We thank Clare A. Edward for technical assistance and Catherine M. Andary for being a second scorer for IF and histopathological analysis. We also thank Elsa N. Bou Ghanem and Manmeet Bhalla for their assistance with the neutrophil killing assays. DMEB was funded through the Canadian Research Chairs program and CIHR. CQ was supported by a CIHR Postdoctoral Fellowship Award. JB was supported by a MIRA fellowship. This study was supported by a project grant from the CIHR (PJT-156291).Peer reviewe

Archer, Stephen L

Bick, Alexander G

Bowdish, Dawn ME

Breznik, Jessica A

buttigieg, Marco M

Cook, Elina K

DeJong, Erica N

Dunham-Snary, Kimberly J

Hindmarch, Charles CT

Kennedy, Allison E

Luo, Yi Zhen

McNaughton, Amy JM

Mewburn, Jeffrey

Quin, Candice

Rauh, Michael J

Sadh, Sanathan

Vlasschaert, Caitlyn

Zhao, Kevin

Journal of Clinical Investigation

English

Aberdeen University Research

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

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

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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https://aura.abdn.ac.uk/bitstream/2164/23820/1/Quin_etal_TJCI_Neutrophil_mediated_innate_VoR.pdf

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

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Aberdeen University Research

Directory of Open Access Journals