GATA2 mutation is associated with immune dysfunction and increased Mycobacterium haemophilum susceptibility in immunocompromised individuals
Ananya Gupta, Shail B. Mehta, Abhimanyu, Bruce A. Rosa, John Martin, Mushtaq Ahmed, Shyamala Thirunavukkarasu, Farheen Fatma, Gaya K. Amarasinghe, Makedonka Mitreva, Thomas C. Bailey, David B. Clifford, Shabaana A. Khader
Ananya Gupta, Shail B. Mehta, Abhimanyu, Bruce A. Rosa, John Martin, Mushtaq Ahmed, Shyamala Thirunavukkarasu, Farheen Fatma, Gaya K. Amarasinghe, Makedonka Mitreva, Thomas C. Bailey, David B. Clifford, Shabaana A. Khader
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Research Article Immunology Infectious disease

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

Abstract

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.

Authors

Ananya Gupta, Shail B. Mehta, Abhimanyu, Bruce A. Rosa, John Martin, Mushtaq Ahmed, Shyamala Thirunavukkarasu, Farheen Fatma, Gaya K. Amarasinghe, Makedonka Mitreva, Thomas C. Bailey, David B. Clifford, Shabaana A. Khader

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Figure 2

Exploring the genetic basis of impaired M. haemophilum–specific proinflammatory responses in individuals with Mh infection.

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Exploring the genetic basis of impaired M. haemophilum–specific proinfla...
(A) Schematic for single nucleotide polymorphism filtering process to identify most causal genes. (B) Proportion of shared synonymous and nonsynonymous SNPs between the samples of the study groups (n = 3 HC, and n = 4 Mh-infected). (C) LoFTools (114) intolerance scores, to identify gene associated with disease. (D) REVEL (70) score to find pathogenicity of nonsynonymous (missense) variants identified in the study. The circle size is proportional to if a HC shares the variant. Orange denotes only Mh-infected variants, blue has 1 HC sharing the variant, and black represent only 3 Mh-infected and 1 HC sharing the mutation. (E) The GATA2 gene showing the exons and location of the mutant identified in this study and examples of gain-of-function (green) and loss-of-function (red) mutations.