Project Summary The worldwide human population continually faces the challenge of seasonal influenza and other aggressive respiratory virus infections. While the focus of research is usually on pulmonary manifestations, there is emerging evidence that virus-induced “cytokine storm” as well as direct infection of cardiac tissue causes heart dysfunction during influenza and other respiratory virus infections. A therapeutic approach that mitigates virus-induced inflammation and restores cardiopulmonary integrity is urgently needed to treat virus-induced multi-organ injuries. MG53 is a member of the TRIM protein family and plays an essential role in cell membrane repair. We show previously that systemic administration of recombinant human MG53 (rhMG53) protein protects against injuries to the heart and lung in rodent and large animal models. Here we present new data that reveal a vital role for MG53 in cardiopulmonary protection associated with virus infection. In addition to facilitating tissue repair, MG53 also has an anti-inflammatory role in immunity. Human macrophages express MG53 and loss of MG53 leads to increased type I interferon and IL-6 production in virus infection due to hyperactivation of NF-κB. MG53 knockout mice infected with influenza virus display increased tissue inflammation and morbidity even though virus titers are comparable to wild type mice. Intravenous administration of rhMG53 prevents death of wild type mice subjected to a lethal influenza virus challenge, by reducing cytokine storm and preventing tissue damage through inhibition of pyroptosis. These findings establish a new paradigm for treatment of infectious disease and identify MG53 as a new target for control of virus-induced tissue injury. We hypothesize that the dual function of MG53 in tissue-repair and limiting inflammation will combat cardiopulmonary injury caused by influenza virus. We will dissect the roles of MG53 in preserving heart and lung function following influenza virus infection using custom-generated MG53 loss of function and gain of function mouse models. We will elucidate the molecular underpinnings and interplay between MG53 inhibition of both pyroptosis and NF-κB signaling as host-defense mechanisms in the heart and lungs upon exposure to influenza virus. We will further establish the dosing and timing strategies for administration of rhMG53 in mice to establish the prophylactic and therapeutic windows for ameliorating virus-induced multi-organ failure. Since MG53 is not directly antiviral, potential exists for combination therapy of rhMG53 with antivirals to effectively treat virus-induced cardiopulmonary injury. Thus, we will quantify synergistic effects of treating influenza virus-infected mice with rhMG53 and FDA-approved anti- influenza drugs on cardiac and lung viral titers, pathology, and function.

PROJECT NARRATIVE Our world is continually facing the challenge of influenza and other aggressive viral infections in epidemic proportions on a yearly basis. This project will examine the biology of MG53, a tissue repair gene, in cardiopulmonary protection associated with viral infection. Our findings with the dual function of MG53 in tissue repair and anti-inflammation shall provide novel means to mitigate virus-induced multi-organ injuries.