Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model

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 with 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.

Evaluation of two different vaccine platforms for immunization against melioidosis and glanders

“…The vaccines were prepared and administered to C57BL/6 mice in accordance with the scheme described for the preceding study. We chose to use the MSHR5855 strain in these studies so that we could evaluate the vaccine efficacy in a clinical isolate from Northern Australia with documented neurological involvement in non-human primates (Trevino et al, 2021 ). This is in contrast with the K96243 isolate, a common laboratory stain that was originally a clinical isolate from Thailand.…”

Marmosets as models of infectious diseases

“…Two studies (model development and characterization and therapeutic efficacy) Mouse, Guinea pigs, Rabbits, Cynomolgus monkey (Lever et al, 2008;Nelson et al, 2011b;Ben-Shmuel et al, 2018;Perry et al, 2020;Stratilo et al, 2020 Mouse, Goats, African green monkey, Rhesus monkey, Invertebrates (Woods, 2002;Nelson et al, 2011a;Rowland et al, 2012a;Soffler et al, 2012;Laws et al, 2013;Nelson et al, 2015;Ganesan et al, 2020;Nelson et al, 2021;Trevino et al, 2021;Nelson et al, 2022a;Ngugi et al, 2022)…”

Detection of low-level animal-to-animal transmission in BALB/c mouse models of melioidosis

“…Most patients have coexisting risk factors for the disease including diabetes, excessive alcohol use, chronic lung or renal disease, and other immunocompromising conditions (Currie et al, 2010;Currie, 2015;Limmathurotsakul et al, 2016;Dance and Limmathurotsakul, 2018;Wiersinga et al, 2018;Kaewrakmuk et al, 2023). Several animal models have been developed to study the pathogenesis of melioidosis (Leakey et al, 1998;Conejero et al, 2011;Limmathurotsakul et al, 2015;Welkos et al, 2015;Amemiya et al, 2017;Bearss et al, 2017;Trevino et al, 2018;Trevino et al, 2021;Nelson et al, 2023). The BALB/c is a highly susceptible strain of mice and is typically used to model acute melioidosis; in contrast, the C57BL/6 mouse strain is significantly more resistant, representing a more chronic model of disease which is often used for vaccine evaluation (Leakey et al, 1998;Tan et al, 2008;Lever et al, 2009;Srisurat et al, 2010;Conejero et al, 2011;Massey et al, 2014;Amemiya et al, 2017;Bearss et al, 2017;Trevino et al, 2018;Funnell et al, 2019;Nelson et al, 2023).…”