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
View: Text | PDF
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

×

Figure 1

Impaired M. haemophilum–specific proinflammatory responses in individuals with Mh infection.

Options: View larger image (or click on image) Download as PowerPoint
Impaired M. haemophilum–specific proinflammatory responses in individual...
(A) Study design schematic. (B) Heatmap of –log10 P value of cytokine responses to PHA, Mab, and Mh stimulations as compared with their saline controls. One-way ANOVA with Tukey’s multiple-comparison test was used. Color indicates significant comparisons. The cytokines are arranged from most to least significant in various conditions. (C–K) Specific cytokine responses to various stimulations as outlined in A. The cytokine levels are reported in (pg/mL) and mean ± SEM is plotted. Solid filled circles represent HCs in 4 different colors and rectangle represent the Mh-infected patients in 4 colors. The treatment is shown on the x axis; 2-tailed Student t test was used for the Mh comparisons between the HC and Mh-infected individuals. *P < 0.05, **P < 0.01.