Influenza A virus hijacks monocyte trafficking to damage the heart and impair cardiac function 3069

Abstract Description Infections by influenza A viruses (IAV) remain an unceasing threat to human health. Although much of its pathogenesis is confined to the lung, there is clinical evidence that IAV can inflame and damage the heart. Our understanding of how this occurs, however, is incomplete. While studies in mice and humans suggest the heart can support low levels of IAV replication, the cell type principally receptive to productive replication or how IAV may translocate to the myocardium from the anatomically distinct lung remains unknown. Herein, we describe a hijacked pulmonary/cardiac immunological axis, whereby IAV-infected monocytes preferentially traffic from the lung to the heart in a CCL2-dependent manner via the systemic circulation, differentiate into cardiac macrophages, and promote the dissemination of the virus to cardiomyocytes that support active viral replication. Presence of IAV in the heart then promotes TLR3-dependent IFN-I production by monocytes, which signals through the IFN-I receptor (IFNAR1) on cardiomyocytes to cause damage and compromise heart function. Therapeutically dampening this IFN-I/IFNAR1 axis specifically on cardiomyocytes using cutting-edge modified mRNA technology or limiting monocyte accumulation in the heart protected the heart following infection. Our results uncover a targetable axis for clinical intervention to mitigate cardiovascular risk following infection and more broadly describe novel intricacies of IAV pathogenesis. Funding Sources Supported by the Charles H. Revson Foundation, the NHLBI/NIH and the CIHR. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)