Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques

Abstract

To identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development. IMPORTANCEOld World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus-infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens. Since their discovery in the early 20th century, arenaviruses have been consistently associated with outbreaks of severe illness, including viral hemorrhagic fever (VHF) and encephalitis. Arenaviruses are bisegmented, ambisense, single-stranded, negative-sense RNA viruses t...

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

“…Animals are leukopenic, have a slight decrease in platelet counts, and are consistent with liver involvement, raised liver enzymes (ALT and AST). Cynomolgus macaques exposed to LASV (Josiah or Z-132) have a similar clinical presentation, with the exception that facial edema was a prominent early sign and some neurological manifestations were observed [ 101 , 115 , 120 , 157 ]. However, not all cases of NHP infection by human pathogenic OW arenaviruses represent a transcript of the human disease.…”

“…However, not all cases of NHP infection by human pathogenic OW arenaviruses represent a transcript of the human disease. LUJV, lethal in 4 of 5 human cases, produced only mild illness in cynomolgus macaques [ 120 ]. Similarly, LASV isolated from a fatal case (strain AV) had an alternative disease course and failed to produce uniformly fatal disease in NHPs [ 160 ].…”

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

“…NK cell responses are important for survival in human Ebola virus disease cases ( 28 , 29 ). Differences in the timing of NK cell responses are a key difference in non-lethal, mild disease and lethal, severe (Lassa virus) infections in macaques ( 30 ), suggesting the species-specific NK cell responses observed here warrant further exploration. For comparison, and as described in the accompanying paper by Buechler et al ., olive baboons and rhesus monkeys infected with SWBV-1 also developed increases in NK and CD8 + T-cell numbers, with CD8 + T-cell numbers remaining elevated through the observation period.…”

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

“…NK cell responses are important for survival in human Ebola virus disease cases [29,30]. Differences in the timing of NK cell responses are also a key difference in non-lethal, mild disease and lethal, severe Lassa virus infections in macaques [31], suggesting the species-specific NK cell responses observed here warrant further exploration. For comparison, and as described in the recent paper by Buechler et al [11], olive baboons and rhesus monkeys infected with the SHFV-related Southwest baboon virus 1 (SWBV-1) also developed increases in NK and CD8 + T-cell numbers, with CD8 + T-cell frequency remained elevated throughout the observation period.…”