Journal articles: 'Pneumonic Tularemia'

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Ellis, Jill, Petra C. F. Oyston, Michael Green, and Richard W. Titball. "Tularemia." Clinical Microbiology Reviews 15, no. 4 (October 2002): 631–46. http://dx.doi.org/10.1128/cmr.15.4.631-646.2002.

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SUMMARY Francisella tularensis is the etiological agent of tularemia, a serious and occasionally fatal disease of humans and animals. In humans, ulceroglandular tularemia is the most common form of the disease and is usually a consequence of a bite from an arthropod vector which has previously fed on an infected animal. The pneumonic form of the disease occurs rarely but is the likely form of the disease should this bacterium be used as a bioterrorism agent. The diagnosis of disease is not straightforward. F. tularensis is difficult to culture, and the handling of this bacterium poses a significant risk of infection to laboratory personnel. Enzyme-linked immunosorbent assay- and PCR-based methods have been used to detect bacteria in clinical samples, but these methods have not been adequately evaluated for the diagnosis of pneumonic tularemia. Little is known about the virulence mechanisms of F. tularensis, though there is a large body of evidence indicating that it is an intracellular pathogen, surviving mainly in macrophages. An unlicensed live attenuated vaccine is available, which does appear to offer protection against ulceroglandular and pneumonic tularemia. Although an improved vaccine against tularemia is highly desirable, attempts to devise such a vaccine have been limited by the inability to construct defined allelic replacement mutants and by the lack of information on the mechanisms of virulence of F. tularensis. In the absence of a licensed vaccine, aminoglycoside antibiotics play a key role in the prevention and treatment of tularemia.

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HORN, M., and L. ZICKUHR. "PNEUMONIC TULAREMIA: A CASE PRESENTATION." Chest 161, no. 6 (June 2022): A142. http://dx.doi.org/10.1016/j.chest.2021.12.174.

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Gregory, Stephen H., Stephanie Mott, Jennifer Phung, Jinhee Lee, Leonard Moise, Julie A. McMurry, William Martin, and Anne S. De Groot. "Epitope-based vaccination against pneumonic tularemia." Vaccine 27, no. 39 (August 2009): 5299–306. http://dx.doi.org/10.1016/j.vaccine.2009.06.101.

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Bonnier, Alyssa, Santu Saha, Adam Austin, and Biplab K. Saha. "An Unusual Etiology of Fluorodeoxyglucose Avid Intrathoracic Lymph Nodes." Prague Medical Report 125, no. 1 (2024): 79–86. http://dx.doi.org/10.14712/23362936.2024.8.

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A middle-aged man in his 50s, active smoker, presented to the pulmonary office for lung cancer evaluation. On a low-dose computed tomography for lung cancer screening, he was found to have an 8 mm endobronchial lesion in the right main stem bronchus. A PET-CT revealed no endobronchial lesion, but incidentally, fluorodeoxyglucose (FDG) avidity was present in the right hilar (SUV 13.2) and paratracheal lymph nodes (LNs). He underwent bronchoscopy and EBUS-TBNA of station 7 and 10 R LNs. The fine needle aspiration (FNA) revealed necrotizing epithelioid granuloma. The acid-fast bacilli (AFB) and Grocott methenamine silver (GMS) stains were negative. He had suffered from pneumonic tularemia 13 months ago and immunohistochemical staining for Francisella tularensis on FNA samples at Center for Disease Control and Prevention was negative. The intense positron emission tomography (PET) avidity was attributed to prior tularemic intrathoracic lymphadenitis without active tularemia, a rare occurrence. To the best of our knowledge, PET-positive intrathoracic lymph node beyond one year without evidence of active tularemia has not been previously reported.

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Nicol, McKayla J., David R. Williamson, David E. Place, and Girish S. Kirimanjeswara. "Differential Immune Response Following Intranasal and Intradermal Infection with Francisella tularensis: Implications for Vaccine Development." Microorganisms 9, no. 5 (April 30, 2021): 973. http://dx.doi.org/10.3390/microorganisms9050973.

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Francisella tularensis (Ft) is a Gram-negative, facultative intracellular coccobacillus that is the etiological agent of tularemia. Interestingly, the disease tularemia has variable clinical presentations that are dependent upon the route of infection with Ft. Two of the most likely routes of Ft infection include intranasal and intradermal, which result in pneumonic and ulceroglandular tularemia, respectively. While there are several differences between these two forms of tularemia, the most notable disparity is between mortality rates: the mortality rate following pneumonic tularemia is over ten times that of the ulceroglandular disease. Understanding the differences between intradermal and intranasal Ft infections is important not only for clinical diagnoses and treatment but also for the development of a safe and effective vaccine. However, the immune correlates of protection against Ft, especially within the context of infection by disparate routes, are not yet fully understood. Recent advances in different animal models have revealed new insights in the complex interplay of innate and adaptive immune responses, indicating dissimilar patterns in both responses following infection with Ft via different routes. Further investigation of these differences will be crucial to predicting disease outcomes and inducing protective immunity via vaccination or natural infection.

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Nelson, Christina A., Jessica Winberg, Taylor D. Bostic, K. Meryl Davis, and Shannon Fleck-Derderian. "Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993–2023." Clinical Infectious Diseases 78, Supplement_1 (January 31, 2024): S15—S28. http://dx.doi.org/10.1093/cid/ciad736.

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Abstract Background Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. Methods Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. Results Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. Conclusions Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.

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Jacobs, Richard F., Yoland M. Condrey, and Terry Yamauchi. "Tularemia in Adults and Children: A Changing Presentation." Pediatrics 76, no. 5 (November 1, 1985): 818–22. http://dx.doi.org/10.1542/peds.76.5.818.

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Tularemia, a febrile zoonosis with six clinical types, recently has been shown to occur at an increased incidence in children compared with previous reports. Ulceroglandular and glandular tularemia are still the most common types, but pneumonic tularemia has increased in incidence. However, with these changes, an overall decline in mortality has been observed. Children exhibit fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than affected adults. The complication of late lymph node suppuration is found in half of the tularemia patients with lymphadenopathy. A high index of clinical suspicion and a good medical history and physical examination confirmed by specific serologic studies are the critical factors in the successful diagnosis of tularemia in children.

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Lovchik, Julie A., Douglas S. Reed, Julie A. Hutt, Fangfang Xia, Rick L. Stevens, Thero Modise, Eileen M. Barry, and Terry H. Wu. "Identification of an Attenuated Substrain of Francisella tularensis SCHU S4 by Phenotypic and Genotypic Analyses." Pathogens 10, no. 6 (May 22, 2021): 638. http://dx.doi.org/10.3390/pathogens10060638.

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Pneumonic tularemia is a highly debilitating and potentially fatal disease caused by inhalation of Francisella tularensis. Most of our current understanding of its pathogenesis is based on the highly virulent F. tularensis subsp. tularensis strain SCHU S4. However, multiple sources of SCHU S4 have been maintained and propagated independently over the years, potentially generating genetic variants with altered virulence. In this study, the virulence of four SCHU S4 stocks (NR-10492, NR-28534, NR-643 from BEI Resources and FTS-635 from Battelle Memorial Institute) along with another virulent subsp. tularensis strain, MA00-2987, were assessed in parallel. In the Fischer 344 rat model of pneumonic tularemia, NR-643 and FTS-635 were found to be highly attenuated compared to NR-10492, NR-28534, and MA00-2987. In the NZW rabbit model of pneumonic tularemia, NR-643 caused morbidity but not mortality even at a dose equivalent to 500x the LD50 for NR-10492. Genetic analyses revealed that NR-10492 and NR-28534 were identical to each other, and nearly identical to the reference SCHU S4 sequence. NR-643 and FTS-635 were identical to each other but were found to have nine regions of difference in the genomic sequence when compared to the published reference SCHU S4 sequence. Given the genetic differences and decreased virulence, NR-643/FTS-635 should be clearly designated as a separate SCHU S4 substrain and no longer utilized in efficacy studies to evaluate potential vaccines and therapeutics against tularemia.

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Williams, Mark S. "Efficacy of Doxycycline and Ciprofloxacin for Treatment of Pneumonic Tularemia in Cynomolgus Macaques." Clinical Infectious Diseases 78, Supplement_1 (January 31, 2024): S7—S14. http://dx.doi.org/10.1093/cid/ciad668.

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Abstract Background The incidence of pneumonic tularemia is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCMs) in humans. The US Food and Drug Administration’s Animal Model Qualification Program under the Drug Development Tools Program is a regulatory pathway for animal models used in MCM efficacy testing and approval under the Animal Rule. The National Institute of Allergy and Infectious Diseases and Biomedical Advanced Research and Development Authority worked together to qualify the cynomolgus macaque model of pneumonic tularemia. Methods Using the model parameters and end points defined in the qualified model, efficacy of the antibiotics doxycycline and ciprofloxacin was evaluated in separate studies. Antibiotic administration, aimed to model approved human dosing, was initiated at time points of 24 hours or 48 hours after onset of fever as an indicator of disease. Results Upon aerosol exposure (target dose of 1000 colony-forming units) to Francisella tularensis SchuS4, 80% of vehicle-treated macaques succumbed or were euthanized. Ciprofloxacin treatment led to 10 of 10 animals surviving irrespective of treatment time. Doxycycline administered at 48 hours post-fever led to 10 of 10 animals surviving, while 9/10 animals survived in the group treated with doxycycline 24 hours after fever. Selected surviving animals in both the placebo and doxycycline 48-hour group showed residual live bacteria in peripheral tissues, while there were no bacteria in tissues from ciprofloxacin-treated macaques. Conclusions Both doxycycline and ciprofloxacin were efficacious in treatment of pneumonic tularemia, although clearance of bacteria may be different between the 2 drugs.

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Hahn, Mark M., Cheryl A. Triplett, Michael S. Anderson, Jennifer I. Smart, Karine Litherland, Stephen Keech, Franziska von Siebenthal, Mark Jones, Andrew J. Phipps, and Lisa N. Henning. "Ceftobiprole Medocaril Is an Effective Post-Exposure Treatment in the Fischer 344 Rat Model of Pneumonic Tularemia." Antibiotics 12, no. 8 (August 19, 2023): 1337. http://dx.doi.org/10.3390/antibiotics12081337.

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Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model.

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MIR, MAHNOOR, and CHRISTOPHER DAYTON. "A CASE OF PNEUMONIC TULAREMIA MIMICKING COVID-19." Chest 160, no. 4 (October 2021): A373. http://dx.doi.org/10.1016/j.chest.2021.07.374.

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Maranan, Melinda C., Deborah Schiff, Daniel C. Johnson, Cyril Abrahams, Mark Wylam, and Susan I. Gerber. "Pneumonic Tularemia in a Patient with Chronic Granulomatous Disease." Clinical Infectious Diseases 25, no. 3 (September 1997): 630–33. http://dx.doi.org/10.1086/513777.

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Feldman, Katherine A., Russell E. Enscore, Sarah L. Lathrop, Bela T. Matyas, Michael McGuill, Martin E. Schriefer, Donna Stiles-Enos, David T. Dennis, Lyle R. Petersen, and Edward B. Hayes. "An Outbreak of Primary Pneumonic Tularemia on Martha's Vineyard." New England Journal of Medicine 345, no. 22 (November 29, 2001): 1601–6. http://dx.doi.org/10.1056/nejmoa011374.

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Frick, Ondraya M., Virginia A. Livingston, Chris A. Whitehouse, Sarah L. Norris, Derron A. Alves, Paul R. Facemire, Douglas S. Reed, and Aysegul Nalca. "The Natural History of Aerosolized Francisella tularensis Infection in Cynomolgus Macaques." Pathogens 10, no. 5 (May 13, 2021): 597. http://dx.doi.org/10.3390/pathogens10050597.

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Tularemia is a severe, zoonotic infection caused by the Gram-negative bacterium Francisella tularensis. Inhalation results in a rapid, severe bacterial pneumonia and sepsis, which can be lethal. Because the cynomolgus macaque is the accepted nonhuman primate model for tularemia, we conducted a natural history study of pneumonic tularemia by exposing macaques to target inhaled doses of 50, 500, or 5000 colony forming units (CFU) of F. tularensis subsp. tularensis SCHU S4. Two animals within the 50 CFU group (calculated doses of 10 and 11 CFU) survived the challenge, while the remainder succumbed to infection. Exposure of cynomolgus macaques to aerosolized SCHU S4 resulted in fever, anorexia, increased white blood cell counts, lymphopenia, thrombocytopenia, increased liver enzymes, alterations in electrocardiogram (ECG), and pathological changes typical of infection with F. tularensis, regardless of the challenge dose. Blood pressure dropped during the febrile phase, particularly as temperature began to drop and macaques succumbed to the disease. ECG analysis indicated that in 33% of the macaques, heart rate was not elevated during the febrile phase (Faget’s sign; pulse-temperature disassociation), which has been reported in a similar percentage of human cases. These results indicated that infection of cynomolgus macaques with aerosolized F. tularensis results in similar disease progression and outcome as seen in humans, and that cynomolgus macaques are a reliable animal model to test medical countermeasures against aerosolized F. tularensis.

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Periasamy, Sivakumar, Timothy Sellati, and Jonathan Harton. "Lung infiltrates containing myeloid-derived suppressor cells impair protective immunity in pneumonic tularemia caused by Francisella tularemia (P3082)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 187.14. http://dx.doi.org/10.4049/jimmunol.190.supp.187.14.

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Abstract Inhalation of low (~10) numbers of Francisella tularensis, a biothreat category ‘A’ agent, causes acute pneumonia and death; two key features of pneumonic tularemia emphasizing deficiency in the host response to pathogen. We previously reported that early establishment of an immunosuppressive milieu in the lungs favored unfettered and exponential growth of F. tularensis in mice, suggesting a role for immunosuppressive cells in the pathogenesis of tularemia. A comprehensive multicolor flow cytometer analysis for immune cells in the lungs and spleen was performed to address this issue. F. tularensis-infected mice had a high frequency of infiltrating myeloid (CD11b+) cells, but no change in the frequencies of B220+, CD4+, or CD8+ lymphoid cells in lungs and spleen. A majority of the infiltrating myeloid cells were CD11b+CD11c-Ly6G+Ly6C+, a phenotype consistent with immature or myeloid-derived suppressor cells (MDSC). The frequencies of neutrophils (Gr-1+F4/80-) and macrophages (Gr-1-F4/80+) were also increased. Consistent with myeloid cell recruitment, levels of mouse KC, MCP-1 and IL-17A were increased in the lungs. Despite a rapid accumulation of myeloid cells in the lungs, these cells fail to control bacterial replication. Our results suggest that a significant portion of the CD11b+CD11c-Ly6G+Ly6C+ infiltrating cells are likely MDSC, which impair protective immune responses and cause necrotizing inflammation in the lungs and death of F. tularensis-infected mice.

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Cowley, Siobhán C. "Editorial: Proinflammatory cytokines in pneumonic tularemia: too much too late?" Journal of Leukocyte Biology 86, no. 3 (September 2009): 469–70. http://dx.doi.org/10.1189/jlb.0309119.

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MATYAS, B. T., H. S. NIEDER, and S. R. TELFORD. "Pneumonic Tularemia on Martha's Vineyard: Clinical, Epidemiologic, and Ecological Characteristics." Annals of the New York Academy of Sciences 1105, no. 1 (March 29, 2007): 351–77. http://dx.doi.org/10.1196/annals.1409.013.

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&NA;. "AN OUTBREAK OF PRIMARY PNEUMONIC TULAREMIA ON MARTHA???S VINEYARD." Infectious Diseases in Clinical Practice 11, no. 1 (January 2002): 39. http://dx.doi.org/10.1097/00019048-200201000-00019.

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Reed, Douglas S., Emily Olsen, Jennifer Bowling, Katherine Willett, Karsten Hazlett, and Eileen Barry. "Role of antibody in vaccine-mediated protection against pneumonic tularemia in the rabbit model." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 168.12. http://dx.doi.org/10.4049/jimmunol.204.supp.168.12.

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Abstract Francisella tularensis, a gram negative coccobacillus, is the causative agent of tularemia, a severe zoonotic infection. When inhaled, as few as 15 cfu is sufficient to cause disease. There is concern that tularemia could be used as a biological weapon so vaccines are urgently needed. We have previously shown that the New Zealand White (NZW) rabbit is a good model of human disease; after exposure to small particle aerosols containing virulent F. tularensis at doses as low as 66 cfu, naive NZW rabbits develop fever within 3 days and succumb within 4–7 days. Disease pathology in the NZW rabbit strongly resembles what has been reported in humans. Recombinant derivatives of a virulent strain of F. tularensis are highly attenuated in NZW rabbits and protect against aerosol challenge with virulent F. tularensis. The level of protection is dependent on the strain used, the route of vaccination, and the number of vaccinations. Using a prime-boost small particle aerosol vaccination regimen, 73% percent of rabbits survived a robust (100 LD50) challenge when vaccinated with a strain that is deficient in the aromatic amino acid synthase pathway. Pre-challenge, post-vaccination plasma IgG and IgM titers against heat-killed F. tularensis correlate with protection. A single inoculation of plasma from hyper-immune rabbits extended the survival of naïve rabbits by one day. We will report our efforts to evaluate the role of antibody in protection of NZW rabbits against tularemia, including passive immunization of mice using purified immunoglobulin from hyper-immune rabbits and in vitro assays of antibody function.

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Brunet, Camille D., Aurélie Hennebique, Julien Peyroux, Isabelle Pelloux, Yvan Caspar, and Max Maurin. "Presence of Francisella tularensis subsp. holarctica DNA in the Aquatic Environment in France." Microorganisms 9, no. 7 (June 28, 2021): 1398. http://dx.doi.org/10.3390/microorganisms9071398.

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In 2018, the incidence of tularemia increased twofold in the west of France, with many pneumonic forms, suggesting environmental sources of infection. We investigated the presence of Francisellatularensis subsp. holarctica and other Francisella species DNA in the natural aquatic environment of this geographic area. Two sampling campaigns, in July 2019 and January 2020, allowed the collection of 87 water samples. Using a combination of real-time PCR assays, we tested the presence of either Francisella sp., F. tularensis/F. novicida, and F. tularensis subsp. holarctica, the latter being the only tularemia agent in Europe. Among 57 water samples of the first campaign, 15 (26.3%) were positive for Francisella sp., nine (15.8%) for F. tularensis and/or F. novicida, and four (7.0%) for F. tularensis subsp. holarctica. Ratios were 25/30 (83.3%), 24/30 (80.0%), and 4/30 (13.3%) for the second campaign. Among the thirty sites sampled during the two campaigns, nine were positive both times for Francisella sp., seven for F. tularensis and/or F. novicida, and one for F. tularensis subsp. holarctica. Altogether, our study reveals a high prevalence of Francisella sp. DNA (including the tularemia agent) in the studied aquatic environment. This aquatic environment could therefore participate in the endemicity of tularemia in the west of France.

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Malik, Salma, Vishesh Paul, Thara Damodaran, Deepa Prabakhar, Amir Khan, and Sharjeel Ahmad. "648. Rapid, Non-invasive Detection of Cryptic Tularemia Using a Plasma-Based Microbial Cell-Free DNA Next-Generation Sequencing Test." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S426. http://dx.doi.org/10.1093/ofid/ofab466.845.

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Abstract Background Francisella tularensis causes severe infections and is a Category A potential bioterrorism agent but its microbiological diagnosis can be challenging. The diagnosis of tularemia is limited by non-specific protean clinical symptoms that overlap with other infectious syndromes, the fastidious nature of Francisella tularensis, along with insensitivity and poor specificity of serology. Rapid, non-invasive diagnosis of tularemia by microbial cell-free DNA (mcfDNA) next-generation sequencing (NGS) of plasma offers a means to overcome these limitations. Methods The Karius Test™ (KT) detects and quantifies mcfDNA in molecules/µL (MPM) from >1400 organisms in plasma (performed at the CLIA certified/CAP accredited Karius laboratory). KT detections of Francisella tularensis were compiled from three medical centers with clinical review by healthcare providers. Results KT detected Francisella tularensis in four patients. All were adult males in whom the diagnosis was unexpected. The most common symptoms were fever and chest pain. White blood cell count neutrophilic predominance and abnormal chest X-ray findings were found in three cases. A broad infectious disease work-up was performed with the initiation of broad spectrum empiric antibiotics in all cases. KT was the first test to identify Francisella tularensis as the microbiological diagnosis with a time to diagnosis of 2.25 days (avg) +/- 0.5 from sample collection (one day from sample receipt in all cases), enabling narrowed, targeted antibiotic treatment. Francisella tularensis mcfDNA concentration was 1772 MPM (avg) +/- 1914. KT was the only test to establish the diagnosis in two cases; tularemia serologies were confirmatory in two cases, one of which had confirmatory culture from lymph node biopsy. Three patients were diagnosed with the pneumonic form of the illness and one with a visceral glandular form. Possible epidemiological exposures were identified in all cases. Conclusion KT enabled rapid, non-invasive, plasma-based diagnosis of diverse clinical manifestations of invasive tularemia against a competing broad infectious and non-infectious differential diagnosis. Timely diagnosis enabled targeted narrowing of antibiotic therapy and successful treatment of pneumonic and glandular forms of the infection. Disclosures All Authors: No reported disclosures

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Lembo, Annalisa, Mark Pelletier, Ravi Iyer, Michele Timko, Jan C. Dudda, T. Eoin West, Christopher B. Wilson, Adeline M. Hajjar, and Shawn J. Skerrett. "Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia." Journal of Immunology 180, no. 11 (May 19, 2008): 7574–81. http://dx.doi.org/10.4049/jimmunol.180.11.7574.

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Chang, Yie-Hwa, Duc M. Duong, Johannes B. Goll, David C. Wood, Travis L. Jensen, Luming Yin, Casey E. Gelber, et al. "Proteomic Analysis of Human Immune Responses to Live-Attenuated Tularemia Vaccine." Vaccines 8, no. 3 (July 24, 2020): 413. http://dx.doi.org/10.3390/vaccines8030413.

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Francisella tularensis (F. tularensis) is an intracellular pathogen that causes a potentially debilitating febrile illness known as tularemia. F. tularensis can be spread by aerosol transmission and cause fatal pneumonic tularemia. If untreated, mortality rates can be as high as 30%. To study the host responses to a live-attenuated tularemia vaccine, peripheral blood mononuclear cell (PBMC) samples were assayed from 10 subjects collected pre- and post-vaccination, using both the 2D-DIGE/MALDI-MS/MS and LC-MS/MS approaches. Protein expression related to antigen processing and presentation, inflammation (PPARγ nuclear receptor), phagocytosis, and gram-negative bacterial infection was enriched at Day 7 and/or Day 14. Protein candidates that could be used to predict human immune responses were identified by evaluating the correlation between proteome changes and humoral and cellular immune responses. Consistent with the proteomics data, parallel transcriptomics data showed that MHC class I and class II-related signals important for protein processing and antigen presentation were up-regulated, further confirming the proteomic results. These findings provide new biological insights that can be built upon in future clinical studies, using live attenuated strains as immunogens, including their potential use as surrogates of protection.

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Wu, Terry H., Julie A. Hutt, Kristin A. Garrison, Lyudmila S. Berliba, Yan Zhou, and C. Rick Lyons. "Intranasal Vaccination Induces Protective Immunity against Intranasal Infection with Virulent Francisella tularensis Biovar A." Infection and Immunity 73, no. 5 (May 2005): 2644–54. http://dx.doi.org/10.1128/iai.73.5.2644-2654.2005.

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ABSTRACT The inhalation of Francisella tularensis biovar A causes pneumonic tularemia associated with high morbidity and mortality rates in humans. Exposure to F. tularensis usually occurs by accident, but there is increasing awareness that F. tularensis may be deliberately released in an act of bioterrorism or war. The development of a vaccine against pneumonic tularemia has been limited by a lack of information regarding the mechanisms required to protect against this disease. Vaccine models for F. tularensis in inbred mice would facilitate investigations of the protective mechanisms and significantly enhance vaccine development. Intranasal vaccination with the attenuated live vaccine strain (LVS) of F. tularensis reproducibly protected BALB/c mice, but not C57BL/6 mice, against intranasal and subcutaneous challenges with a virulent clinical isolate of F. tularensis biovar A (NMFTA1). The resistance of LVS-vaccinated BALB/c mice to intranasal NMFTA1 challenge was increased 100-fold by boosting with live NMFTA1 but not with LVS. The protective response was specific for F. tularensis and required both CD4 and CD8 T cells. The vaccinated mice appeared outwardly healthy for more than 2 months after NMFTA1 challenge, even though NMFTA1 was recovered from more than half of the vaccinated mice. These results show that intranasal vaccination induces immunity that protects BALB/c mice from intranasal infection by F. tularensis biovar A.

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Malik, Meenakshi, Chandra Shekhar Bakshi, Bikash Sahay, Aaloki Shah, Steven A. Lotz, and Timothy J. Sellati. "Toll-Like Receptor 2 Is Required for Control of Pulmonary Infection with Francisella tularensis." Infection and Immunity 74, no. 6 (June 2006): 3657–62. http://dx.doi.org/10.1128/iai.02030-05.

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ABSTRACT Toll-like receptor 2 (TLR2) deficiency enhances murine susceptibility to infection by Francisella tularensis as indicated by accelerated mortality, higher bacterial burden, and greater histopathology. Analysis of pulmonary cytokine levels revealed that TLR2 deficiency results in significantly lower levels of tumor necrosis factor alpha and interleukin-6 but increased amounts of gamma interferon and monocyte chemoattractant protein 1. This pattern of cytokine production may contribute to the exaggerated pathogenesis seen in TLR2−/− mice. Collectively, these findings suggest that TLR2 plays an important role in tempering the host response to pneumonic tularemia.

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HUSNA, ASHMA UL, MUNISH R ADHIKARI, DIVYA KHAREL, YAN JIANG, and GREGORY POLCHA. "UNDERSTANDING THE NEED FOR A BROAD DIFFERENTIAL DIAGNOSIS: A CASE OF PNEUMONIC TULAREMIA." Chest 162, no. 4 (October 2022): A560. http://dx.doi.org/10.1016/j.chest.2022.08.434.

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Bossi, P., A. Tegnell, A. Baka, F. van Loock, A. Werner, J. Hendriks, H. Maidhof, and G. Gouvras. "Bichat guidelines for the clinical management of tularaemia and bioterrorism-related tularaemia." Eurosurveillance 9, no. 12 (December 1, 2004): 27–28. http://dx.doi.org/10.2807/esm.09.12.00503-en.

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Francisella tularensis is one of the most infectious pathogenic bacteria known, requiring inoculation or inhalation of as few as 10 organisms to initiate human infection. Inhalational tularaemia following intentional release of a virulent strain of F. tularensis would have great impact and cause high morbidity and mortality. Another route of contamination in a deliberate release could be contamination of water. Seven clinical forms, according to route of inoculation (skin, mucous membranes, gastrointestinal tract, eyes, respiratory tract), dose of the inoculum and virulence of the organism (types A or B) are identified. The pneumonic form of the disease is the most likely form of the disease should this bacterium be used as a bioterrorism agent. Streptomycin and gentamicin are currently considered the treatment of choice for tularemia. Quinolone is an effective alternative drug. No isolation measures for patients with pneumonia are necessary. Streptomycin, gentamicin, doxycycline or ciprofloxacin are recommended for post-exposure prophylaxis.

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Ray, Heather J., Yu Cong, Ashlesh K. Murthy, Dale M. Selby, Karl E. Klose, Jeffrey R. Barker, M. Neal Guentzel, and Bernard P. Arulanandam. "Oral Live Vaccine Strain-Induced Protective Immunity against Pulmonary Francisella tularensis Challenge Is Mediated by CD4+ T Cells and Antibodies, Including Immunoglobulin A." Clinical and Vaccine Immunology 16, no. 4 (February 11, 2009): 444–52. http://dx.doi.org/10.1128/cvi.00405-08.

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ABSTRACT Francisella tularensis is an intracellular gram-negative bacterium and the etiological agent of pulmonary tularemia. Given the high degrees of infectivity in the host and of dissemination of bacteria following respiratory infection, immunization strategies that target mucosal surfaces are critical for the development of effective vaccines against this organism. In this study, we have characterized the efficacy of protective immunity against pneumonic tularemia following oral vaccination with F. tularensis LVS (live vaccine strain). Mice vaccinated orally with LVS displayed colocalization of LVS with intestinal M cells, with subsequent enhanced production of splenic antigen-specific gamma interferon and of systemic and mucosal antibodies, including immunoglobulin A (IgA). LVS-vaccinated BALB/c mice were highly protected against intranasal (i.n.) SCHU S4 challenge and exhibited significantly less bacterial replication in the lungs, liver, and spleen than mock-immunized animals. Depletion of CD4+ T cells significantly abrogated the protective immunity, and mice deficient in B cells or IgA displayed partial protection against SCHU S4 challenge. These results suggest that oral vaccination with LVS induces protective immunity against i.n. challenge with F. tularensis SCHU S4 by a process mediated cooperatively by CD4+ T cells and antibodies, including IgA.

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Dembek, Z. F., R. L. Buckman, S. K. Fowler, and J. L. Hadler. "Missed Sentinel Case of Naturally Occurring Pneumonic Tularemia Outbreak: Lessons for Detection of Bioterrorism." Journal of the American Board of Family Medicine 16, no. 4 (July 1, 2003): 339–42. http://dx.doi.org/10.3122/jabfm.16.4.339.

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Yaglom, Hayley, Edwin Rodriguez, Marlene Gaither, Mare Schumacher, Natalie Kwit, Christina Nelson, Joel Terriquez, et al. "Notes from the Field: Fatal Pneumonic Tularemia Associated with Dog Exposure — Arizona, June 2016." MMWR. Morbidity and Mortality Weekly Report 66, no. 33 (August 25, 2017): 891. http://dx.doi.org/10.15585/mmwr.mm6633a5.

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Russo, Brian C., Joseph Horzempa, Dawn M. O'Dee, Deanna M. Schmitt, Matthew J. Brown, Paul E. Carlson, Ramnik J. Xavier, and Gerard J. Nau. "A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence." Infection and Immunity 79, no. 9 (June 13, 2011): 3665–76. http://dx.doi.org/10.1128/iai.00135-11.

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ABSTRACTTularemia is a debilitating febrile illness caused by the category A biodefense agentFrancisella tularensis. This pathogen infects over 250 different hosts, has a low infectious dose, and causes high morbidity and mortality. Our understanding of the mechanisms by whichF. tularensissenses and adapts to host environments is incomplete. Polyamines, including spermine, regulate the interactions ofF. tularensiswith host cells. However, it is not known whether responsiveness to polyamines is necessary for the virulence of the organism. Through transposon mutagenesis ofF. tularensissubsp.holarcticalive vaccine strain (LVS), we identified FTL_0883 as a gene important for spermine responsiveness. In-frame deletion mutants of FTL_0883 and FTT_0615c, the homologue of FTL_0883 inF. tularensissubsp.tularensisSchu S4 (Schu S4), elicited higher levels of cytokines from human and murine macrophages compared to wild-type strains. Although deletion of FTL_0883 attenuated LVS replication within macrophagesin vitro, the Schu S4 mutant with a deletion in FTT_0615c replicated similarly to wild-type Schu S4. Nevertheless, both the LVS and the Schu S4 mutants were significantly attenuatedin vivo. Growth and dissemination of the Schu S4 mutant was severely reduced in the murine model of pneumonic tularemia. This attenuation depended on host responses to elevated levels of proinflammatory cytokines. These data associate responsiveness to polyamines with tularemia pathogenesis and define FTL_0883/FTT_0615c as anF. tularensisgene important for virulence and evasion of the host immune response.

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Anderson, Rebecca V., Deborah D. Crane, and Catharine M. Bosio. "Long lived protection against pneumonic tularemia is correlated with cellular immunity in peripheral, not pulmonary, organs." Vaccine 28, no. 40 (September 2010): 6562–72. http://dx.doi.org/10.1016/j.vaccine.2010.07.072.

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Sanapala, Shilpa, Jieh-Juen Yu, Ashlesh K. Murthy, Weidang Li, M. Neal Guentzel, James P. Chambers, Karl E. Klose, and Bernard P. Arulanandam. "Perforin- and Granzyme-Mediated Cytotoxic Effector Functions Are Essential for Protection against Francisella tularensis following Vaccination by the Defined F. tularensis subsp. novicida ΔfopCVaccine Strain." Infection and Immunity 80, no. 6 (April 9, 2012): 2177–85. http://dx.doi.org/10.1128/iai.00036-12.

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ABSTRACTA licensed vaccine againstFrancisella tularensisis currently not available. TwoFrancisella tularensissubsp.novicida(herein referred to by its earlier name,Francisella novicida) attenuated strains, the ΔiglBand ΔfopCstrains, have previously been evaluated as potential vaccine candidates against pneumonic tularemia in experimental animals.F. novicidaΔiglB, aFrancisellapathogenicity island (FPI) mutant, is deficient in phagosomal escape and intracellular growth, whereasF. novicidaΔfopC, lacking the outer membrane lipoprotein FopC, which is required for evasion of gamma interferon (IFN-γ)-mediated signaling, is able to escape and replicate in the cytosol. To dissect the difference in protective immune mechanisms conferred by these two vaccine strains, we examined the efficacy of theF. novicidaΔiglBand ΔfopCmutants against pulmonary live-vaccine-strain (LVS) challenge and found that both strains provided comparable protection in wild-type, major histocompatibility complex class I (MHC I) knockout, and MHC II knockout mice. However,F. novicidaΔfopC-vaccinated but notF. novicidaΔiglB-vaccinated perforin-deficient mice were more susceptible and exhibited greater bacterial burdens than similarly vaccinated wild-type mice. Moreover, perforin produced by natural killer (NK) cells and release of granzyme contributed to inhibition of LVS replication within macrophages. This NK cell-mediated LVS inhibition was enhanced with anti-F. novicidaΔfopCimmune serum, suggesting antibody-dependent cell-mediated cytotoxicity (ADCC) inF. novicidaΔfopC-mediated protection. Overall, this study provides additional immunological insight into the basis for protection conferred by live attenuatedF. novicidastrains with different phenotypes and supports further investigation of this organism as a vaccine platform for tularemia.

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Reed, Douglas S., Le'Kneitah Smith, Tammy Dunsmore, Anita Trichel, Luis A. Ortiz, Kelly Stefano Cole, and Eileen Barry. "Pneumonic Tularemia in Rabbits Resembles the Human Disease as Illustrated by Radiographic and Hematological Changes after Infection." PLoS ONE 6, no. 9 (September 13, 2011): e24654. http://dx.doi.org/10.1371/journal.pone.0024654.

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Schmitt, Deanna, Dawn O'Dee, Matthew Brown, Jospeh Horzempa, Brian Russo, and Gerard Nau. "IL-15/IL-15Rα improves immune cell survival but does not reduce disease severity following pulmonary infection with the intracellular bacterium Francisella tularensis (56.27)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 56.27. http://dx.doi.org/10.4049/jimmunol.186.supp.56.27.

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Abstract The potent anti-apoptotic cytokine IL-15 regulates the development and function of a wide range of innate and adaptive immune cells. Treatment with IL-15 in combination with IL-15Rα prevents apoptosis and immunosuppression in mouse models of sepsis. Inhalation of Francisella tularensis results in an acute pneumonia that demonstrates many of the hallmarks of sepsis including bacteremia and hypercytokinemia. We and others have observed widespread cell death in the lung following infection with virulent F. tularensis strain Schu S4. The predominant cell populations depleted are lymphocytes and neutrophils. Cell numbers declined in Schu S4-infected mice despite high levels of chemokines in the lung and correlated with an increase in TUNEL-positive cells. This supports the conclusion that immune cell depletion was due to cell death, and not a lack of recruitment. To determine whether this cell depletion was contributing to Schu S4 pathogenesis, mice were treated with IL-15/IL-15Rα prior to infection. IL-15/IL-15Rα treatment significantly increased the number of viable lung cells in Schu S4-infected mice compared to mock-treated controls, however, no difference in bacterial burden or disease severity was observed. These data suggest that depletion of immune cells by F. tularensis does not contribute to the morbidity and mortality associated with pneumonic tularemia. Moreover, IL-15/IL-15Rα may not be generally applicable to treat sepsis of different etiologies.

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Li, Zilu, Daniel L. Clemens, Bai-Yu Lee, Barbara Jane Dillon, Marcus A. Horwitz, and Jeffrey I. Zink. "Mesoporous Silica Nanoparticles with pH-Sensitive Nanovalves for Delivery of Moxifloxacin Provide Improved Treatment of Lethal Pneumonic Tularemia." ACS Nano 9, no. 11 (October 9, 2015): 10778–89. http://dx.doi.org/10.1021/acsnano.5b04306.

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Bar-On, Liat, Hila Cohen, Uri Elia, Shahar Rotem, Adi Bercovich-Kinori, Erez Bar-Haim, Theodor Chitlaru, and Ofer Cohen. "Protection of vaccinated mice against pneumonic tularemia is associated with an early memory sentinel-response in the lung." Vaccine 35, no. 50 (December 2017): 7001–9. http://dx.doi.org/10.1016/j.vaccine.2017.10.053.

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Stinson, Elizabeth, Le'Kneitah P. Smith, Kelly Stefano Cole, Eileen M. Barry, and Douglas S. Reed. "Respiratory and oral vaccination improves protection conferred by the live vaccine strain against pneumonic tularemia in the rabbit model." Pathogens and Disease 74, no. 7 (August 9, 2016): ftw079. http://dx.doi.org/10.1093/femspd/ftw079.

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Priyantha, M. A. R. "Francisella tularensis: a zoonotic pathogen among wild rodents and arthropods - a possible threat in future." Sri Lanka Veterinary Journal 70, no. 1 (September 6, 2023): 13–21. http://dx.doi.org/10.4038/slvj.v70i1.76.

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Francisella tularensis is a Gram-negative coccobacillus and an aerobic bacterium. It causes a zoonotic disease called tularemia in humans. Four subspecies have been found in F. tularensis as F. tularensis subsp. Tularensis (Type A strains), F. tularensis subsp. Holarctica (Type B strains), F. tularensis subsp. mediasiatica, and F. tularensis subsp. Novicida. Rearing rabbits and different kinds of rodents as pets are becoming popular in Sri Lanka, veterinarians need to be knowledgeable on emerging pathogens such as F. tularensis, to diagnose the disease within a short time. Therefore, the objective of this paper is to update veterinarians on possible emerging infections to improve the health of pets and to minimize possible zoonotic infections. The clinical outcome caused by Francisella is a debilitating febrile disease in humans. Francisella has been isolated from hundreds of animal species in the world. Being a diverse host range, associated ecological factors relating transmission of Francisella in the environment is largely unknown. F. tularensis type A was reported to be common in North America while occasionally found in Europe. Type B was found commonly in the Northern hemisphere and in Australia. Tularemia is a sporadic disease, and a small infectious dose is required for an infection in humans. The clinical signs and symptoms of tularaemia depend on the route of infection. Six types of clinical forms were identified as ulceroglandular, glandular, oropharyngeal, oculoglandular, pneumonic and typhoidal in humans. Diagnosis of tularemia in humans is based on epidemiology, clinical findings and laboratory confirmation. Microagglutination test, indirect immunofluorescence assay (IFA) and Enzymelinked immunosorbent assay ELISA are widely used as diagnostic tests. Several conventional and qPCR have been optimized to detect the organism in clinical samples. Antimicrobials such as aminoglycosides, tetracycline, quinolones, and chloramphenicol were used to minimize clinical complications. Utilization of treated water, usage of gloves on handling wild rabbits and rodents, thorough cooking of bush meat, usage of insect repellents, protection of stored food from rodents, wearing masks, ticks-free clothes, keeping away from weeds, cleaning pets from external parasites have been identified as the main preventive strategies against tularaemia in human. No commercial vaccine is found in the market yet against F. tularensis. This can be an emerging and threatening disease in the future with ongoing changes in arthropod parasites in the ecosystem followed by climatic changes in the world.

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Sutherland, Marjorie D., Andrew W. Goodyear, Ryan M. Troyer, Jeffrey C. Chandler, Steven W. Dow, and John T. Belisle. "Post-exposure immunization against Francisella tularensis membrane proteins augments protective efficacy of gentamicin in a mouse model of pneumonic tularemia." Vaccine 30, no. 33 (July 2012): 4977–82. http://dx.doi.org/10.1016/j.vaccine.2012.05.037.

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Kouadio, Koffi Isidore, Taro Kamigaki, and Hitoshi Oshitani. "Strategies for Communicable Diseases Response After Disasters in Developing Countries." Journal of Disaster Research 4, no. 5 (October 1, 2009): 298–308. http://dx.doi.org/10.20965/jdr.2009.p0298.

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Communicable diseases represent a public health problem in developing countries and especially in those affected by disasters, necessitating an appropriate and coordinated response from national and international partners. The importance of rapid epidemiological assessment for public health planning and resources allocation is critical. Our review assesses the communicable diseases after natural disasters and conflict and describes a comprehensive intervention strategy towards their control. Several factors that promote disease transmission after disasters interact synergically, facilitating the occurrence of communicable diseases outbreaks. Diarrheal diseases, Hepatitis, Measles, Meningitis, Acute Respiratory Infection, Malaria were commonly described after natural disasters and conflicts situations. Tularemia, Lassa Fever, Pneumonic Plague were mainly described after conflicts. Other diseases including Diphtheria, Influenza and Pertusis has been less documented in disaster and refugee settings, but have potential to spread rapidly in overcrowded situations. These outbreaks may be avoidable by appropriate planning and intervention. Adequate shelter and sanitation, water and food safety, appropriate surveillance, immunization and management approach as well health education will be strongly required towards the reduction of morbidity and mortality. In addition further research is needed to improve intervention strategies as well as in the area of early warning system.

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Clemens, Daniel L., Bai-Yu Lee, Sheba Plamthottam, Michael V. Tullius, Ruining Wang, Chia-Jung Yu, Zilu Li, Barbara Jane Dillon, Jeffrey I. Zink, and Marcus A. Horwitz. "Nanoparticle Formulation of Moxifloxacin and Intramuscular Route of Delivery Improve Antibiotic Pharmacokinetics and Treatment of Pneumonic Tularemia in a Mouse Model." ACS Infectious Diseases 5, no. 2 (November 27, 2018): 281–91. http://dx.doi.org/10.1021/acsinfecdis.8b00268.

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Lee, Bai-Yu, Zilu Li, Daniel L. Clemens, Barbara Jane Dillon, Angela A. Hwang, Jeffrey I. Zink, and Marcus A. Horwitz. "Redox-Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap-Tops Enhances Efficacy Against Pneumonic Tularemia in Mice." Small 12, no. 27 (June 1, 2016): 3690–702. http://dx.doi.org/10.1002/smll.201600892.

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Furuya, Yoichi, Girish S. Kirimanjeswara, Sean Roberts, and Dennis W. Metzger. "Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection." Infection and Immunity 81, no. 9 (July 8, 2013): 3434–41. http://dx.doi.org/10.1128/iai.00408-13.

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ABSTRACTFrancisella tularensis, the causative agent of tularemia, is most deadly in the pneumonic form; therefore, mucosal immunity is an important first line of defense against this pathogen. We have now evaluated the lethality of primaryF. tularensislive vaccine strain (LVS) pulmonary infection in mice that are defective in IgA (IgA−/−mice), the predominant mucosal Ig isotype. The results showed that IgA−/−mice were more susceptible than IgA+/+mice to intranasalF. tularensisLVS infection, despite developing higher levels of LVS-specific total, IgG, and IgM antibodies in the bronchoalveolar lavage specimens following infection. In addition, the absence of IgA resulted in a significant increase in bacterial loads and reduced survival. Interestingly, IgA−/−mice had lower pulmonary gamma interferon (IFN-γ) levels and decreased numbers of IFN-γ-secreting CD4+and CD8+T cells in the lung on day 9 postinfection compared to IgA+/+mice. Furthermore, IgA−/−mice displayed reduced interleukin 12 (IL-12) levels at early time points, and supplementing IgA−/−mice with IL-12 prior to LVS challenge induced IFN-γ production by NK cells and rescued them from mortality. Thus, IgA−/−mice are highly susceptible to primary pulmonary LVS infections not only because of IgA deficiency but also because of reduced IFN-γ responses.

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Rodriguez, Annette Rose, JiehJuen Yu, Ashlesh Murthy, M. Neal Guentzel, Karl E. Klose, James P. Chambers, Thomas G. Forsthurber, Michael T. Berton, and Bernard P. Arulanandam. "Mast cells induce alternative activation and inhibit caspase-3 mediated apoptosis of Francisella tularensis infected macrophages (44.24)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 44.24. http://dx.doi.org/10.4049/jimmunol.182.supp.44.24.

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Abstract Francisella tularensis is a highly infectious Gram-negative bacterial pathogen and the causative agent of pneumonic tularemia. We recently demonstrated inhibition of F. tularensis LVS replication in macrophages via mast cell production of interleukin-4 (IL-4). We have further analyzed the interactions of mast cells and macrophages using a primary bone marrow derived mast cell-macrophage co-culture system and determined that mast cells inhibit F. tularensis-induced macrophage apoptosis. Specifically, mast cells co-cultured with macrophages significantly reduced intramacrophage LVS growth and expression of apoptotic proteins caspase-3 (19.9%) and PARP (Poly-ADP ribose polymerase, 16.0%) compared to macrophages cultured alone (48.2% and 56.4%, respectively). The inhibition of LVS-induced apoptosis within infected macrophages also was seen by the direct addition of recombinant IL-4 and corresponded with up-regulation of mannose receptor expression and arginase activity which are associated with the alternative activation of macrophages. Moreover, IL4R-/- mice were more susceptible to intranasal challenge and exhibited greater caspase-3 activity in lung macrophages (12.9%) compared to similarly challenged wild-type (4.7%) animals. These results support a role for mast cells and IL-4 in control of bacterial replication and apoptosis following pulmonary LVS infection. National Institutes of Health grant PO1 AI057986; NIH/NIGMS MBRS-RISE GM60655

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West, T. Eoin, Mark R. Pelletier, Melanie C. Majure, Annalisa Lembo, Adeline M. Hajjar, and Shawn J. Skerrett. "Inhalation of Francisella novicida ΔmglA causes replicative infection that elicits innate and adaptive responses but is not protective against invasive pneumonic tularemia." Microbes and Infection 10, no. 7 (June 2008): 773–80. http://dx.doi.org/10.1016/j.micinf.2008.04.008.

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Balagopal, Ashwin, Amanda Shearer MacFarlane, Nrusingh Mohapatra, Shilpa Soni, John S. Gunn, and Larry S. Schlesinger. "Characterization of the Receptor-Ligand Pathways Important for Entry and Survival of Francisella tularensis in Human Macrophages." Infection and Immunity 74, no. 9 (September 2006): 5114–25. http://dx.doi.org/10.1128/iai.00795-06.

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ABSTRACT Inhalational pneumonic tularemia, caused by Francisella tularensis, is lethal in humans. F. tularensis is phagocytosed by macrophages followed by escape from phagosomes into the cytoplasm. Little is known of the phagocytic mechanisms for Francisella, particularly as they relate to the lung and alveolar macrophages. Here we examined receptors on primary human monocytes and macrophages which mediate the phagocytosis and intracellular survival of F. novicida. F. novicida association with monocyte-derived macrophages (MDM) was greater than with monocytes. Bacteria were readily ingested, as shown by electron microscopy. Bacterial association was significantly increased in fresh serum and only partially decreased in heat-inactivated serum. A role for both complement receptor 3 (CR3) and Fcγ receptors in uptake was supported by studies using a CR3-expressing cell line and by down-modulation of Fcγ receptors on MDM, respectively. Consistent with Fcγ receptor involvement, antibody in nonimmune human serum was detected on the surface of Francisella. In the absence of serum opsonins, competitive inhibition of mannose receptor (MR) activity on MDM with mannan decreased the association of F. novicida and opsonization of F. novicida with lung collectin surfactant protein A (SP-A) increased bacterial association and intracellular survival. This study demonstrates that human macrophages phagocytose more Francisella than monocytes with contributions from CR3, Fcγ receptors, the MR, and SP-A present in lung alveoli.

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Horzempa, Joseph, Dawn M. O'Dee, Robert M. Q. Shanks, and Gerard J. Nau. "Francisella tularensis ΔpyrF Mutants Show that Replication in Nonmacrophages Is Sufficient for Pathogenesis In Vivo." Infection and Immunity 78, no. 6 (April 12, 2010): 2607–19. http://dx.doi.org/10.1128/iai.00134-10.

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ABSTRACT The pathogenesis of Francisella tularensis has been associated with this bacterium's ability to replicate within macrophages. F. tularensis can also invade and replicate in a variety of nonphagocytic host cells, including lung and kidney epithelial cells and hepatocytes. As uracil biosynthesis is a central metabolic pathway usually necessary for pathogens, we characterized ΔpyrF mutants of both F. tularensis LVS and Schu S4 to investigate the role of these mutants in intracellular growth. As expected, these mutant strains were deficient in de novo pyrimidine biosynthesis and were resistant to 5-fluoroorotic acid, which is converted to a toxic product by functional PyrF. The F. tularensis ΔpyrF mutants could not replicate in primary human macrophages. The inability to replicate in macrophages suggested that the F. tularensis ΔpyrF strains would be attenuated in animal infection models. Surprisingly, these mutants retained virulence during infection of chicken embryos and in the murine model of pneumonic tularemia. We hypothesized that the F. tularensis ΔpyrF strains may replicate in cells other than macrophages to account for their virulence. In support of this, F. tularensis ΔpyrF mutants replicated in HEK-293 cells and normal human fibroblasts in vitro. Moreover, immunofluorescence microscopy showed abundant staining of wild-type and mutant bacteria in nonmacrophage cells in the lungs of infected mice. These findings indicate that replication in nonmacrophages contributes to the pathogenesis of F. tularensis.

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Barrigan, Lydia, Shraddha Tuladhar, Jason Brunton, Matthew Woolard, Ching-ju Chen, Divey Saini, Richard Frothingham, Gregory Sempowski, Thomas Kawula, and Jeffrey Frelinger. "Altered host immune responses, not lowered growth, are the mechanism of attenuation of Francisella tularensis clpB (P3126)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 186.10. http://dx.doi.org/10.4049/jimmunol.190.supp.186.10.

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Abstract Bacterial infections typically initiate both innate and adaptive immune responses. Bacterial attenuation is thought of as altered bacterial growth in the presence of constant immune pressure. In vivo screens have identified F. tularensis genes necessary for virulence. While many of these mutations render F. tularensis incapable of intracellular growth, some mutations have no impact on intracellular growth. We hypothesize that these F. tularensis mutants are attenuated because they induce an altered host immune response. We were particularly interested in the F. tularensis LVS mutant clpB (FTL_0094). Our LVS clpB strain is attenuated in pneumonic tularemia yet we did not observe an intracellular growth defect in bone marrow derived macrophages. We showed that LVS clpB induced an altered innate, but equivalent adaptive, immune response compared to LVS. In B6 mice, LVS clpB induced pro-inflammatory cytokine production in the lung early after infection in contrast to wild-type LVS infection. LVS clpB provoked a robust protective adaptive immune response similar in magnitude to LVS, but with increased IFN-γ and IL-17A production in the lung as measured by mean fluorescence intensity. Altogether, our results indicate that LVS clpB is attenuated due to altered host immunity and not an intrinsic growth defect. These results also indicate that disruption of non-essential gene(s) that cause attenuation, like F. tularensis clpB, can help elucidate bacterial immune evasion mechanisms.

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Wyatt, Elliott V., Karina Diaz, Amanda Griffin, Jed Rasmussen, Deborah Crane, Bradley Jones, and Catharine M. Bosio. "Optimal replication and suppression of inflammation by virulent Francisella tularensis is achieved through reprogramming of host glycolysis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 66.7. http://dx.doi.org/10.4049/jimmunol.196.supp.66.7.

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Abstract Francisella tularensis (Ft) is a gram negative, facultative intracellular bacterium that is the causative agent of pneumonic tularemia. Inhalation of as a few as 15 organisms can result in lethal infection. The virulence of Ft is attributed to the bacterium’s ability to both evade and suppress the activation of macrophages. However, the mechanisms and bacterial components required for evasion and suppression by Ft are unclear. Activation of macrophages and induction of antimicrobial responses requires a metabolic shift from oxidative phosphorylation to aerobic glycolysis. Thus, we postulated that Ft manipulates host metabolism as a mechanism of virulence. We established that virulent Ft suppresses induction of aerobic glycolysis among infected macrophages. Moreover, utilizing purified capsule and defined capsule mutants, we elucidated a novel role for Ft capsule as a component contributing to this suppression. The requirement for inhibition of host cell glycolysis in Ft pathogenesis was confirmed via direct inhibition of glycolysis using 2-deoxyglucose. Addition of 2-DG to macrophages infected with capsule mutants partially restored the early intracellular survival and replication of these bacteria, and impaired the secretion of pro-inflammatory cytokines that is typical of infection with these mutants. Together, our data demonstrate that manipulation of host metabolism is an important component of Ft pathogenesis and uncovers a previously unappreciated function of bacterial capsule in the virulence of Ft.

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Journal articles on the topic 'Pneumonic Tularemia'

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