Lipid abnormalities and hepatic dysfunction associated with Yersinia pestis infection in non‐human primate model

Abstract

Aerosolized Yersinia pestis causes pneumonic plague and is a highly virulent form of the infection. When left untreated, the fatality rate is very high, and survivors can suffer from complex clinical consequences. The exact mechanisms of disease progression are presently unclear. In this study, we used metabolite profiling to gain mechanistic insight into the progression of the disease. African green monkeys (Chlorocebus sabaeus) were challenged with the highly virulent Y. pestis strain CO92 by the aerosol route, plasma samples were obtained, and untargeted metabolomics profiling of plasma was performed using both liquid and gas chromatography with mass spectrometry. At early time points post‐exposure (6–18 h), we found increases in the abundance of certain polyunsaturated fatty acids, long chain fatty acids, carnitines, and dicarboxylate fatty acids in exposed animals when compared to their time‐matched control samples. The metabolites from lysolipids and bile acid metabolism pathways were lower in exposed animals when compared to their time‐matched controls during the entire course of infection. Many of the metabolites from amino acid pathways were perturbed, and a few from the leucine, isoleucine, and valine pathways were elevated during the course of infection, whereas metabolites from the urea cycle, arginine, and proline pathways were lower. The presence of branched chain amino acids in plasma, in addition to mobilization of fatty acids for subsequent β‐oxidation, indicated an increased energy demand. The involvement of several lipid pathways post‐infection suggested that there was activation of biological pathways linked to inflammation and oxidative stress. Enrichment analysis indicated perturbations in the bile acid pathway during the entire course of infection along with multiple metabolites that may have involvement in liver function indicating potential hepatic dysfunction. Integration of metabolomics and transcriptomics data from blood identified linoleate as a core metabolite with cross‐talk with multiple genes from various time points. Collectively, the data from this study provided new insights into the mechanisms of Y. pestis pathogenesis and into the host‐pathogen interactions that shape the outcome of the infection.Disclaimers: Research was conducted in compliance with the Animal Welfare Act, and all other Federal requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.Support or Funding InformationFunding Support from DTRA is highly acknowledgedThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.