GATA2 mutation is associated with immune dysfunction and increased Mycobacterium haemophilum susceptibility in immunocompromised individuals

Infections with nontuberculous mycobacterium (NTM) are on the rise. Here, we investigated an uncommon NTM infection, by M. haemophilum (Mh, n = 4), from a shared geographic location in the United States. All patients had underlying immunosuppressive conditions or treatments. We identified that all these individuals had a nonsynonymous mutation in GATA2 gene, which was absent in healthy controls (HCs, n = 4) from the same geographic area (Missouri, USA). Whole blood from these individuals had attenuated cytokine responses to Mh stimulation for IL-1β, IL-6, IL-8, MIP-1α and MIP-1β, but not to phytohemagglutinin (PHA) or another NTM, M. abscessus. Impaired whole blood transcriptional responses in individuals with GATA2 mutation included heightened Ras-homolog (Rho) guanosine triphosphate hydrolases (GTPase) and lowered TGF-β responses, among others. Our results highlight that, comparatively, M. abscessus and Mh elicit differential immune responses in humans. We identify a 23-gene signature that distinguished host response to Mh and M. abscessus and show that in vitro GATA2 siRNA knockdown indeed attenuated cytokine responses to Mh. Thus, we provide evidence that links GATA2 mutation and immune dysfunction in individuals with compromised immunity to Mh infection in humans and outline host factors associated with the immune response of this clinically relevant NTM.