Human Metapneumovirus Escapes NK Cell Recognition through the Downregulation of Stress-Induced Ligands for NKG2D.

Mohammad Diab,Einat Seidel,Eran Bacharach,Ofer Mandelboim,Dominik Schmiedel

doi:10.3390/v12070781

Abstract

The Pneumoviridae family includes human metapneumovirus (HMPV) and human orthopneumovirus, which is also known as a respiratory syncytial virus (HRSV). These are large enveloped, negative single-strand RNA viruses. HMPV and HRSV are the human members, which commonly infect children. HMPV, which was discovered in 2001, infects most children until the age of five, which causes an influenza-like illness. The interaction of this virus with immune cells is poorly understood. In this study, we show that HMPV evades natural killer (NK) cell attack by downregulating stress-induced ligands for the activating receptor NKG2D including: Major histocompatibility complex (MHC) class I polypeptide-related sequences A and B (MICA, MICB), UL16 binding proteins ULBP2, and ULBP3, but not ULBP1. Mechanistically, we show that the viral protein G is involved in the downregulation of ULBP2 and that the viral protein M2.2 is required for MICA and MICB downregulation. These findings emphasize the importance of NK cells, in general, and NKG2D, in particular, in controlling HMPV infection, which opens new avenues for treating HMPV.

Highlights

Natural killer (NK) cells that belong to the innate immune system play an important role in the immune surveillance and elimination of transformed cells, virus-infected cells, bacteria, and fungi [1,2,3,4,5,6,7,8].The killing activity of NK cells is regulated by several activating and inhibitory receptors [6,9].The activating receptor family include, among others, the Natural Cytotoxicity Receptors (NCRs): NKp30, NKp44, and NKp46 (NCR1 in mice) and natural killer group 2D NKG2D
We have previously shown that human metapneumovirus (HMPV) infection affects the expression of an unknown NKp46 ligand [32]
We investigated NKG2D ligands during the infection with HPMV, which lacked the G protein (HMPV/∆G) since this recombinant virus has been shown to upregulate the expression of an unknown NKp46 ligand [32]

Summary

Introduction

The activating receptor family include, among others, the Natural Cytotoxicity Receptors (NCRs): NKp30, NKp44, and NKp46 (NCR1 in mice) and natural killer group 2D NKG2D. The NCR family of receptors recognize several ligands including pathogen-derived ones [6]. NKG2D recognizes ligands in which expression is induced following stresses such as heat shock, deoxyribonucleic acid (DNA) damage, transformation, and virus infection. Eight different stress-induced ligands were identified, which include the major histocompatibility complex (MHC) class I polypeptide-related sequences A and B (MICA, MICB) and a family of UL16 binding proteins 1–6 (ULBP 1–6). The stress-induced ligands are differentially expressed on the cell surface under various conditions. All of them are Viruses 2020, 12, 781; doi:10.3390/v12070781 www.mdpi.com/journal/viruses

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Results

Conclusion