Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules - Journal of Virology

1. Ariella Glasner^a,
2. Esther Oiknine-Djian^b,
3. Yiska Weisblum^b,
4. Mohammad Diab^a,
5. Amos Panet^c,
6. Dana G. Wolf^b and
7. Ofer Mandelboim^a

1. ^aLautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University Medical School, Jerusalem, Israel
2. ^bClinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
3. ^cDepartment of Biochemistry and Chanock Center for Virology, IMRIC, Faculty of Medicine, The Hebrew University Jerusalem, Israel

ABSTRACT

NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.

IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-β-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.

KEYWORDS

FOOTNOTES

• • Received 10 May 2017.
  • Accepted 21 August 2017.
  • Accepted manuscript posted online 6 September 2017.
• Address correspondence to Ofer Mandelboim, oferm{at}ekmd.huji.ac.il.

• A.G. and E.O.-D. contributed equally to this article. D.G.W. and O.M. are co-senior authors.

• Citation Glasner A, Oiknine-Djian E, Weisblum Y, Diab M, Panet A, Wolf DG, Mandelboim O. 2017. Zika virus escapes NK cell detection by upregulating major histocompatibility complex class I molecules. J Virol 91:e00785-17. http://ift.tt/2yRXTWd.

• Copyright © 2017 American Society for Microbiology.

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