Loss of 7-Dehydrocholesterol Reductase-mediated cholesterol biosynthesis activates IRF3 and inhibits control of Mycobacterium marinum infection

Cholesterol immunometabolism is a critical controller of immunopathology in respiratory infections such as tuberculosis. Smith-Lemli-Opitz syndrome (SLOS) patients are affected by a loss of 7-dehydrocholesterol reductase (DHCR7) function and have elevated 7-dehydrocholesterol (7DHC) and reduced cholesterol. Increased 7DHC has been found to be protective against viral infections in a range of infection models however SLOS patients have a higher susceptibility to respiratory infection. Here we use the zebrafish- Mycobacterium marinum infection model to demonstrate a compromised innate immune response to bacterial infection in the absence of dhcr7 . We correlate increased 7DHC with increased activation of the IRF3/type I interferon axis and demonstrate Irf3 is a targetable signaling node to restore anti-bacterial immunity in a dhcr7 -depleted background. Plain English summary Loss of 7-dehydrocholesterol reductase causes Smith-Lemli-Opitz syndrome. One of the metabolic features of Smith-Lemli-Opitz syndrome is increased 7-dehydrocholesterol (7DHC). We find increased 7DHC inhibits the ability of zebrafish to control mycobacterial infection by mis-activating an antiviral immune response at the expense of a protective anti-bacterial immune response. Our study suggests the susceptibility to respiratory infections and increased neuroinflammation in Smith-Lemli-Opitz syndrome could be treated by targeting the antiviral protein IRF3.