Title: Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families

Abstract

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) is a host protein with reported cell-intrinsic antiviral activity against several RNA viruses. The proposed basis for the activity against negative-sense RNA viruses is the binding to exposed 5'-triphosphates (5'-ppp) on the genome of viral RNA. However, recent studies reported relatively low binding affinities of IFIT1 for 5;-ppp RNA, suggesting that IFIT1 may not interact efficiently with this moiety under physiological conditions. To evaluate the ability of IFIT1 to have an impact on negative-sense RNA viruses, we infected Ifit1–/– and wild-type control mice and primary cells with four negative-sense RNA viruses (influenza A virus [IAV], La Crosse virus [LACV], Oropouche virus [OROV], and Ebola virus) corresponding to three distinct families. Unexpectedly, a lack of Ifit1 gene expression did not result in increased infection by any of these viruses in cell culture. Analogously, morbidity, mortality, and viral burdens in tissues were identical between Ifit1–/– and control mice after infection with IAV, LACV, or OROV. Finally, deletion of the human IFIT1 protein in A549 cells did not affect IAV replication or infection, and reciprocally, ectopic expression of IFIT1 in HEK293T cells did not inhibit IAV infection. To explain the lack of antiviral activity against IAV,more » we measured the binding affinity of IFIT1 for RNA oligonucleotides resembling the 5' ends of IAV gene segments. The affinity for 5'-ppp RNA was approximately 10-fold lower than that for non-2'-O-methylated (cap 0) RNA oligonucleotides. Based on this analysis, we conclude that IFIT1 is not a dominant restriction factor against negative-sense RNA viruses. Negative-sense RNA viruses, including influenza virus and Ebola virus, have been responsible for some of the most deadly outbreaks in recent history. The host interferon response and induction of antiviral genes contribute to the control of infections by these viruses. IFIT1 is highly induced after virus infection and reportedly has antiviral activity against several RNA and DNA viruses. However, its role in restricting infection by negative-sense RNA viruses remains unclear. In this paper, we evaluated the ability of IFIT1 to inhibit negative-sense RNA virus replication and pathogenesis both in vitro and in vivo. Detailed cell culture and animal studies demonstrated that IFIT1 is not a dominant restriction factor against three different families of negative-sense RNA viruses.« less

Authors:

Pinto, Amelia K. ^[1]; Williams, Graham D. ^[1]; Szretter, Kristy J. ^[1]; White, James P. ^[1]; Proença-Módena, José Luiz ^[2]; Liu, Gai ^[1]; Olejnik, Judith ^[3]; Brien, James D. ^[1]; Ebihara, Hideki ^[4]; Mühlberger, Elke ^[3]; Amarasinghe, Gaya ^[1]; Diamond, Michael S. ^[1]; Boon, Adrianus C. M. ^[1]

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+ Show Author Affiliations

1. Washington Univ. School of Medicine, St. Louis, MO (United States)
2. Washington Univ. School of Medicine, St. Louis, MO (United States); Univ. of Campinas (UNICAMP), SP (Brazil)
3. Boston Univ. School of Medicine, MA (United States)
4. Rocky Mountain Labs, Hamilton, MT (United States)

Publication Date:

Wed Aug 19 00:00:00 EDT 2015

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:

National Institutes of Health (NIH); NIAID

OSTI Identifier:

1351392

Grant/Contract Number:  

U54 AI057160; R01 AI104972; R01 AI104002; GM: 007067; F32 AI112274

Resource Type:

Accepted Manuscript

Journal Name:

Journal of Virology

Additional Journal Information:

Journal Volume: 89; Journal Issue: 18; Journal ID: ISSN 0022-538X

Publisher:

American Society for Microbiology

Country of Publication:

United States

Language:

ENGLISH

Subject:

59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES