NK cells on the ViP stage of COVID-19

Abstract

Clinical course and outcome of viral infections mostly depends on the adequate orchestration of both innate and adaptive immune response to the viral noxa. The loss of this balance emerged to be critical during SARS-CoV-2 infection, in which an unleashed cytokine response (the so called “cytokine storm”) has been implicated as the main cause of morbidity and mortality in COVID-19 cases [1]. Therefore, disrupting the escalation of molecular events that lead to severe COVID-19 is an urgent and still unmetmedical need. By interrogating over 45,000 transcriptomic datasets of viral pandemics (SARS-CoV-1, MERS, swine flu, bird flu, influenza A/B, Ebola, Zika, HIV, HCV), in this issue of EBioMedicine, Sahoo and colleagues [2] progressively shortlist candidate transcripts involved in aberrant host immune response to viral infections, describing an invariant 166-gene signature highly conserved among respiratory viral pandemics (named Viral Pandemic, ViP signature). Within the ViP signature, the authors further identify a 20-gene subset associated with severe/fatal disease (severe-ViP signature), eventually pointing out the IL15-IL15RA axis as the major player in immune response derangement, triggering NK cells exhaustion, senescence and apoptosis. The ViP and severe ViP-signatures clearly unveil: (i) a paradigmatic host response to infectious noxa, including viral, bacterial and fungal; (ii) a paradigmatic host response derangement associated to a worse clinical course and outcome, centered on IL15-IL15RA cytokine system and its effects on NK cells, eventually providing a mechanistic model of severe COVID-19 in which the prolonged exposure of NK cells to a IL15-storm (originating in the lung) significantly hampers their function, leading to an exhausted phenotype which facilitates virus spread to other organs. IL-15 is the most important cytokine for NK cell development, activation and function [3,4]. However, it has been shown that chronic NKG2C receptor stimulation on adaptive NK cells in combination with IL-15 exposure, leads to robust proliferation and functional cell