Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function
Candice Quin, … , Michael J. Rauh, Dawn M.E. Bowdish
Candice Quin, … , Michael J. Rauh, Dawn M.E. Bowdish
Published April 4, 2024
Citation Information: J Clin Invest. 2024;134(11):e171002. https://doi.org/10.1172/JCI171002.
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Research Article Immunology Infectious disease

Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function

Abstract

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2–knockout (Tet2–/–) and floxed control mice (Tet2fl/fl) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2–/– mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2–/– mice. We delineated the transcriptional landscape of Tet2–/– neutrophils and found that, while inflammation-related pathways were upregulated in Tet2–/– neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by Tet2–/– neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

Authors

Candice Quin, Erica N. DeJong, Elina K. Cook, Yi Zhen Luo, Caitlyn Vlasschaert, Sanathan Sadh, Amy J.M. McNaughton, Marco M. Buttigieg, Jessica A. Breznik, Allison E. Kennedy, Kevin Zhao, Jeffrey Mewburn, Kimberly J. Dunham-Snary, Charles C.T. Hindmarch, Alexander G. Bick, Stephen L. Archer, Michael J. Rauh, Dawn M.E. Bowdish

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Figure 1

CHIP is positively associated with incident pneumonia caused by Streptococcus pneumoniae.

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CHIP is positively associated with incident pneumonia caused by Streptoc...
(A) CHIP is positively associated with incident all-cause pneumonia among 438,421 individuals in the UK Biobank without a history of pneumonia in a Cox proportional hazards regression model adjusted for age, age2, sex, smoking history, history of chronic inflammatory lung disease (COPD), and 10 principal components of genetic ancestry. In a model adding an interaction term for a common SNP in the IL6 receptor associated with lower IL6 signaling (rs2228415), CHIP is associated with incident confirmed S. pneumoniae pneumonia. The CHIP × rs2228415 interaction term is significantly below 0, suggesting that lower IL6R signaling mitigates the effects of CHIP on pneumonia risk. (B–G) Leukocyte populations were quantified in whole blood from CHIP carriers and noncarriers in a local cohort using flow cytometry. Compared with noncarriers, the numbers of (B) peripheral blood monocytes (No CHIP [78.4 ± 12.9]; CHIP [147.6 ± 37.5]), (C) classical monocytes (No CHIP [62.4 ± 7.7]; CHIP [138.3 ± 35.9]), and (D) neutrophils (No CHIP [990 ± 117]; CHIP [1709 ± 281]), were increased in CHIP carriers. Chemokines (E) CXCL1 (No CHIP [10.5 ± 0.23]; CHIP [9.7 ± 0.26]), and (F) CXCL5 (No CHIP [12.7 ± 0.25]; CHIP [11.6 ± 0.32]), were decreased in the sera of CHIP carriers. (G) Surface expression of CD64 was decreased on circulating blood neutrophils in CHIP carriers (No CHIP [474.9 ± 113.5]; CHIP [106.6 ± 53.0]). Data are presented as box and whisker plots, minimum to maximum, where the center line represents the median and each dot is a participant. Sample size: 16 No CHIP, 6 CHIP participants. Significant outliers removed using ROUT method. MFI, Geometric Mean Fluorescence Intensity. Significance was assessed by Mann-Whitney test. *P ≤ 0.05, **P ≤ 0.01.