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

Abstract

225/250 28 ARTICLE: 4729/5000 29 ABSTRACT Simian hemorrhagic fever virus (SHFV) causes a fulminant and typically 30 lethal viral hemorrhagic fever (VHF) in macaques (Cercopithecinae: Macaca spp.) but 31 causes subclinical infections in patas monkeys (Cercopithecinae: Erythrocebus patas). 32 This difference in disease course offers a unique opportunity to compare host-33 responses to infection by a VHF-causing virus in biologically similar susceptible and 34 refractory animals. Patas and rhesus monkeys were inoculated side-by-side with SHFV. 35 In contrast to the severe disease observed in rhesus monkeys, patas monkeys 36 developed a limited clinical disease characterized by changes in complete blood counts, 37 serum chemistries, and development of lymphadenopathy. Viremia was measurable 2 38 days after exposure and its duration varied by species. Infectious virus was detected in 39 terminal tissues of both patas and rhesus monkeys. Varying degrees of overlap in 40 changes in serum concentrations of IFN-γ, MCP-1, and IL-6 were observed between 41 patas and rhesus monkeys, suggesting the presence of common and species-specific 42 cytokine responses to infection. Similarly, quantitative immunohistochemistry of terminal 43 livers and whole blood flow cytometry revealed varying degrees of overlap in changes in 44 macrophages, natural killer cells, and T-cells. The unexpected degree of overlap in 45 host-response suggests that relatively small subsets of a host's response to infection 46 may be responsible for driving pathogenesis that results in a hemorrhagic fever. 47 Furthermore, comparative SHFV infection in patas and rhesus monkeys offers an 48 experimental model to characterize host-response mechanisms associated with viral 49 hemorrhagic fever and evaluate pan-viral hemorrhagic fever countermeasures. 50 IMPORTANCE Host-response mechanisms involved in pathogenesis of VHFs remain 51 poorly understood. An underlying challenge is separating beneficial, inconsequential, 52 and detrimental host-responses during infection. The comparison of host-responses to 53 infection with the same virus in biologically similar animals that have drastically different 54 disease manifestations allows for the identification of pathogenic mechanisms. SHFV, a 55 surrogate virus for human VHF-causing viruses likely causes subclinical infection in 56 African monkeys such as patas monkeys but can cause severe disease in Asian 57 macaque monkeys. Data from the accompanying article by Buechler et al. support that 58 infection of macaques and baboons with non-SHFV simarteviruses can establish 59 persistent or long-term subclinical infections. Baboons, macaques, and patas monkeys 60 are relatively closely taxonomically related (Cercopithecidae: Cercopithecinae) and 61 therefore offer a unique opportunity to dissect how host-response differences determine 62 disease outcome in VHFs.63