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Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model.
PLoS Negl Trop Dis. 2021 02; 15(2):e0009125.PN

Abstract

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. B. pseudomallei is a potential bioterrorism agent due to its high infectivity, especially via inhalation, and its inherent resistance to antimicrobials. There is currently no vaccine for melioidosis and antibiotic treatment can fail due to innate drug resistance, delayed diagnosis and treatment, or insufficient duration of treatment. A well-characterized animal model that mimics human melioidosis is needed for the development of new medical countermeasures. This study first characterized the disease progression of melioidosis in the African green monkey (AGM) and rhesus macaque (RM) for non-human primate model down-selection. All AGMs developed acute lethal disease similar to that described in human acute infection following exposure to aerosolized B. pseudomallei strain HBPUB10134a. Only 20% of RMs succumbed to acute disease. Disease progression, immune response and pathology of two other strains of B. pseudomallei, K96243 and MSHR5855, were also compared using AGMs. These three B. pseudomallei strains represent a highly virulent strain from Thailand (HBPUB101034a), a highly virulent strains from Australia (MSHR5855), and a commonly used laboratory strains originating from Thailand (K96243). Animals were observed for clinical signs of infection and blood samples were analyzed for cytokine responses, blood chemistry and leukocyte changes in order to characterize bacterial infection. AGMs experienced fever after exposure to aerosolized B. pseudomallei at the onset of acute disease. Inflammation, abscesses and/or pyogranulomas were observed in lung with all three strains of B. pseudomallei. Inflammation, abscesses and/or pyogranulomas were observed in lymph nodes, spleen, liver and/or kidney with B. pseudomallei, HBPUB10134a and K96243. Additionally, the Australian strain MSHR5855 induced brain lesions in one AGM similar to clinical cases of melioidosis seen in Australia. Elevated serum levels of IL-1β, IL-1 receptor antagonist, IL-6, MCP-1, G-CSF, HGF, IFNγ, MIG, I-TAC, and MIP-1β at terminal end points can be significantly correlated with non-survivors with B. pseudomallei infection in AGM. The AGM model represents an acute model of B. pseudomallei infection for all three strains from two geographical locations and will be useful for efficacy testing of vaccines and therapeutics against melioidosis. In summary, a dysregulated immune response leading to excessive persistent inflammation and inflammatory cell death is the key driver of acute melioidosis. Early intervention in these pathways will be necessary to counter B. pseudomallei and mitigate the pathological consequences of melioidosis.

Authors+Show Affiliations

Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Biostatistics Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Pathology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Pathology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

33571211

Citation

Trevino, Sylvia R., et al. "Comparative Virulence of Three Different Strains of Burkholderia Pseudomallei in an Aerosol Non-human Primate Model." PLoS Neglected Tropical Diseases, vol. 15, no. 2, 2021, pp. e0009125.
Trevino SR, Dankmeyer JL, Fetterer DP, et al. Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model. PLoS Negl Trop Dis. 2021;15(2):e0009125.
Trevino, S. R., Dankmeyer, J. L., Fetterer, D. P., Klimko, C. P., Raymond, J. L. W., Moreau, A. M., Soffler, C., Waag, D. M., Worsham, P. L., Amemiya, K., Ruiz, S. I., Cote, C. K., & Krakauer, T. (2021). Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model. PLoS Neglected Tropical Diseases, 15(2), e0009125. https://doi.org/10.1371/journal.pntd.0009125
Trevino SR, et al. Comparative Virulence of Three Different Strains of Burkholderia Pseudomallei in an Aerosol Non-human Primate Model. PLoS Negl Trop Dis. 2021;15(2):e0009125. PubMed PMID: 33571211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model. AU - Trevino,Sylvia R, AU - Dankmeyer,Jennifer L, AU - Fetterer,David P, AU - Klimko,Christopher P, AU - Raymond,Jo Lynne W, AU - Moreau,Alicia M, AU - Soffler,Carl, AU - Waag,David M, AU - Worsham,Patricia L, AU - Amemiya,Kei, AU - Ruiz,Sara I, AU - Cote,Christopher K, AU - Krakauer,Teresa, Y1 - 2021/02/11/ PY - 2020/06/16/received PY - 2021/01/11/accepted PY - 2021/02/24/revised PY - 2021/2/12/pubmed PY - 2021/6/23/medline PY - 2021/2/11/entrez SP - e0009125 EP - e0009125 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 15 IS - 2 N2 - Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. B. pseudomallei is a potential bioterrorism agent due to its high infectivity, especially via inhalation, and its inherent resistance to antimicrobials. There is currently no vaccine for melioidosis and antibiotic treatment can fail due to innate drug resistance, delayed diagnosis and treatment, or insufficient duration of treatment. A well-characterized animal model that mimics human melioidosis is needed for the development of new medical countermeasures. This study first characterized the disease progression of melioidosis in the African green monkey (AGM) and rhesus macaque (RM) for non-human primate model down-selection. All AGMs developed acute lethal disease similar to that described in human acute infection following exposure to aerosolized B. pseudomallei strain HBPUB10134a. Only 20% of RMs succumbed to acute disease. Disease progression, immune response and pathology of two other strains of B. pseudomallei, K96243 and MSHR5855, were also compared using AGMs. These three B. pseudomallei strains represent a highly virulent strain from Thailand (HBPUB101034a), a highly virulent strains from Australia (MSHR5855), and a commonly used laboratory strains originating from Thailand (K96243). Animals were observed for clinical signs of infection and blood samples were analyzed for cytokine responses, blood chemistry and leukocyte changes in order to characterize bacterial infection. AGMs experienced fever after exposure to aerosolized B. pseudomallei at the onset of acute disease. Inflammation, abscesses and/or pyogranulomas were observed in lung with all three strains of B. pseudomallei. Inflammation, abscesses and/or pyogranulomas were observed in lymph nodes, spleen, liver and/or kidney with B. pseudomallei, HBPUB10134a and K96243. Additionally, the Australian strain MSHR5855 induced brain lesions in one AGM similar to clinical cases of melioidosis seen in Australia. Elevated serum levels of IL-1β, IL-1 receptor antagonist, IL-6, MCP-1, G-CSF, HGF, IFNγ, MIG, I-TAC, and MIP-1β at terminal end points can be significantly correlated with non-survivors with B. pseudomallei infection in AGM. The AGM model represents an acute model of B. pseudomallei infection for all three strains from two geographical locations and will be useful for efficacy testing of vaccines and therapeutics against melioidosis. In summary, a dysregulated immune response leading to excessive persistent inflammation and inflammatory cell death is the key driver of acute melioidosis. Early intervention in these pathways will be necessary to counter B. pseudomallei and mitigate the pathological consequences of melioidosis. SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/33571211/Comparative_virulence_of_three_different_strains_of_Burkholderia_pseudomallei_in_an_aerosol_non_human_primate_model_ L2 - https://dx.plos.org/10.1371/journal.pntd.0009125 DB - PRIME DP - Unbound Medicine ER -