AUTHOR=Chiang Chih-Yuan , Zhong Yang , Ward Michael D. , Lane Douglas J. , Kenny Tara , Rosario-Acevedo Raysa , Eaton Brett P. , Treviño Sylvia R. , Chance Taylor B. , Hu Meghan , Worsham Patricia L. , Waag David M. , Moore Richard T. , Cazares Lisa H. , Cote Christopher K. , Zhou Yingyao , Panchal Rekha G. 

TITLE=Proteomic Analysis of Non-human Primate Peripheral Blood Mononuclear Cells During Burkholderia mallei Infection Reveals a Role of Ezrin in Glanders Pathogenesis

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.625211

DOI=10.3389/fmicb.2021.625211

ISSN=1664-302X

ABSTRACT=<p><italic>Burkholderia mallei</italic>, 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. <italic>B. mallei</italic> 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 <italic>B. mallei</italic> infection, have been observed in <italic>in vitro</italic> 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 (<italic>Macaca mulatta</italic>), African green monkeys (<italic>Chlorocebus sabaeus</italic>), and cynomolgus macaques (<italic>Macaca fascicularis</italic>) exposed to aerosolized <italic>B. mallei</italic>. 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 <italic>B. mallei</italic> 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 <italic>B. mallei</italic> 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 <italic>B. mallei</italic> infections in the NHP model.</p>