Characterization of lesion formation in marmosets following inhalational challenge with different strains of <i>Burkholderia pseudomallei</i>

Nelson, Michelle; Núñez, Alejandro; Ngugi, Sarah A.; Sinclair, Adam; Atkins, Timothy P.

doi:10.1111/iep.12161

Cited by 16 publications

(26 citation statements)

References 21 publications

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“…While we chose to examine AGM and RM, an alternative NHP model using common marmosets ( Callithrix Jacchus ) has been described in the literature [ 37 , 39 ]. Marmosets are exquisitely sensitive to many infections and the same was observed for infection with B .…”

Section: Discussionmentioning

confidence: 99%

“…pseudomallei were compared in various murine models of infection [ 26 – 30 ], few comparative studies address the virulence of clinical isolates from diverse geographical locations in NHP models of infection. Isolates from different geographical regions display phylogenetic differences [ 38 ] as well as lethality and pathogenicity profiles in animal models of melioidosis [ 27 – 30 , 39 ]. This study further compares the virulence of three different isolates of B .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Currently most MCMs for melioidosis are evaluated in animal models for their effectiveness against acute disease; the mouse model being the most widely used (Warawa, ) although larger animal models have been evaluated for instance: Rhesus macaques (Yingst, Facemire et al . 2014); African Green monkeys (Yeager et al ) and marmosets (Nelson et al ; Nelson et al ; Nelson et al ). Aerosolized doses of <10 CFU per animal B. pseudomallei NCTC 13392 caused a lethal infection by day 3–4 in marmosets, indicating these animals are highly susceptible to this strain (Nelson et al ; Erratum, ).…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependant acute or subacute disease caused byBurkholderia pseudomalleistrain NCTC 13392 in a BALB/c aerosol model of infection

et al. 2019

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Aims The goal of this study was to examine, for the first time, the virulence and pathogenicity of aerosolized Burkholderia pseudomallei, strain NCTC 13392, in BALB/c mice in order to develop an animal model for testing novel medical countermeasures (MCMs) for the treatment of human acute and subacute (a disease state between acute and chronic) melioidosis. Methods and Results BALB/c mice were exposed to varying doses of aerosolized bacteria. Acute disease was seen in animals exposed to a very‐high dose (≥103 CFU per animal) and death occurred 3–4 days postchallenge (pc). Bacteria were detected in the lungs, liver, kidney and spleen. In contrast, animals exposed to a low dose (<10 CFU per animal) survived to the end of the study (day 30 pc) but developed weight loss, a bacterial tissue burden and increasing clinical signs of infection from day 20 pc onwards, mimicking a subacute form of the disease. Pathological changes in the tissues mirrored these findings. Conclusions This proof of concept study has shown that B. pseudomallei strain NCTC 13392 is virulent and pathogenic in BALB/c mice, when delivered by aerosol. By varying the doses of aerosolized bacteria it was possible to mimic characteristics of both human acute and subacute melioidosis, at the same time, within the same study. Significance and Impact of the Study Burkholderia pseudomallei, the aetiological agent of melioidosis, causes a serious and often fatal disease in humans and animals. Novel MCMs are urgently needed for both public health and biodefense purposes. The present model provides a useful tool for the assessment and evaluation of new MCMs (e.g. therapeutics and vaccines) and offers the potential for testing new treatments for both subacute to chronic and acute melioidosis prior to human clinical trials.

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“…B . pseudomallei 1026b was originally isolated in 1993, and has since become a commonly used isolate for inhalation studies using animal models of melioidosis [ 26 , 32 – 36 ]. The day prior to an experiment, 200 μL of thawed single use frozen aliquots of B .…”

Section: Methodsmentioning

confidence: 99%

“…AGIs were selected for evaluation as they are a common collection device utilized in many published studies with B . pseudomallei [ 21 – 24 , 26 , 27 , 31 – 33 ]. Midget impingers were selected as a liquid sampler with the potential for more gentle collection than the AGI.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of four sampling devices for Burkholderia pseudomallei laboratory aerosol studies

et al. 2021

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Previous field and laboratory studies investigating airborne Burkholderia pseudomallei have used a variety of different aerosol samplers to detect and quantify concentrations of the bacteria in aerosols. However, the performance of aerosol samplers can vary in their ability to preserve the viability of collected microorganisms, depending on the resistance of the organisms to impaction, desiccation, or other stresses associated with the sampling process. Consequently, sampler selection is critical to maximizing the probability of detecting viable microorganisms in collected air samples in field studies and for accurate determination of aerosol concentrations in laboratory studies. To inform such decisions, the present study assessed the performance of four laboratory aerosol samplers, specifically the all-glass impinger (AGI), gelatin filter, midget impinger, and Mercer cascade impactor, for collecting aerosols containing B. pseudomallei generated from suspensions in two types of culture media. The results suggest that the relative performance of the sampling devices is dependent on the suspension medium utilized for aerosolization. Performance across the four samplers was similar for aerosols generated from suspensions supplemented with 4% glycerol. However, for aerosols generated from suspensions without glycerol, use of the filter sampler or an impactor resulted in significantly lower estimates of the viable aerosol concentration than those obtained with either the AGI or midget impinger. These results demonstrate that sampler selection has the potential to affect estimation of doses in inhalational animal models of melioidosis, as well as the likelihood of detection of viable B. pseudomallei in the environment, and will be useful to inform design of future laboratory and field studies.

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Characterization of lesion formation in marmosets following inhalational challenge with different strains of Burkholderia pseudomallei

Cited by 16 publications

References 21 publications

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

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

Dose‐dependant acute or subacute disease caused byBurkholderia pseudomalleistrain NCTC 13392 in a BALB/c aerosol model of infection

Evaluation of four sampling devices for Burkholderia pseudomallei laboratory aerosol studies

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