Differential Responses of Disease-Resistant and Disease-Susceptible Primate Macrophages and Myeloid Dendritic Cells to Simian Hemorrhagic Fever Virus Infection

Abstract

Simian hemorrhagic fever virus (SHFV) causes a fatal hemorrhagic fever in macaques but an asymptomatic, persistent infection in baboons. To investigate factors contributing to this differential infection outcome, the targets of SHFV infection, macrophages (M⌽s) and myeloid dendritic cells (mDCs), were differentiated from macaque and baboon peripheral blood monocytes and used to compare viral replication and cell responses. SHFV replicated in >90% of macaque M⌽s but in only ϳ10% of baboon M⌽s. Although SHFV infected ϳ50% of macaque and baboon mDCs, virus replication was efficient in macaque but not in baboon mDCs. Both types of macaque cultures produced higher virus yields than baboon cultures. A more efficient type I interferon response and the production of proinflammatory cytokines, including interleukin-1␤ (IL-1␤), IL-6, IL-12/23(p40), tumor necrosis factor alpha (TNF-␣), and macrophage inflammatory protein 1␣ (MIP-1␣), in response to SHFV infection were observed in macaque but not baboon cultures, suggesting less efficient counteraction of these responses by viral proteins in macaque cells. Baboon cultures produced higher levels of IL-10 than macaque cultures both prior to and after SHFV infection. In baboon but not macaque cell cultures, SHFV infection upregulated IL-10R1, a subunit of the IL-10 receptor (IL-10R), and also SOCS3, a negative regulator of proinflammatory cytokine production. Incubation of macaque cultures with human IL-10 before and/or after SHFV infection decreased production of IL-6, IL-1␤, and MIP-1␣ but not TNF-␣, suggesting a role for IL-10 in suppressing SHFV-induced proinflammatory cytokine production in macaques.

Two Novel Simian Arteriviruses in Captive and Wild Baboons (Papio spp.)

“…Importantly, simian arterivirus infection has never been demonstrated in a free-living patas monkey, and monkeys from the two species known to harbor simian arteriviruses in nature, the red colobus (Procolobus rufomitratus tephrosceles) and the red-tailed guenon (Cercopithecus ascanius schmidti), were not associated with past outbreaks of SHF in macaques (2,13,14). Grivets (Chlorocebus aethiops) and baboons (genus Papio) have long been suspected of harboring simian arteriviruses in captivity, but empirical evidence demonstrating infection of these hosts, either in the wild or in captivity, has, to our knowledge, never been presented (6,15).…”

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

“…Patas monkeys did not react with IL-6 concentration increases to SHFV infection, whereas increased IL-6 concentrations in SHFV infected rhesus were observed in this experiment and have been previously reported ( 10 , 13 , 14 ). This difference is of particular interest as IL-6 has been associated with non-survival in SHFV-infected rhesus monkeys, and because decreased concentrations of IL-6 were seen in in vitro infection of monocyte-derived macrophages and dendritic cells from baboons ( 13 , 15 ). Given the potential role of IL-6 in human VHFs, our model offers an opportunity to explore the potential of therapies, such as neutralizing antibodies, aimed at modulating IL-6 responses during infection.…”

“…The virus is highly virulent in rhesus monkeys ( Macaca mulatta ), crab-eating macaques ( Macaca fasicularis ), stump-tailed macaques ( Macaca arctoides ), and Japanese macaques ( Macaca fuscata ), but SHFV causes little to no disease in African primates such as patas monkeys or baboons ( 11 , 13 , 14 ). SHFV infection in macaques mirrors aspects of human VHFs, such as Ebola virus disease, by inducing fever, edema, coagulopathy, hepatocellular degeneration and necrosis, and elevated inflammatory cytokine concentrations ( 13–15 ). Like all VHFs, simian hemorrhagic fever (SHF) is thought to be driven by a dysregulated host-response leading to a dysregulated immune response and poor viral clearance ( 13 , 14 , 16 ).…”

Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys

“…In DMVV-1-infected animals, we found mildly elevated concentrations of several proinflammatory cytokines that are produced by activated macrophages, including IL-1␤, GM-CSF, MIP-1␤, EGF, MCP-1, and TNF-␣. Although these associations did not reach statistical significance, this pattern of cytokine associations is biologically intriguing: macrophages support the replication of simian hemorrhagic fever virus (SHFV) (the simian arterivirus type strain) in vitro and are thought to be the primary cell type infected by simian arteriviruses in vivo, as has been shown for other nonsimian arteriviruses (34,56). Additionally, increased expression of IL-10, an anti-inflammatory cytokine which we also found to have elevated levels in DMVV-1-infected vervets (albeit to nonsignificant levels), is associated with a reduction in virulence for both simian and nonsimian arteriviruses (56)(57)(58).…”

“…Although these associations did not reach statistical significance, this pattern of cytokine associations is biologically intriguing: macrophages support the replication of simian hemorrhagic fever virus (SHFV) (the simian arterivirus type strain) in vitro and are thought to be the primary cell type infected by simian arteriviruses in vivo, as has been shown for other nonsimian arteriviruses (34,56). Additionally, increased expression of IL-10, an anti-inflammatory cytokine which we also found to have elevated levels in DMVV-1-infected vervets (albeit to nonsignificant levels), is associated with a reduction in virulence for both simian and nonsimian arteriviruses (56)(57)(58). Macaques infected with SHFV have increased plasma concentrations of proinflammatory cytokines but not increased levels of IL-10, possibly suggesting that IL-10 may be a host factor that protects African monkeys from simian arterivirus pathogenesis and SHF (59,60).…”