HUMAN ALVEOLAR MACROPHAGE FUNCTION IS IMPAIRED IN TUBERCULOSIS CONTACTS WITH DIABETES

Léanie Kleynhans; Carine Kunsevi-Kilola; Happy Tshivhula; Tariq Webber; Alana Keyser; Nicole Prins; Candice I Snyders; Ayanda Shabangu; Virginie Rozot; Martin Kidd; Hao Zhang; Hong Cai; Yufeng Wang; Adam D Ewing; Stephanus T Malherbe; Abul K Azad; Eusondia Arnett; Blanca I Restrepo; Larry S Schlesinger; Katharina Ronacher

doi:10.21203/rs.3.rs-5489046/v1

HUMAN ALVEOLAR MACROPHAGE FUNCTION IS IMPAIRED IN TUBERCULOSIS CONTACTS WITH DIABETES

Res Sq [Preprint]. 2024 Nov 28:rs.3.rs-5489046. doi: 10.21203/rs.3.rs-5489046/v1.

Authors

Léanie Kleynhans^{1

2

3}, Carine Kunsevi-Kilola¹, Happy Tshivhula¹, Tariq Webber¹, Alana Keyser⁴, Nicole Prins¹, Candice I Snyders¹, Ayanda Shabangu¹, Virginie Rozot⁵, Martin Kidd⁶, Hao Zhang⁷, Hong Cai⁷, Yufeng Wang⁷, Adam D Ewing², Stephanus T Malherbe¹, Abul K Azad⁸, Eusondia Arnett⁸, Blanca I Restrepo^{8

9

10}, Larry S Schlesinger⁸, Katharina Ronacher^{1

2

3}

Affiliations

¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, SA MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
² Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
³ Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia.
⁴ Vaccines for Africa, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
⁵ South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
⁶ Centre for Statistical Consultation, Stellenbosch University, Stellenbosch, South Africa.
⁷ Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, TX, USA.
⁸ Texas Biomedical Research Institute, San Antonio, TX, USA.
⁹ Department of Epidemiology, School of Public Health-Brownsville Campus, University of Texas Health Science Center at Houston, Brownsville, TX, USA.
¹⁰ South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA.

Abstract

Type 2 diabetes (T2D) increases susceptibility to tuberculosis (TB) with the underlying mechanisms remaining unknown. To determine whether immune dysfunction in the lung contributes to TB susceptibility, we obtained paired human alveolar macrophages (HAMs) and monocyte-derived macrophages (MDMs) from TB-exposed individuals with/without T2D. Upon infection with Mycobacterium tuberculosis (M.tb), T2D-HAMs had more M.tb growth and produced more TNF. There were fewer neutrophils in the bronchoalveolar lavage of T2D patients which was inversely correlated with M.tb growth. Both T2D-HAMs and MDMs expressed less CD32, with T2D patients having fewer M1-like MDMs. T2D-MDMs produced less IL-1RA and CSF2. Overall M.tb-induced gene expression was delayed in T2D-HAMs, but genes involved in negative regulation of neutrophil migration were upregulated. T2D-HAM DNA was hypermethylated compared to control HAMs, however genes linked to TNF signalling were hypomethylated. We show here the first in-depth analysis of T2D-HAMs providing an explanation for more severe TB in T2D patients.

Keywords: alveolar macrophages; bronchoalveolar lavage; monocyte derived macrophages; mycobacterial growth; tuberculosis; type 2 diabetes.

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Preprint

Abstract

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