Type I interferon responses contribute to immune protection against mycobacterial infection

Reasons for the spectrum of severity of active tuberculosis (TB) disease are incompletely understood. We sought to identify master regulators of host immune responses that determine disease severity in pulmonary TB. We performed molecular profiling of human in vivo immune responses to discover associations with the extent of radiographic TB disease in a patient cohort. We then undertook mechanistic studies to test causality for the observed associations using the zebrafish larval Mycobacterium marinum infection model. Transcriptional profiling of human immune recall responses to tuberculin skin test (TST) challenge, a surrogate for immune responses to TB in the lung, revealed that type I interferon activity in the TST transcriptome was inversely associated with radiological disease severity. Abrogation of type I interferon signalling, achieved by CRISPR-mediated mutagenesis of stat2 , led to increased susceptibility of zebrafish larvae to M. marinum infection, as a result of reduced recruitment of myeloid cells required to restrict mycobacterial growth, to the site of disease. Our data support a host protective role for type I interferon responses in mycobacterial infection, with potential applications for risk-stratification of adverse outcomes and development of a host-directed therapy to mitigate against severe disease.