Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

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-␤). 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-␤-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 Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression

“…In our system, CXCL14 restoration of MHC-I expression must overcome the activity of both HPV oncoproteins that have been shown to suppress MHC-I surface expression through multiple mechanisms. Finally, in support of modest changes of MHC-I enacting protection against CD8 + T-cell killing, a recent publication has reported that Zika virus upregulates MHC-I expression to protect the cell from NK-cell killing [42]. Although the shifts in MHC-I were modest, it was sufficient to enact protection from NK-cell killings.…”

Zika virus and the nonmicrocephalic fetus: why we should still worry

“…(84, 86) Other mechanisms of flavivirus innate immune antagonism include induction of major histocompatibility expression (MHC-I) on the surface of infected cells to evade natural killer cell-mediated lysis. (89, 90) The viral NS1 protein can also dysregulate the humoral complement system, thus allowing the virus to evade both direct destruction and destruction of infected cells. (91, 92) Thus, flaviviruses excel at evading the innate immune response by preventing host cell recognition of viral pathogen-associated molecular patterns and inhibiting antiviral signaling pathways.…”

Microbial killing by NK cells

“…). However, expression of NK receptors is suppressed in HIV patients, which dampen NK response and infections, and Zika virus up‐regulated MHC I molecules to escape NK cell detection . It was reported at the meeting that herpes viruses evade NK cell killing through down‐regulating NKG2D ligands by HHV‐6A proteins U20 and U21 (Abstract 75).…”

“…However, expression of NK receptors is suppressed in HIV patients, which dampen NK response and infections, 40,43 and Zika virus up-regulated MHC I molecules to escape NK cell detection. 44 45 TRAIL is a cell-death inducing ligand and plays a role in the antimetastatic and antiviral functions of NK cells and in the regulatory function of NK cells in eliminating virus-specific T cells during chronic inflammation. New findings showed that NKp46 is an intrinsic regulator of TRAIL protein expression in liver resident type 1 innate lymphoid cells (Abstract 17).…”