Calming the storm: Immunoregulatory receptor NLRX1 and its role in the immune response to SARS-CoV-2

Abstract One of the most characteristic clinical disease presentations of severe COVID-19 is the ‘Cytokine Storm,’ stemming from dysregulation of the immune response. This overproduction of proinflammatory cytokines in response to SARS-CoV-2 is responsible for Acute Respiratory Distress Syndrome (ARDS) in adult patients and the Multisystem Inflammatory Syndrome (MIS) of pediatric patients hospitalized with severe COVID-19. Pattern recognition receptor NLRX1 is a member of the NOD-like receptor family with complex involvement in antiviral immunity. It has been reported in the literature in many contexts to be anti-inflammatory by inhibiting NF-kB and interferon signaling-critical pathways in anti-SARS-CoV-2 immunity. Here we show that loss of NLRX1 impacts immune responses to SARS-CoV-2 both in cell culture and in mice. While Nlrx1 −/−mice showed similar overall morbidity, there were temporary increases in weight loss at multiple time points post infection. SARS-CoV-2 infection of Nlrx1 −/−mice also resulted in an increase in viral titer in the lungs at 2 dpi, despite having higher degrees of airway inflammation. Data in both cell culture and animal challenges report differences in immune activation, showing differences in cytokine production with changes in expression of NLRX1. Together, these experiments uncover another enigmatic function of NLRX1 while simultaneously offering pathways related to NLRX1 as possible therapeutic targets to help mitigate the effects of the ‘cytokine storm’ of severe COVID-19. Finally, these data also add to the growing field regarding SARS-CoV-2 and its pathobiology in an understudied context of immune regulation and continue to explore NLRX1 and its many curious roles in antiviral immunity.