Proteomic Analysis of Non-human Primate Peripheral Blood Mononuclear Cells During Burkholderia mallei Infection Reveals a Role of Ezrin in Glanders Pathogenesis
| Autor: | Chih-Yuan Chiang, Christopher K. Cote, Yang Zhong, Rekha G. Panchal, Raysa Rosario-Acevedo, David M. Waag, Lisa H. Cazares, Yingyao Zhou, Taylor B. Chance, Patricia L. Worsham, Sylvia R. Trevino, Douglas Lane, Michael D. Ward, Tara Kenny, Brett P. Eaton, Richard T. Moore, Meghan Hu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Chemokine 030106 microbiology biothreat agent Cytoskeletal protein binding Peripheral blood mononuclear cell Burkholderia mallei Microbiology 03 medical and health sciences proteomics inflammatory responses medicine innate immunity Innate immune system biology Glanders medicine.disease biology.organism_classification QR1-502 Intracellular signal transduction 030104 developmental biology glanders Nucleoside metabolic process biology.protein |
| Zdroj: | Frontiers in Microbiology, Vol 12 (2021) |
| DOI: | 10.3389/fmicb.2021.625211/full |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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