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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 Article has an altmetric score of 9

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

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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 5

Loss of Tet2 impairs bactericidal capacity of neutrophils.

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Loss of Tet2 impairs bactericidal capacity of neutrophils.
(A) There wer...
(A) There were no differences in bacterial killing between Tet2fl/fl and Tet2–/– BM-derived macrophages. (B) Bacterial binding and uptake, measured with pHrodo-Red-labeled Streptococcus pneumoniae, showed decreased pathogen uptake in Tet2–/– neutrophils (Tet2fl/fl [500 ± 14.6]; Tet2–/– [296 ± 14.1]) compared with Tet2fl/fl neutrophils. (C) Intracellular killing of engulfed S. pneumoniae was reduced in Tet2–/– neutrophils (Tet2fl/fl [78.5 ± 3.5]; Tet2–/– [58.3 ± 4.1]). (D–J) Functional assays comparing Tet2fl/fl versus Tet2–/– neutrophils over 30 minutes coculture with Staphylococcus aureus. n = 4 independent experiments each. (D) Phagocytosis of S. aureus was impaired in Tet2–/– neutrophils compared with Tet2fl/fl neutrophils. Mean ± SD of percentages of cells with certain counts of internalized bacteria. Significance tested with χ2 test. (E) Representative image showing GFP-labeled bacteria (green) at end of 30 minutes coincubation with neutrophils. Scale bar: 100 μm. (F–H) Migration qualities of Tet2–/– neutrophils in response to S. aureus were impaired compared with Tet2fl/fl neutrophils. (F) Mean ± SD of percentages of cells travelling certain max distances. Significance tested with χ2 test. (G) Representative tracks of cells over 30 minutes coincubation with S. aureus. Scale bar: 100 μm. (H) Mean maximum distances travelled (left) and mean speeds of top 20% of cells (right). Significance tested with paired t test and Wilcoxon, respectively. (I) Neutrophil extracellular traps (NETs) were less expansive in Tet2–/– (72 μm2 [range 54–106]) versus. Tet2fl/fl neutrophils (183 μm2 [range 115–312]). Boxes represent median [IQR] of individual NETs quantified, with minimum to maximum whiskers; Mann-Whitney test. (J) Representative image of NETs stained for dsDNA (Alexa568, yellow), nuclear DNA, (DAPI, blue), mitochondria (MitoTracker, red), S. aureus (GFP, green). Scale bar: 100 μm. (K) Immature neutrophil counts were higher in the circulation of Tet2–/– mice (0.45 ± 0.16; n = 7) versus Tet2fl/fl mice (0.07 ± 0.01; n = 7).

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