title: 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.
  
  
  OBJECTIVE
  Old 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.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tchitchek
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
authors.forename: David
authors.initials: D
authors.lastname: Safronetz
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Carter
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Williams
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Haddock
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, Seattle, Washington, USA honey@uw.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D016923:Cell Death; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006482:Hemorrhagic Fevers, Viral / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D007249:Inflammation / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D007835:Lassa Fever / Q000473:pathology / Q000821:virology; D007836:Lassa virus / Q000472:pathogenicity; D007963:Leukocytes, Mononuclear / Q000276:immunology; D063927:Lujo virus / Q000472:pathogenicity*; D008252:Macaca fascicularis; D013997:Time Factors