Abstract
Burkholderia mallei, the causative agent of glanders, is a gram-negative intracellular bacterium. Depending on different routes of infection, the disease is manifested by pneumonia, septicemia, and chronic infections of the skin. B. mallei poses a serious biological threat due to its ability to infect via aerosol route, resistance to multiple antibiotics and to date there are no US Food and Drug Administration (FDA) approved vaccines available. Induction of innate immunity, inflammatory cytokines and chemokines following B. mallei infection, have been observed in in vitro and small rodent models; however, a global characterization of host responses has never been systematically investigated using a non-human primate (NHP) model. Here, using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we identified alterations in expression levels of host proteins in peripheral blood mononuclear cells (PBMCs) originating from naïve rhesus macaques (Macaca mulatta), African green monkeys (Chlorocebus sabaeus), and cynomolgus macaques (Macaca fascicularis) exposed to aerosolized B. mallei. Gene ontology (GO) analysis identified several statistically significant overrepresented biological annotations including complement and coagulation cascade, nucleoside metabolic process, vesicle-mediated transport, intracellular signal transduction and cytoskeletal protein binding. By integrating an LC-MS/MS derived proteomics dataset with a previously published B. mallei host-pathogen interaction dataset, a statistically significant predictive protein-protein interaction (PPI) network was constructed. Pharmacological perturbation of one component of the PPI network, specifically ezrin, reduced B. mallei mediated interleukin-1β (IL-1β). On the contrary, the expression of IL-1β receptor antagonist (IL-1Ra) was upregulated upon pretreatment with the ezrin inhibitor. Taken together, inflammasome activation as demonstrated by IL-1β production and the homeostasis of inflammatory response is critical during the pathogenesis of glanders. Furthermore, the topology of the network reflects the underlying molecular mechanism of B. mallei infections in the NHP model.
Highlights
Burkholderia mallei, a gram-negative intracellular bacterium, is the etiological agent of glanders
While Non-human primates (NHPs) species such as the African green monkey, the rhesus macaque, and the cynomolgus macaque have been successfully used as animal models that mimic human infections for biothreat agents such as Yersinia pestis, Bacillus anthracis, and Coxiella burnetti, there is few data on the clinical course of aerosolized B. mallei infections in NHP’s (Henning et al, 2012; Hammamieh et al, 2016; Gregory et al, 2019)
By utilizing the LC-MS/MS approach, we identified host proteins with altered expression in PBMCs obtained from rhesus macaques, African green monkeys and cynomolgus macaques exposed to B. mallei infection
Summary
Burkholderia mallei, a gram-negative intracellular bacterium, is the etiological agent of glanders. Personnel who work in close proximity with infected animals or manipulate the organism in laboratory settings are at risk of exposure. Treatment of glanders usually involves extended regimens of multiple antibiotics (Lipsitz et al, 2012). Given that B. mallei is resistant to multiple antibiotics, elicits both acute and chronic infection and could potentially be used as a bioweapon, it is categorized a Tier 1 select biological agent by both the US Department of Health and Human Services and the US Department of Agriculture. Better understanding of the disease progression and host-pathogen interactions using proteomic analysis, in a well-characterized animal model such as Non-human primates (NHPs), which closely mimic human infection, is critical
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