Characterization of the plasma proteome of nonhuman primates during Ebola virus disease or melioidosis: a host response comparison

Michael D Ward,Ernst E Brueggemann,Raven E Reitstetter,Kelly Wetzel,Sina Bavari,Cary Retterer,Lisa H Cazares,Robert B Norgren,Travis K Warren,Ginger C Donnelly,Rekha G Panchal,Christopher R Mahone,Sylvia Trevino,Tara Kenny

doi:10.1186/s12014-019-9227-3

Abstract

BackgroundIn-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host’s immunological and physiological responses. Ebola virus (EBOV) causes a highly lethal infection termed Ebola virus disease (EVD) in primates and humans. The Gram negative non-spore forming bacillus Burkholderia pseudomallei (Bp) causes melioidosis in primates and humans, characterized by severe pneumonia with high mortality. We sought to examine the host response to infection with these two bio-threat pathogens using established animal models to provide information on the feasibility of pre-symptomatic diagnosis, since the induction of host molecular signaling networks can occur before clinical presentation and pathogen detection.MethodsHerein we report the quantitative proteomic analysis of plasma collected at various times of disease progression from 10 EBOV-infected and 5 Bp-infected nonhuman primates (NHP). Our strategy employed high resolution LC–MS/MS and a peptide-tagging approach for relative protein quantitation. In each infection type, for all proteins with > 1.3 fold abundance change at any post-infection time point, a direct comparison was made with levels obtained from plasma collected daily from 5 naïve rhesus macaques, to determine the fold changes that were significant, and establish the natural variability of abundance for endogenous plasma proteins.ResultsA total of 41 plasma proteins displayed significant alterations in abundance during EBOV infection, and 28 proteins had altered levels during Bp infection, when compared to naïve NHPs. Many major acute phase proteins quantitated displayed similar fold-changes between the two infection types but exhibited different temporal dynamics. Proteins related to the clotting cascade, immune signaling and complement system exhibited significant differential abundance during infection with EBOV or Bp, indicating a specificity of the response.ConclusionsThese results advance our understanding of the global plasma proteomic response to EBOV and Bp infection in relevant primate models for human disease and provide insight into potential innate immune response differences between viral and bacterial infections.

Highlights

In-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host’s immunological and physiological responses
Intramuscular infection of rhesus macaques with 1000 plaque-forming units (PFU) of Ebola virus (EBOV) resulted in all nonhuman primates (NHP) becoming febrile between Days 3–5 PI and mortality occurred between Days 6 and 9 PI
Our approach to the characterization of the rhesus macaque plasma host response to infection is novel in comparison with other studies because we have 1) sampled naïve NHP to better define the variability of acute phase proteins during the sampling period, and 2) compared the rhesus proteomic response in two different infection types (EVD vs. melioidosis)

Summary

Introduction

In-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host’s immunological and physiological responses. Ebola virus (EBOV) causes a highly lethal infection termed Ebola virus disease (EVD) in primates and humans. We sought to examine the host response to infection with these two bio-threat pathogens using established animal models to provide information on the feasibility of pre-symptomatic diagnosis, since the induction of host molecular signaling networks can occur before clinical presentation and pathogen detection. Ebola virus (EBOV) causes a highly virulent systemic disease, Ebola virus disease (EVD) that results in hemorrhagic fever (in both primates and humans) with high fatality rates. The general symptomatic profile of EVD resembles that of malaria, yellow fever, Lassa fever and typhoid fever, which are endemic to SubSaharan Africa, complicating diagnosis and containment efforts [3]. NHP models of EBOV infection have provided the most informative data related to the pathology and host response. Lymphopenia, thrombocytopenia, neutrophilia and coagulopathy develop as EVD progresses [7, 8] along with a pro-inflammatory cytokine/ chemokine response [9]

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