lu, Steven M. Erb, Lindsay Edwards, Jeannette Guarner, Patricia W. Greer, Doan C. Nguyen i in. "Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals". Journal of Virology 79, nr 18 (15.09.2005): 11788–800. http://dx.doi.org/10.1128/jvi.79.18.11788-11800.2005.
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ABSTRACT The spread of highly pathogenic avian influenza H5N1 viruses across Asia in 2003 and 2004 devastated domestic poultry populations and resulted in the largest and most lethal H5N1 virus outbreak in humans to date. To better understand the potential of H5N1 viruses isolated during this epizootic event to cause disease in mammals, we used the mouse and ferret models to evaluate the relative virulence of selected 2003 and 2004 H5N1 viruses representing multiple genetic and geographical groups and compared them to earlier H5N1 strains isolated from humans. Four of five human isolates tested were highly lethal for both mice and ferrets and exhibited a substantially greater level of virulence in ferrets than other H5N1 viruses isolated from humans since 1997. One human isolate and all four avian isolates tested were found to be of low virulence in either animal. The highly virulent viruses replicated to high titers in the mouse and ferret respiratory tracts and spread to multiple organs, including the brain. Rapid disease progression and high lethality rates in ferrets distinguished the highly virulent 2004 H5N1 viruses from the 1997 H5N1 viruses. A pair of viruses isolated from the same patient differed by eight amino acids, including a Lys/Glu disparity at 627 of PB2, previously identified as an H5N1 virulence factor in mice. The virus possessing Glu at 627 of PB2 exhibited only a modest decrease in virulence in mice and was highly virulent in ferrets, indicating that for this virus pair, the K627E PB2 difference did not have a prevailing effect on virulence in mice or ferrets. Our results demonstrate the general equivalence of mouse and ferret models for assessment of the virulence of 2003 and 2004 H5N1 viruses. However, the apparent enhancement of virulence of these viruses in humans in 2004 was better reflected in the ferret.
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Chen, Zhaokun, Qinghua Huang, Shaohua Yang, Shuai Su, Baoquan Li, Ning Cui i Chuantian Xu. "A Well-Defined H9N2 Avian Influenza Virus Genotype with High Adaption in Mammals was Prevalent in Chinese Poultry Between 2016 to 2019". Viruses 12, nr 4 (11.04.2020): 432. http://dx.doi.org/10.3390/v12040432.
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H9N2 subtype avian influenza virus (AIV) is widely prevalent in poultry, and the virus is becoming adaptive to mammals, which poses pandemic importance. Here, BALB/c mice were employed as a model to evaluate the adaption in mammals of 21 field H9N2 viruses isolated from avian species between 2016 to 2019 in China. The replication capacity of the viruses was evaluated in the lungs of mice. The pathogenicity of the viruses were compared by weight loss and lung lesions from infected mice. The whole genomic sequences of the viruses were further characterized to define the associated phenotypes of the H9N2 viruses in vitro and in vivo. The results showed that most viruses could replicate well and cause lesions in the mouse lungs. The propagation capacity in MDCK cells and damage to respiratory tissues of the infected mice corresponded to relative viral titers in the mouse lungs. Further genome analysis showed that all of the H9N2 viruses belonged to the same genotype, G57, and contained a couple of amino acid substitutions or deletions that have been demonstrated as avian-human markers. Additionally, nine amino acids residues in seven viral proteins were found to be correlated with the replication phenotypes of the H9N2 viruses in mammals. The study demonstrated that a well-defined H9N2 AIV genotype with high adaption in mammals was prevalent in China in recent years. Further investigations on the role of the identified residues and continuous surveillance of newly identified mutations associated with host adaption should be strengthened to prevent any devastating human influenza pandemics.
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Gao, Peng, Shinji Watanabe, Toshihiro Ito, Hideo Goto, Krisna Wells, Martha McGregor, A. James Cooley i Yoshihiro Kawaoka. "Biological Heterogeneity, Including Systemic Replication in Mice, of H5N1 Influenza A Virus Isolates from Humans in Hong Kong". Journal of Virology 73, nr 4 (1.04.1999): 3184–89. http://dx.doi.org/10.1128/jvi.73.4.3184-3189.1999.
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ABSTRACT An H5N1 avian influenza A virus was transmitted to humans in Hong Kong in 1997. Although the virus causes systemic infection and is highly lethal in chickens because of the susceptibility of the hemagglutinin to furin and PC6 proteases, it is not known whether it also causes systemic infection in humans. The clinical outcomes of infection in Hong Kong residents ranged widely, from mild respiratory disease to multiple organ failure leading to death. Therefore, to understand the pathogenesis of influenza due to these H5N1 isolates, we investigated their virulence in mice. The results identified two distinct groups of viruses: group 1, for which the dose lethal for 50% of mice (MLD50) was between 0.3 and 11 PFU, and group 2, for which the MLD50 was more than 103 PFU. One day after intranasal inoculation of mice with 100 PFU of group 1 viruses, the virus titer in lungs was 107 PFU/g or 3 log units higher than that for group 2 viruses. Both types of viruses had replicated to high titers (>106 PFU/g) in the lungs by day 3 and maintained these titers through day 6. More importantly, only the group 1 viruses caused systemic infection, replicating in nonrespiratory organs, including the brain. Immunohistochemical analysis demonstrated the replication of a group 1 virus in brain neurons and glial cells and in cardiac myofibers. Phylogenetic analysis of all viral genes showed that both groups of Hong Kong H5N1 viruses had formed a lineage distinct from those of other viruses and that genetic reassortment between H5N1 and H1 or H3 human viruses had not occurred. Since mice and humans harbor both the furin and the PC6 proteases, we suggest that the virulence mechanism responsible for the lethality of influenza viruses in birds also operates in mammalian hosts. The failure of some H5N1 viruses to produce systemic infection in our model indicates that multiple, still-to-be-identified, factors contribute to the severity of H5N1 infection in mammals. In addition, the ability of these viruses to produce systemic infection in mice and the clear differences in pathogenicity among the isolates studied here indicate that this system provides a useful model for studying the pathogenesis of avian influenza virus infection in mammals.
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Li, Zejun, Hualan Chen, Peirong Jiao, Guohua Deng, Guobin Tian, Yanbing Li, Erich Hoffmann, Robert G. Webster, Yumiko Matsuoka i Kangzhen Yu. "Molecular Basis of Replication of Duck H5N1 Influenza Viruses in a Mammalian Mouse Model". Journal of Virology 79, nr 18 (15.09.2005): 12058–64. http://dx.doi.org/10.1128/jvi.79.18.12058-12064.2005.
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ABSTRACT We recently analyzed a series of H5N1 viruses isolated from healthy ducks in southern China since 1999 and found that these viruses had progressively acquired the ability to replicate and cause disease in mice. In the present study, we explored the genetic basis of this change in host range by comparing two of the viruses that are genetically similar but differ in their ability to infect mice and have different pathogenicity in mice. A/duck/Guangxi/22/2001 (DKGX/22) is nonpathogenic in mice, whereas A/duck/Guangxi/35/2001 (DKGX/35) is highly pathogenic. We used reverse genetics to create a series of single-gene recombinants that contained one gene from DKGX/22 and the remaining seven gene segments from DKGX/35. We find that the PA, NA, and NS genes of DKGX/22 could attenuate DKGX/35 virus to some extent, but PB2 of DKGX/22 virus attenuated the DKGX/35 virus dramatically, and an Asn-to-Asp substitution at position 701 of PB2 plays a key role in this function. Conversely, of the recombinant viruses in the DKGX/22 background, only the one that contains the PB2 gene of DKGX/35 was able to replicate in mice. A single amino acid substitution (Asp to Asn) at position 701 of PB2 enabled DKGX/22 to infect and become lethal for mice. These results demonstrate that amino acid Asn 701 of PB2 is one of the important determinants for this avian influenza virus to cross the host species barrier and infect mice, though the replication and lethality of H5N1 influenza viruses involve multiple genes and may result from a constellation of genes. Our findings may help to explain the expansion of the host range and lethality of the H5N1 influenza viruses to humans.
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Feng, Xiaoxiao, Zeng Wang, Jianzhong Shi, Guohua Deng, Huihui Kong, Shiyu Tao, Changyao Li, Liling Liu, Yuntao Guan i Hualan Chen. "Glycine at Position 622 in PB1 Contributes to the Virulence of H5N1 Avian Influenza Virus in Mice". Journal of Virology 90, nr 4 (9.12.2015): 1872–79. http://dx.doi.org/10.1128/jvi.02387-15.
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ABSTRACTWe isolated two H5N1 viruses, A/duck/Hunan/S4020/2008 (DK/08) and A/chicken/Guangxi/S2039/2009 (CK/09), from live-bird markets during routine surveillance and found that these two viruses are genetically similar but differ in their replication and virulence in mice. The CK/09 virus is lethal for mice with a 50% mouse lethal dose (MLD50) of 1.6 log1050% egg infectious doses (EID50), whereas the DK/08 virus is nonpathogenic for mice with an MLD50value of 6.2 log10EID50. We explored the genetic basis of the virulence difference of these two viruses by generating a series of reassortant viruses and mutants in the lethal virus CK/09 background and evaluating their virulence in mice. We found that the PB1 gene of the DK/08 virus dramatically attenuated the virulence of the CK/09 virus and that the amino acid at position 622 in PB1 made an important contribution. We further demonstrated that the mutation of glycine (G) to aspartic acid (D) at position 622 in PB1 partially impaired the binding of PB1 to viral RNA, thereby dramatically decreasing the polymerase activity and attenuating H5N1 virus virulence in mice. Our results identify a novel virulence-related marker of H5N1 influenza viruses and provide a new target for live attenuated vaccine development.IMPORTANCEH5N1 avian influenza viruses have caused the deaths of nearly 60% of the humans that they have infected since 1997 and clearly represent a threat to public health. A thorough understanding of the genetic basis of virulence determinants will provide important insights for antiviral drug and live attenuated vaccine development. Several virulence-related markers in the PB2, PA, M1, and NS1 proteins of H5N1 viruses have been identified. In this study, we isolated two H5N1 avian influenza viruses that are genetically similar but differ in their virulence in mice, and we identified a new virulence-related marker in the PB1 gene. We found that the mutation of glycine (G) to aspartic acid (D) at position 622 in PB1 partially impairs the binding of PB1 to viral RNA, thereby attenuating H5N1 virus virulence in mice. This newly identified virulence-related marker could be applied to the development of live attenuated vaccines against H5N1 influenza.
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Ruscetti, S., R. Matthai i M. Potter. "Susceptibility of BALB/c mice carrying various DBA/2 genes to development of Friend murine leukemia virus-induced erythroleukemia." Journal of Experimental Medicine 162, nr 5 (1.11.1985): 1579–87. http://dx.doi.org/10.1084/jem.162.5.1579.
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Using a series of BALB/c mice congenic for various DBA/2 genes, we were able to establish that DBA/2 mice carry a gene on chromosome 5, at or near the Rmcfr locus, that plays a major role in resistance to early erythroleukemia induced by injection of Friend murine leukemia virus (F-MuLV) into newborn mice. The fact that this gene controls the replication of mink cell focus-inducing (MCF) viruses strengthens the case for these viruses playing a crucial role in the development of erythroleukemia, since failure to replicate MCF viruses results in resistance to early erythroleukemia. The expression of the Rmcfr gene is correlated with the constitutive expression of an MCF virus-related envelope glycoprotein that apparently blocks the receptor for MCF viruses, preventing their spread. Thus, the Rmcfr gene is either a structural gene for this unique protein, which can block the receptor for MCF viruses, or is a regulatory gene that controls expression of such a structural gene. Although the Rmcfr gene is clearly involved in resistance to the early erythroleukemia induced by F-MuLV, it appears to have no effect on the late myeloid, lymphoid or erythroid diseases that appear in DBA/2 and other strains of mice after injection of F-MuLV, consistent with data indicating that replication of MCF viruses is not required for the development of these late diseases. Our studies with congenic and backcross mice also indicate that, in addition to the Rmcfr gene, other genes of DBA/2 origin may contribute to resistance to F-MuLV-induced early erythroleukemia by mechanisms other than blocking the replication of MCF viruses.
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Zamarin, Dmitriy, Mila B. Ortigoza i Peter Palese. "Influenza A Virus PB1-F2 Protein Contributes to Viral Pathogenesis in Mice". Journal of Virology 80, nr 16 (15.08.2006): 7976–83. http://dx.doi.org/10.1128/jvi.00415-06.
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ABSTRACT The influenza virus PB1-F2 protein is a novel protein previously shown to be involved in induction of cell death. Here we characterize the expression and the function of the protein within the context of influenza viral infection in tissue culture and a mouse model. We show that the C-terminal region of the protein can be expressed from a downstream initiation codon and is capable of interaction with the full-length protein. Using this knowledge, we generated influenza viruses knocked out for the expression of PB1-F2 protein and its downstream truncation products. Knocking out the PB1-F2 protein had no effect on viral replication in tissue culture but diminished virus pathogenicity and mortality in mice. The viruses replicated to similar levels in mouse lungs by day 3 postinfection, suggesting that the knockout did not impair viral replication. However, while the PB1-F2 knockout viruses were cleared after day 5, the wild-type viruses were detectable in mouse lungs until day 7, implying that expression of PB1-F2 resulted in delayed clearance of the viruses by the host immune system. Based on our findings and on the fact that the PB1 genomic segment was always newly introduced into some pandemic influenza viruses of the last century, we speculate that the PB1-F2 protein plays an important role in pathogenesis of influenza virus infection and may be an important contributor to pathogenicity of pandemic influenza viruses.
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Kiseleva, Irina, Andrey Rekstin, Mohammad Al Farroukh, Ekaterina Bazhenova, Anastasia Katelnikova, Ludmila Puchkova i Larisa Rudenko. "Non-Mouse-Adapted H1N1pdm09 Virus as a Model for Influenza Research". Viruses 12, nr 6 (29.05.2020): 590. http://dx.doi.org/10.3390/v12060590.
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The number of lung-adapted influenza viruses is limited. Most of them are not antigenically related to current circulating viruses. Viruses similar to recent strains are required for screening modern antiviral compounds and studying new vaccine candidates against novel influenza viruses. The process by which an influenza virus adapts to a new host is rather difficult. The aim of this study was to select a non-adapted current virus whose major biological properties correspond to those of classical lab-adapted viruses. Mice were inoculated intranasally with non-lung-adapted influenza viruses of subtype H1N1pdm09. They were monitored closely for body weight loss, mortality outcomes and gross pathology for 14 days following inoculation, as well as viral replication in lung tissue. Lung-adapted PR8 virus was used as a control. The tested viruses multiplied equally well in the lower respiratory tract of mice without prior adaptation but dramatically differed in lethality; the differences in their toxicity and pathogenicity in mice were established. A/South Africa/3626/2013 (H1N1)pdm09 virus was found to be an appropriate candidate to replace PR8 as a model virus for influenza research. No prior adaptation to the animal model is needed to reach the pathogenicity level of the classical mouse-adapted PR8 virus.
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Pasieka, Tracy Jo, Cristian Cilloniz, Betty Lu, Thomas H. Teal, Sean C. Proll, Michael G. Katze i David A. Leib. "Host Responses to Wild-Type and Attenuated Herpes Simplex Virus Infection in the Absence of Stat1". Journal of Virology 83, nr 5 (24.12.2008): 2075–87. http://dx.doi.org/10.1128/jvi.02007-08.
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ABSTRACT Humans and mice lacking the interferon signaling molecule Stat1 are sensitive to a variety of pathogens due to their presumed inability to mount a strong innate immune response. The herpes simplex virus type 1 (HSV-1) virion host shutoff (vhs) protein is a multifunctional immunomodulator that counteracts the innate immune response and viruses lacking vhs are attenuated and effective live vaccines in animal models. To investigate the interplay of viruses with an immunocompromised host, we performed functional genomics analyses on control and Stat1−/− mouse corneas infected with wild-type or vhs-null viruses. In control mice, correlative with viral growth, both viruses induced a transient increase in immunomodulators, followed by viral clearance. In contrast, infection of the Stat1−/− mice induced a heightened and prolonged induction of inflammatory modulators for both viruses, manifesting as a significant immune cell infiltrate and ocular disease. Moreover, while wild-type virus infection of Stat1−/− was always lethal, vhs-null infection was rarely lethal. There was a significant increase in Stat3- and interleukin-6 (IL-6)-dependent transcription in Stat1−/− mice, implicating the Stat3 and IL-6 pathways in the observed ocular pathology. Further, infected Stat1−/− mice showed phosphorylated Stat3 in the corneal epithelium. Our data show a role for vhs in evading innate host responses and a role for Stat1 in limiting virus infection and for facilitating an appropriate nonpathological inflammatory response.
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Shriner, Susan A., Kaci K. VanDalen, Nicole L. Mooers, Jeremy W. Ellis, Heather J. Sullivan, J. Jeffrey Root, Angela M. Pelzel i Alan B. Franklin. "Low-Pathogenic Avian Influenza Viruses in Wild House Mice". PLoS ONE 7, nr 6 (15.06.2012): e39206. http://dx.doi.org/10.1371/journal.pone.0039206.
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Zhang, Shen-Ying, Oliver Harschnitz, Lorenz Studer i Jean-Laurent Casanova. "Neuron-intrinsic immunity to viruses in mice and humans". Current Opinion in Immunology 72 (październik 2021): 309–17. http://dx.doi.org/10.1016/j.coi.2021.07.004.
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Osorio, Yanira, i Homayon Ghiasi. "Comparison of Adjuvant Efficacy of Herpes Simplex Virus Type 1 Recombinant Viruses Expressing TH1 and TH2 Cytokine Genes". Journal of Virology 77, nr 10 (15.05.2003): 5774–83. http://dx.doi.org/10.1128/jvi.77.10.5774-5783.2003.
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ABSTRACT The adjuvant effects of cytokines in humoral and cell-mediated immunity to herpes simplex virus type 1 (HSV-1) have been examined in mice using HSV-1 recombinant viruses expressing murine interleukin-2 (IL-2), IL-4, or gamma interferon (IFN-γ) gene. Groups of naive BALB/c mice were immunized intraperitoneally with one or three doses of the HSV-1 recombinant viruses expressing IL-2, IL-4, or IFN-γ or with parental control virus. Despite similar replication kinetics, these three recombinant viruses elicited different immune responses to HSV-1 on immunization. Immunization with the recombinant virus expressing IL-4 elicited a humoral response of greater magnitude than immunization with the recombinant viruses expressing IL-2 or IFN-γ or with parental virus. In contrast, immunization with recombinant virus expressing IL-2 elicited a higher cytotoxic T-cell response than immunization with viruses expressing IL-4 or IFN-γ. Stimulation in vitro of splenocytes obtained from the mice immunized with UV-inactivated HSV-1 McKrae resulted in a TH1 pattern of cytokine expression irrespective of the recombinant virus used in the immunization. As observed for the parental virus, both CD4+ and CD8+ T cells contributed equally to the production of IL-2 by the splenocytes of mice immunized with any of the three recombinant viruses. However, the pattern of IFN-γ production by CD4+ and CD8+ T cells differed according to the recombinant virus used. After lethal ocular challenge, all immunized mice were protected completely against death and manifestations of eye disease caused by HSV-1, which are typical responses in unimmunized mice. Mice immunized with IL-4-expressing virus cleared the virus from their eyes more rapidly than mice immunized with IL-2- or IFN-γ-expressing virus. Taken together, our results suggest that, in contrast to IFN-γ which did not exhibit an adjuvant effect, both IL-4 and IL-2 act as adjuvants in immunization with HSV, with IL-4 showing greater efficacy.
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Chan, Mable, Anders Leung, Tamiko Hisanaga, Brad Pickering, Bryan D. Griffin, Robert Vendramelli, Nikesh Tailor i in. "H7N9 Influenza Virus Containing a Polybasic HA Cleavage Site Requires Minimal Host Adaptation to Obtain a Highly Pathogenic Disease Phenotype in Mice". Viruses 12, nr 1 (5.01.2020): 65. http://dx.doi.org/10.3390/v12010065.
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Low pathogenic avian influenza (LPAI) H7N9 viruses have recently evolved to gain a polybasic cleavage site in the hemagglutinin (HA) protein, resulting in variants with increased lethality in poultry that meet the criteria for highly pathogenic avian influenza (HPAI) viruses. Both LPAI and HPAI variants can cause severe disease in humans (case fatality rate of ~40%). Here, we investigated the virulence of HPAI H7N9 viruses containing a polybasic HA cleavage site (H7N9-PBC) in mice. Inoculation of mice with H7N9-PBC did not result in observable disease; however, mice inoculated with a mouse-adapted version of this virus, generated by a single passage in mice, caused uniformly lethal disease. In addition to the PBC site, we identified three other mutations that are important for host-adaptation and virulence in mice: HA (A452T), PA (D347G), and PB2 (M483K). Using reverse genetics, we confirmed that the HA mutation was the most critical for increased virulence in mice. Our study identifies additional disease determinants in a mammalian model for HPAI H7N9 virus. Furthermore, the ease displayed by the virus to adapt to a new host highlights the potential for H7N9-PBC viruses to rapidly acquire mutations that may enhance their risk to humans or other animal species.
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Swanson, Ingrid, Brooke A. Jude, Annie R. Zhang, Andrew Pucker, Zachary E. Smith i Tatyana V. Golovkina. "Sequences within the gag Gene of Mouse Mammary Tumor Virus Needed for Mammary Gland Cell Transformation". Journal of Virology 80, nr 7 (1.04.2006): 3215–24. http://dx.doi.org/10.1128/jvi.80.7.3215-3224.2006.
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ABSTRACT Previously, we identified a group of replication-competent exogenous mouse mammary tumor viruses that failed to induce mammary tumors in susceptible mice. Sequence comparison of tumorigenic and tumor-attenuated virus variants has linked the ability of virus to cause high-frequency mammary tumors to the gag gene. To determine the specific sequences within the gag gene that contribute to tumor induction, we constructed five distinct chimeric viruses that have various amino acid coding sequences of gag derived from a tumor-attenuated virus replaced by those of highly tumorigenic virus and tested these viruses for tumorigenic capacities in virus-susceptible C3H/HeN mice. Comparing the tumorigenic potentials of these viruses has allowed us to map the region responsible for tumorigenesis to a 253-amino-acid region within the CA and NC regions of the Gag protein. Unlike C3H/HeN mice, BALB/cJ mice develop tumors when infected with all viral variants, irrespective of the gag gene sequences. Using genetic crosses between BALB/cJ and C3H/HeN mice, we were able to determine that the mechanism that confers susceptibility to Gag-independent mammary tumors in BALB/cJ mice is inherited as a dominant trait and is controlled by a single gene, called mammary tumor susceptibility (mts), that maps to chromosome 14.
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Murphy, Jenny A., Rebecca J. Duerst, Tracy J. Smith i Lynda A. Morrison. "Herpes Simplex Virus Type 2 Virion Host Shutoff Protein Regulates Alpha/Beta Interferon but Not Adaptive Immune Responses during Primary Infection In Vivo". Journal of Virology 77, nr 17 (1.09.2003): 9337–45. http://dx.doi.org/10.1128/jvi.77.17.9337-9345.2003.
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ABSTRACT The herpes simplex virus (HSV) virion host shutoff (vhs) protein, the product of the UL41 (vhs) gene, is an important determinant of HSV virulence. vhs has been implicated in HSV interference with host antiviral immune responses, down-regulating expression of major histocompatibility complex molecules to help HSV evade host adaptive immunity. The severe attenuation of vhs-deficient viruses in vivo could reflect their inability to escape immune detection. To test this hypothesis, BALB/c or congenic SCID mice were infected intravaginally (i.vag.) with the HSV type 2 (HSV-2) vhs null mutant 333d41 or the vhs rescue virus 333d41R. vhs-deficient virus remained severely attenuated in SCID mice compared with rescue virus, indicating that vhs regulation of adaptive immune responses does not influence HSV pathogenesis during acute infection. Innate antiviral effectors remain intact in SCID mice; prominent among these is alpha/beta interferon (IFN-α/β). The attenuation of HSV-2 vhs mutants could reflect their failure to suppress IFN-α/β-mediated antiviral activity. To test this hypothesis, 129 and congenic IFN-α/β receptor-deficient (IFN-α/βR−/−) mice were infected i.vag. with wild-type virus, vhs null mutants 333-vhsB or 333d41, or the vhs rescue virus 333d41R. Whereas vhs-deficient viruses showed greatly reduced replication in the genital mucosa of 129 mice compared with wild-type or vhs rescue viruses, they were restored to nearly wild-type levels of replication in IFN-α/βR−/− mice over the first 2 days postinfection. Only wild-type and vhs rescue viruses caused severe genital disease and hind limb paralysis in 129 mice, but infection of IFN-α/βR−/− mice restored the virulence of vhs-deficient viruses. vhs-deficient viruses replicated as vigorously as wild-type and rescue viruses in the nervous systems of IFN-α/βR−/− mice. Restoration was specific for the vhs mutation, because thymidine kinase-deficient HSV-2 did not regain virulence or the capacity to replicate in the nervous systems of IFN-α/βR−/− mice. Furthermore, the defect in the IFN-α/β response was required for restoration of vhs-deficient virus replication and virulence, but the IFN-α/β-stimulated protein kinase R pathway was not involved. Finally, vhs of HSV-2 has a unique capacity to interfere with the IFN-α/β response in vivo, because an HSV-1 vhs null mutant did not recover replication and virulence after i.vag. inoculation into IFN-α/βR−/− mice. These results indicate that vhs plays an important role early in HSV-2 pathogenesis in vivo by interfering with the IFN-α/β-mediated antiviral response.
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Flanagan, E. Brian, Trenton R. Schoeb i Gail W. Wertz. "Vesicular Stomatitis Viruses with Rearranged Genomes Have Altered Invasiveness and Neuropathogenesis in Mice". Journal of Virology 77, nr 10 (15.05.2003): 5740–48. http://dx.doi.org/10.1128/jvi.77.10.5740-5748.2003.
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ABSTRACT Transcription of vesicular stomatitis virus is controlled by the position of a gene relative to the single 3′ genomic promoter: promoter-proximal genes are transcribed at higher levels than those in more 5′ distal positions. In previous work, we generated viruses having rearranged gene orders. These viruses had the promoter-proximal gene that encodes the nucleocapsid protein, N, moved to the second or fourth position in the genome in combination with the glycoprotein gene, G, moved from its usual promoter-distal fourth position to the first or third position. This resulted in three new viruses identified by the positions of the N and G genes in the gene order: G3N4, G1N4, and G1N2. The viruses G3N4 and G1N4 were attenuated for lethality in mice. In the present study, we addressed the basis of this attenuation by measuring the ability of each of the rearranged viruses to travel to and replicate in the olfactory bulb and brain following intranasal inoculation. In addition, the neuropathogenicity, serum cytokine levels, and immunoglobulin G isotype profiles in infected mice were determined. All the viruses reached the olfactory bulb and brain, but the outcomes of these infections were dramatically different. Viruses N1G4(wt) and G1N2 caused lethal encephalitis in 100% of animals within 7 days postinoculation; however, viruses G3N4 and G1N4 were cleared from the brain by 7 days postinoculation and all animals survived without apparent distress. The viruses differed in the distribution and intensity of lesions produced and the type and levels of cytokines induced. Animals inoculated with N1G4(wt) or G1N2 displayed extensive encephalitis and meningitis and had elevated levels of serum gamma interferon compared to what was seen with G3N4- or G1N4-infected mice. In contrast to what occurred with intranasal inoculation, all four viruses caused lethal encephalitis when administered by direct inoculation to the brain, a route that circumvents the majority of the host immune response, demonstrating that G3N4 and G1N4 were not deficient in their abilities to cause disease in the brain. These findings indicate that gene rearrangement and its consequent alteration of gene expression can, without any other changes, alter the viral spread and cytokine response following intranasal infection.
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Chen, Grace L., Elaine W. Lamirande, Chin-Fen Yang, Hong Jin, George Kemble i Kanta Subbarao. "Evaluation of Replication and Cross-Reactive Antibody Responses of H2 Subtype Influenza Viruses in Mice and Ferrets". Journal of Virology 84, nr 15 (26.05.2010): 7695–702. http://dx.doi.org/10.1128/jvi.00511-10.
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ABSTRACT H2 influenza viruses have not circulated in humans since 1968, and therefore a large segment of the population would likely be susceptible to infection should H2 influenza viruses reemerge. The development of an H2 pandemic influenza virus vaccine candidate should therefore be considered a priority in pandemic influenza preparedness planning. We selected a group of geographically and temporally diverse wild-type H2 influenza viruses and evaluated the kinetics of replication and compared the ability of these viruses to induce a broadly cross-reactive antibody response in mice and ferrets. In both mice and ferrets, A/Japan/305/1957 (H2N2), A/mallard/NY/1978 (H2N2), and A/swine/MO/2006 (H2N3) elicited the broadest cross-reactive antibody responses against heterologous H2 influenza viruses as measured by hemagglutination inhibition and microneutralization assays. These data suggested that these three viruses may be suitable candidates for development as live attenuated H2 pandemic influenza virus vaccines.
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Pruijssers, Andrea J., Holger Hengel, Ty W. Abel i Terence S. Dermody. "Apoptosis Induction Influences Reovirus Replication and Virulence in Newborn Mice". Journal of Virology 87, nr 23 (25.09.2013): 12980–89. http://dx.doi.org/10.1128/jvi.01931-13.
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Apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. It also serves as a robust host response against infection by many viruses. The capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. However, the precise function of apoptosis in viral infection is not well understood. Reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal encephalitis in newborn mice. To determine the effect of apoptosis on reovirus replication in the host, we generated two otherwise isogenic viruses that differ in a single amino acid in viral capsid protein μ1 that segregates with apoptotic capacity. Apoptosis-proficient and apoptosis-deficient viruses were compared for replication, dissemination, tropism, and tissue injury in newborn mice and for the capacity to spread to uninfected littermates. Our results indicate that apoptotic capacity enhances reovirus replication in the brain and consequent neurovirulence but reduces transmission efficiency. The replication advantage of the apoptosis-proficient strain is limited to the brain and correlates with enhanced infectivity of neurons. These studies reveal a new cell type-specific determinant of reovirus virulence.
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Reneer, Z. Beau, Parker J. Jamieson, Amanda L. Skarlupka, Ying Huang i Ted M. Ross. "Computationally Optimized Broadly Reactive H2 HA Influenza Vaccines Elicited Broadly Cross-Reactive Antibodies and Protected Mice from Viral Challenges". Journal of Virology 95, nr 2 (28.10.2020): e01526-20. http://dx.doi.org/10.1128/jvi.01526-20.
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ABSTRACTInfluenza viruses have caused numerous pandemics throughout human history. The 1957 influenza pandemic was initiated by an H2N2 influenza virus. This H2N2 influenza virus was the result of a reassortment event between a circulating H2N2 avian virus and the seasonal H1N1 viruses in humans. Previously, our group has demonstrated the effectiveness of hemagglutinin (HA) antigens derived using computationally optimized broadly reactive antigen (COBRA) methodology against H1N1, H3N2, and H5N1 viruses. Using the COBRA methodology, H2 HA COBRA antigens were designed using sequences from H2N2 viruses isolated from humans in the 1950s and 1960s, as well as H2Nx viruses isolated from avian and mammalian species between the 1950s and 2016. In this study, the effectiveness of H2 COBRA HA antigens (Z1, Z3, Z5, and Z7) was evaluated in DBA/2J mice and compared to that of wild-type H2 HA antigens. The COBRA HA vaccines elicited neutralizing antibodies to the majority of viruses in our H2 HA panel and across all three clades as measured by hemagglutination inhibition (HAI) and neutralization assays. Comparatively, several wild-type HA vaccines elicited antibodies against a majority of the viruses in the H2 HA panel. DBA/2J mice vaccinated with COBRA vaccines showed increase survival for all three viral challenges compared to the wild-type H2 vaccines. In particular, the Z1 COBRA is a promising candidate for future work toward a pandemic H2 influenza vaccine.IMPORTANCE H2N2 influenza has caused at least one pandemic in the past. Given that individuals born after 1968 have not been exposed to H2N2 influenza viruses, a future pandemic caused by H2 influenza is likely. An effective H2 influenza vaccine would need to elicit broadly cross-reactive antibodies to multiple H2 influenza viruses. Choosing a wild-type virus to create a vaccine may elicit a narrow immune response and not protect against multiple H2 influenza viruses. COBRA H2 HA vaccines were developed and evaluated in mice along with wild-type H2 HA vaccines. Multiple COBRA H2 HA vaccines protected mice from all three viral challenges and produced broadly cross-reactive neutralizing antibodies to H2 influenza viruses.
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Mase, Masaji, Nobuhiko Tanimura, Tadao Imada, Masatoshi Okamatsu, Kenji Tsukamoto i Shigeo Yamaguchi. "Recent H5N1 avian Influenza A virus increases rapidly in virulence to mice after a single passage in mice". Journal of General Virology 87, nr 12 (1.12.2006): 3655–59. http://dx.doi.org/10.1099/vir.0.81843-0.
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To evaluate the potential pathogenicity to mammals of the recent H5N1 avian Influenza A virus, viruses recovered from dead mice infected with A/chicken/Yamaguchi/7/2004 isolated in Japan were examined. All recovered viruses from the brains of dead mice infected with this strain (without any prior adaptation to mice) had substituted the amino acid at position 627 of the PB2 protein from glutamic acid to lysine. Their mouse lethality had increased by approximately 5×104 times over that of the original virus. Histopathological analysis reinforced the finding that these variants caused more rapid and severe damage to mice than the original virus. This revealed that it might be useful to characterize the recovered virus to assess its potential pathogenicity to mammals.
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Borrow, P., A. Tishon i M. B. Oldstone. "Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection." Journal of Experimental Medicine 174, nr 1 (1.07.1991): 203–12. http://dx.doi.org/10.1084/jem.174.1.203.
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For viruses to establish persistent infections in their hosts, they must possess some mechanism for evading clearance by the immune system. When inoculated into adult immunocompetent mice, wild-type lymphocytic choriomeningitis virus (LCMV ARM) induces a CD8(+)-mediated cytotoxic T lymphocyte (CTL) response that clears the infection within 7-14 d (CTL+ [P-]). By contrast, variant viruses isolated from lymphoid tissues of persistently infected mice fail to induce a CTL response and are thus able to establish a persistent infection in adult mice (CTL- [P+]). This report compares the interaction of CTL+ (P-) and CTL- (P+) viruses with cells of the immune system. Both types of virus initially bind to 2-4% of CD4+ and CD8+ T lymphocytes and replicate within cells of both subsets. The replication of CTL- (P+) and CTL+ (P-) viruses in lymphocytes in vivo is similar for the first 5 d after initiating infection. Thereafter, in mice infected with CTL- (P+) variants, lymphocytes retain viral genetic information, and infectious virus can be recovered throughout the animals' lives. In contrast, when adult mice are infected with wild-type CTL+ (P-) LCMV ARM, virus is not recovered from lymphocytes for greater than 7 d after infection. A CD8(+)-mediated anti-LCMV CTL response is induced in such mice. Clearance of infected lymphocytes is produced by these LCMV-specific CTLs, as shown by their ability to lyse lymphocytes expressing LCMV determinants in vitro and the fact that depletion of CD8+ lymphocytes before infection with CTL+ (P-) viruses results in levels of infected lymphocytes similar to those found in undepleted CTL- (P+)-infected mice. Hence, CTL-mediated lysis of T lymphocytes carrying infectious virus is a critical factor determining whether virus persists or the infection is terminated.
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Butler, Noah S., Ajai A. Dandekar i Stanley Perlman. "Antiviral Antibodies Are Necessary To Prevent Cytotoxic T-Lymphocyte Escape in Mice Infected with a Coronavirus". Journal of Virology 81, nr 24 (3.10.2007): 13291–98. http://dx.doi.org/10.1128/jvi.01580-07.
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ABSTRACT Mutation within virus-derived CD8 T-cell epitopes can effectively abrogate cytotoxic T-lymphocyte (CTL) recognition and impede virus clearance in infected hosts. These so-called “CTL escape variant viruses” are commonly selected during persistent infections and are associated with rapid disease progression and increased disease severity. Herein, we tested whether antiviral antibody-mediated suppression of virus replication and subsequent virus clearance were necessary for preventing CTL escape in coronavirus-infected mice. We found that compared to wild-type mice, B-cell-deficient mice did not efficiently clear infectious virus, uniformly developed clinical disease, and harbored CTL escape variant viruses. These data directly demonstrate a critical role for antiviral antibody in protecting from the selective outgrowth of CTL escape variant viruses.
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Deng, Guohua, Jianzhong Shi, Jing Wang, Huihui Kong, Pengfei Cui, Fang Zhang, Dan Tan i in. "Genetics, Receptor Binding, and Virulence in Mice of H10N8 Influenza Viruses Isolated from Ducks and Chickens in Live Poultry Markets in China". Journal of Virology 89, nr 12 (8.04.2015): 6506–10. http://dx.doi.org/10.1128/jvi.00017-15.
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We analyzed eight H10N8 viruses isolated from ducks and chickens in live poultry markets from 2009 to 2013 in China. These viruses showed distinct genetic diversity and formed five genotypes: the four duck isolates formed four different genotypes, whereas the four chicken viruses belong to a single genotype. The viruses bound to both human- and avian-type receptors, and four of the viruses caused 12.7% to 22.5% body weight loss in mice.
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Yoshizato, Katsutoshi, i Chise Tateno. "A Human Hepatocyte-Bearing Mouse: An Animal Model to Predict Drug Metabolism and Effectiveness in Humans". PPAR Research 2009 (2009): 1–11. http://dx.doi.org/10.1155/2009/476217.
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Preclinical studies to predict the efficacy and safety of drugs have conventionally been conducted almost exclusively in mice and rats as rodents, despite the differences in drug metabolism between humans and rodents. Furthermore, human () viruses such as hepatitis viruses do not infect the rodent liver. A mouse bearing a liver in which the hepatocytes have been largely repopulated with -hepatocytes would overcome some of these disadvantages. We have established a practical, efficient, and large-scale production system for such mice. Accumulated evidence has demonstrated that these hepatocyte-humanized mice are a useful and reliable animal model, exhibiting -type responses in a series of in vivo drug processing (adsorption, distribution, metabolism, excretion) experiments and in the infection and propagation of hepatic viruses. In this review, we present the current status of studies on chimeric mice and describe their usefulness in the study of peroxisome proliferator-activated receptors.
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Belser, Jessica A., Xuihua Lu, Taronna R. Maines, Catherine Smith, Yan Li, Ruben O. Donis, Jacqueline M. Katz i Terrence M. Tumpey. "Pathogenesis of Avian Influenza (H7) Virus Infection in Mice and Ferrets: Enhanced Virulence of Eurasian H7N7 Viruses Isolated from Humans". Journal of Virology 81, nr 20 (8.08.2007): 11139–47. http://dx.doi.org/10.1128/jvi.01235-07.
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ABSTRACT Before 2003, only occasional case reports of human H7 influenza virus infections occurred as a result of direct animal-to-human transmission or laboratory accidents; most of these infections resulted in conjunctivitis. An increase in isolation of avian influenza A H7 viruses from poultry outbreaks and humans has raised concerns that additional zoonotic transmissions of influenza viruses from poultry to humans may occur. To better understand the pathogenesis of H7 viruses, we have investigated their ability to cause disease in mouse and ferret models. Mice were infected intranasally with H7 viruses of high and low pathogenicity isolated from The Netherlands in 2003 (Netherlands/03), the northeastern United States in 2002-2003, and Canada in 2004 and were monitored for morbidity, mortality, viral replication, and proinflammatory cytokine production in respiratory organs. All H7 viruses replicated efficiently in the respiratory tracts of mice, but only Netherlands/03 isolates replicated in systemic organs, including the brain. Only A/NL/219/03 (NL/219), an H7N7 virus isolated from a single fatal human case, was highly lethal for mice and caused severe disease in ferrets. Supporting the apparent ocular tropism observed in humans following infection with viruses of the H7 subtype, both Eurasian and North American lineage H7 viruses were detected in the mouse eye following ocular inoculation, whereas an H7N2 virus isolated from the human respiratory tract was not. Therefore, in general, the relative virulence and cell tropism of the H7 viruses in these animal models correlated with the observed virulence in humans.
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Kang, Hyun-Mi, Jun-Gu Choi, Kwang-Il Kim, Ha-Young Park, Choi-Kyu Park i Youn-Jeong Lee. "Genetic and antigenic characteristics of H4 subtype avian influenza viruses in Korea and their pathogenicity in quails, domestic ducks and mice". Journal of General Virology 94, nr 1 (1.01.2013): 30–39. http://dx.doi.org/10.1099/vir.0.046581-0.
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In Korea, a nationwide surveillance programme was implemented in 2003 to identify highly pathogenic avian influenza viruses (AIVs). AIVs belonging to one of the most common haemagglutinin subtypes, H4, were isolated from two domestic ducks and 52 wild birds between 2004 and 2010. These H4 AIVs could be further classified into three neuraminidase subtypes: H4N6 (94.4 %), H4N2 (3.7 %) and H4N3 (1.9 %). Phylogenetic analysis revealed that the H4 AIVs had a variety of genetic constellations, with at least nine different genotypes represented. The pathogenicity of these H4 viruses was assessed in quails, domestic ducks and mice. None of the H4 AIVs induced clinical signs in quails or domestic ducks. Viral shedding in quails was relatively high, and virus was recovered up to 5–7 days post-inoculation (p.i.) in oropharyngeal swabs, but the viruses replicated poorly in domestic ducks. Quails may act as an intermediate host in which AIVs are amplified and transmitted to other species. In mice, all of the AIVs were recovered efficiently at relatively high titres from the lungs up to 7 days p.i., demonstrating the potential for AIVs to infect mice directly without prior adaptation. None of the AIVs induced clinical signs nor was any lethal to infected mice. However, there was significant loss of body weight in mice infected with viruses of duck origin. It is suggested that the active surveillance of influenza viruses needs to be enhanced in domestic poultry as well as in wild birds, and that it should include assessment of pathogenicity in animal models.
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Belser, Jessica A., Debra A. Wadford, Claudia Pappas, Kortney M. Gustin, Taronna R. Maines, Melissa B. Pearce, Hui Zeng i in. "Pathogenesis of Pandemic Influenza A (H1N1) and Triple-Reassortant Swine Influenza A (H1) Viruses in Mice". Journal of Virology 84, nr 9 (24.02.2010): 4194–203. http://dx.doi.org/10.1128/jvi.02742-09.
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ABSTRACT The pandemic H1N1 virus of 2009 (2009 H1N1) continues to cause illness worldwide, primarily in younger age groups. To better understand the pathogenesis of these viruses in mammals, we used a mouse model to evaluate the relative virulence of selected 2009 H1N1 viruses and compared them to a representative human triple-reassortant swine influenza virus that has circulated in pigs in the United States for over a decade preceding the current pandemic. Additional comparisons were made with the reconstructed 1918 virus, a 1976 H1N1 swine influenza virus, and a highly pathogenic H5N1 virus. Mice were inoculated intranasally with each virus and monitored for morbidity, mortality, viral replication, hemostatic parameters, cytokine production, and lung histology. All 2009 H1N1 viruses replicated efficiently in the lungs of mice and possessed a high degree of infectivity but did not cause lethal disease or exhibit extrapulmonary virus spread. Transient weight loss, lymphopenia, and proinflammatory cytokine and chemokine production were present following 2009 H1N1 virus infection, but these levels were generally muted compared with a triple-reassortant swine virus and the 1918 virus. 2009 H1N1 viruses isolated from fatal cases did not demonstrate enhanced virulence in this model compared with isolates from mild human cases. Histologically, infection with the 2009 viruses resulted in lesions in the lung varying from mild to moderate bronchiolitis with occasional necrosis of bronchiolar epithelium and mild to moderate peribronchiolar alveolitis. Taken together, these studies demonstrate that the 2009 H1N1 viruses exhibited mild to moderate virulence in mice compared with highly pathogenic viruses.
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Falcón, Ana M., Ana Fernandez-Sesma, Yurie Nakaya, Thomas M. Moran, Juan Ortín i Adolfo García-Sastre. "Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins". Journal of General Virology 86, nr 10 (1.10.2005): 2817–21. http://dx.doi.org/10.1099/vir.0.80991-0.
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It was previously shown that two mutant influenza A viruses expressing C-terminally truncated forms of the NS1 protein (NS1-81 and NS1-110) were temperature sensitive in vitro. These viruses contain HA, NA and M genes derived from influenza A/WSN/33 H1N1 virus (mouse-adapted), and the remaining five genes from human influenza A/Victoria/3/75 virus. Mice intranasally infected with the NS1 mutant viruses showed undetectable levels of virus in lungs at day 3, whereas those infected with the NS1 wild-type control virus still had detectable levels of virus at this time. Nevertheless, the temperature-sensitive mutant viruses induced specific cellular and humoral immune responses similar to those induced by the wild-type virus. Mice immunized with the NS1 mutant viruses were protected against a lethal challenge with influenza A/WSN/33 virus. These results indicate that truncations in the NS1 protein resulting in temperature-sensitive phenotypes in vitro correlate with attenuation in vivo without compromising viral immunogenicity, an ideal characteristic for live attenuated viral vaccines.
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Singh, L. M., i Girish Gupta. "Antiviral efficacy of homœopathic drugs against animal viruses". British Homeopathic Journal 74, nr 03 (lipiec 1985): 168–74. http://dx.doi.org/10.1016/s0007-0785(85)80063-6.
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SummaryThe antiviral effect of homœopathic drugs against two animal viruses, Chicken Embryo Virus (CEV) of fowls and Simliki Forest Virus (SFV), causing encephalitis and death in mice were investigated. In all 10 drugs in 33 potencies were tested against CEV and 8 drugs in 26 potencies showed varying degree of virus inhibition. The drugs that caused 100% inhibition of CEV were Typhoidinum 200, Hydrophobinum 1000, Tuberculinum 1000, Nux vomica 200, and Malandrinum 1000. Of the drugs tested in 11 potencies against SFV, none were found effective in either preventing disease or death of mice infected with this virus.
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Kang, Hyun-Mi, Eun-Kyoung Lee, Byung-Min Song, Jipseol Jeong, Hye-Ryoung Kim, Eun-Jin Choi, Yeun-Kyung Shin, Hee-Soo Lee i Youn-Jeong Lee. "Genetic and pathogenic characteristics of H1 avian and swine influenza A viruses". Journal of General Virology 95, nr 10 (1.10.2014): 2118–26. http://dx.doi.org/10.1099/vir.0.065524-0.
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This study examined the potential for cross-species transmission of influenza viruses by comparing the genetic and pathogenic characteristics of H1 avian influenza viruses (AIVs) with different host origins in Korea. Antigenic and phylogenetic analyses of H1 AIVs circulating in Korea provided evidence of genetic similarity between viruses that infect domestic ducks and those that infect wild birds, although there was no relationship between avian and swine viruses. However, there were some relationships between swine and human viral genes. The replication and pathogenicity of the H1 viruses was assessed in chickens, domestic ducks and mice. Viral shedding in chickens was relatively high. Virus was recovered from both oropharyngeal and cloacal swabs up to 5–10 days post-inoculation. The titres of domestic duck viruses in chickens were much higher than those of wild-bird viruses. Both domestic duck and wild-bird viruses replicated poorly in domestic ducks. None of the swine viruses replicated in chickens or domestic ducks; however, six viruses showed relatively high titres in mice, regardless of host origin, and induced clinical signs such as ruffled fur, squatting and weight loss. Thus, although the phylogenetic and antigenic analyses showed no evidence of interspecies transmission between birds and swine, the results suggest that Korean H1 viruses have the potential to cause disease in mammals. Therefore, we should intensify continuous monitoring of avian H1 viruses in mammals and seek to prevent interspecies transmission.
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Lustig, S., H. D. Danenberg, Y. Kafri, D. Kobiler i D. Ben-Nathan. "Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators." Journal of Experimental Medicine 176, nr 3 (1.09.1992): 707–12. http://dx.doi.org/10.1084/jem.176.3.707.
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The present study was designed to test the effect of bacterial endotoxin on penetration of viruses into the central nervous system (CNS). As a model we used two neurovirulent viruses that lack neuroinvasive capacity: West Nile virus-25 (WN-25) and neuroadapted Sindbis virus (SVN). Administration of lipopolysaccharide (LPS, 100 micrograms/mouse) to CD-1 mice, followed by WN-25 inoculation resulted in 83% encephalitis and death, compared with less than 5% in controls. The results in SVN-inoculated CD-1 mice were quite similar. LPS-treated mice suffered 62% mortality compared with 6% in the nontreated group. No changes in viral neuroinvasiveness were demonstrated in viruses isolated from brains of encephalitic mice, suggesting that neuroinvasion is not due to a selection process for an invasive variant, but to direct penetration of the viruses through the blood-brain barrier (BBB). LPS did not induce WN-25 encephalitis in LPS-insensitive C3H/HeJ mice, compared with 100% neuroinvasion in C3H/HeB mice. Induction of neuroinvasion could be transferred to C3H/HeJ mice by transfusion with serum obtained from LPS-treated, LPS-responsive mice. Passive immunization of CD-1 mice with anti-mTNF antibodies before LPS administration did not prevent LPS-induced WN-25 encephalitis. Furthermore, neutralization of tumor necrosis factor activity in the serum of LPS-treated mice did not abolish its activity, and transfusion-associated encephalitis was observed after the administration of the neutralized serum with WN-25. We suggest that LPS can contribute to virus penetration from the blood into the CNS, a process which turns a mild viral infection into a severe lethal encephalitis. This effect is mediated by soluble factors, and is probably achieved by injury to cerebral microvascular endothelium and modulation of BBB permeability.
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Chen, Zhongying, Celia Santos, Amy Aspelund, Laura Gillim-Ross, Hong Jin, George Kemble i Kanta Subbarao. "Evaluation of Live Attenuated Influenza A Virus H6 Vaccines in Mice and Ferrets". Journal of Virology 83, nr 1 (22.10.2008): 65–72. http://dx.doi.org/10.1128/jvi.01775-08.
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ABSTRACT Avian influenza A virus A/teal/HK/W312/97 (H6N1) possesses seven gene segments that are highly homologous to those of highly pathogenic human influenza H5N1 viruses, suggesting that a W312-like H6N1 virus might have been involved in the generation of the A/HK/97 H5N1 viruses. The continuous circulation and reassortment of influenza H6 subtype viruses in birds highlight the need to develop an H6 vaccine to prevent potential influenza pandemics caused by the H6 viruses. Based on the serum antibody cross-reactivity data obtained from 14 different H6 viruses from Eurasian and North American lineages, A/duck/HK/182/77, A/teal/HK/W312/97, and A/mallard/Alberta/89/85 were selected to produce live attenuated H6 candidate vaccines. Each of the H6 vaccine strains is a 6:2 reassortant ca virus containing HA and NA gene segments from an H6 virus and the six internal gene segments from cold-adapted A/Ann Arbor/6/60 (AA ca), the master donor virus that is used to make live attenuated influenza virus FluMist (intranasal) vaccine. All three H6 vaccine candidates exhibited phenotypic properties of temperature sensitivity (ts), ca, and attenuation (att) conferred by the internal gene segments from AA ca. Intranasal administration of a single dose of the three H6 ca vaccine viruses induced neutralizing antibodies in mice and ferrets and fully protected mice and ferrets from homologous wild-type (wt) virus challenge. Among the three H6 vaccine candidates, the A/teal/HK/W312/97 ca virus provided the broadest cross-protection against challenge with three antigenically distinct H6 wt viruses. These data support the rationale for further evaluating the A/teal/HK/W312/97 ca vaccine in humans.
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Szretter, Kristy J., Shivaprakash Gangappa, Xuihua Lu, Chalanda Smith, Wun-Ju Shieh, Sherif R. Zaki, Suryaprakash Sambhara, Terrence M. Tumpey i Jacqueline M. Katz. "Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice". Journal of Virology 81, nr 6 (20.12.2006): 2736–44. http://dx.doi.org/10.1128/jvi.02336-06.
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ABSTRACT Highly pathogenic avian H5N1 influenza viruses are now widespread in poultry in Asia and have recently spread to some African and European countries. Interspecies transmission of these viruses to humans poses a major threat to public health. To better understand the basis of pathogenesis of H5N1 viruses, we have investigated the role of proinflammatory cytokines in transgenic mice deficient in interleukin-6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1α), IL-1 receptor (IL-1R), or tumor necrosis factor receptor 1 (TNFR1) by the use of two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. The course of disease and the extent of virus replication and spread in IL-6- and MIP-1α-deficient mice were not different from those observed in wild-type mice during acute infection with 1,000 50% mouse infective doses of either H5N1 virus. However, with HK/486 virus, IL-1R-deficient mice exhibited heightened morbidity and mortality due to infection, whereas no such differences were observed with the more virulent HK/483 virus. Furthermore, TNFR1-deficient mice exhibited significantly reduced morbidity following challenge with either H5N1 virus but no difference in viral replication and spread or ultimate disease outcome compared with wild-type mice. These results suggest that TNF-α may contribute to morbidity during H5N1 influenza virus infection, while IL-1 may be important for effective virus clearance in nonlethal H5N1 disease.
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Deeg, Christoph M., Ebrahim Hassan, Pascal Mutz, Lara Rheinemann, Veronika Götz, Linda Magar, Mirjam Schilling i in. "In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein". Journal of Experimental Medicine 214, nr 5 (10.04.2017): 1239–48. http://dx.doi.org/10.1084/jem.20161033.
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Zoonotic transmission of influenza A viruses can give rise to devastating pandemics, but currently it is impossible to predict the pandemic potential of circulating avian influenza viruses. Here, we describe a new mouse model suitable for such risk assessment, based on the observation that the innate restriction factor MxA represents an effective species barrier that must be overcome by zoonotic viruses. Our mouse lacks functional endogenous Mx genes but instead carries the human MX1 locus as a transgene. Such transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses, but were almost as susceptible to infection with influenza viruses of human origin as nontransgenic littermates. Influenza A viruses that successfully established stable lineages in humans have acquired adaptive mutations which allow partial MxA escape. Accordingly, an engineered avian H7N7 influenza virus carrying a nucleoprotein with signature mutations typically found in human virus isolates was more virulent in transgenic mice than parental virus, demonstrating that a few amino acid changes in the viral target protein can mediate escape from MxA restriction in vivo. Similar mutations probably need to be acquired by emerging influenza A viruses before they can spread in the human population.