Clinical Characterization of Host Response to Simian Hemorrhagic Fever Virus Infection in Permissive and Refractory Hosts: A Model for Determining Mechanisms of VHF Pathogenesis.

Jens Kuhn,Connor Buechler,Donna Perry,Kurt Cooper,Adam Bailey,Monica Paneru,John Bernbaum,David O’Connor,Dominique Promeneur,Mahnaz Minai,James Pettitt,Peter Jahrling,Ian Moore,Reed Johnson,Katie Hagen,Joseph Cornish,Kimmo Virtaneva,Steven Mazur,Abigail Lara

doi:10.3390/v11010067

Abstract

Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). This difference in disease course offers a unique opportunity to compare host responses to infection by a VHF-causing virus in biologically similar susceptible and refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. Unlike the severe disease observed in rhesus monkeys, patas monkeys developed a limited clinical disease characterized by changes in complete blood counts, serum chemistries, and development of lymphadenopathy. Viral RNA was measurable in circulating blood 2 days after exposure, and its duration varied by species. Infectious virus was detected in terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in changes in serum concentrations of interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 were observed between patas and rhesus monkeys, suggesting the presence of common and species-specific cytokine responses to infection. Similarly, quantitative immunohistochemistry of livers from terminal monkeys and whole blood flow cytometry revealed varying degrees of overlap in changes in macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in host response suggests that relatively small subsets of a host’s response to infection may be responsible for driving hemorrhagic fever pathogenesis. Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an experimental model to characterize host–response mechanisms associated with viral hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures.

Highlights

Viral hemorrhagic fevers (VHFs) are primarily caused by single-stranded RNA viruses [1].viral hemorrhagic fever (VHF) is a broadly defined syndrome: fever, hepatic and renal complications, large increases in proinflammatory cytokines, and coagulopathy are common features [2,3]
The three Simian hemorrhagic fever virus (SHFV)-inoculated patas monkeys developed axillary and inguinal lymphadenopathy starting on day 10 PI that persisted until the conclusion of the experiment at 21 days PI
ALP, AST, and GGT concentrations remained elevated in the surviving SHFV-inoculated rhesus monkey until the conclusion of the experiment, whereas ALT returned to baseline concentrations

Summary

Introduction

Viral hemorrhagic fevers (VHFs) are primarily caused by single-stranded RNA viruses [1].VHF is a broadly defined syndrome: fever, hepatic and renal complications, large increases in proinflammatory cytokines, and coagulopathy are common features [2,3]. Viral hemorrhagic fevers (VHFs) are primarily caused by single-stranded RNA viruses [1]. Simian hemorrhagic fever virus (SHFV) is a positive-sense, single-stranded RNA virus classified in the family Arteriviridae, which includes equine arteritis virus and porcine reproductive and respiratory syndrome viruses. SHFV, simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV) are known to cause severe disease in Asian macaques of various species [9]. Kibale red colobus virus 1 (KRCV-1) was found to cause a self-limiting disease in crab-eating macaques (Macaca fascicularis) [10]. It is not known whether the other identified simarteriviruses infect or cause disease in macaques or their natural hosts. In combination with an article by Buechler et al [11], we examine infection of natural hosts (patas monkeys [Erythrocebus patas] and olive baboons [Papio anubis]) of simarteriviruses and compare disease course of these simarteriviruses in rhesus monkeys (Macaca mulatta)

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