Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection

Wenxi Xu; Laura M Snell; Mengdi Guo; Giselle Boukhaled; Bethany L Macleod; Ming Li; Michael V Tullius; Cynthia J Guidos; Ming-Sound Tsao; Maziar Divangahi; Marcus A Horwitz; Jun Liu; David G Brooks

doi:10.1016/j.immuni.2021.01.003

Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection

Immunity. 2021 Mar 9;54(3):526-541.e7. doi: 10.1016/j.immuni.2021.01.003. Epub 2021 Jan 29.

Authors

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada.
² Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁴ Department of Medicine and Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
⁶ Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
⁷ Department of Medicine and Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: dbrooks@uhnresearch.ca.

Abstract

Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.

Keywords: CD4 T cells; CyTOF; LCMV; Mycobacterium tuberculosis; T cell differentiation; Th1 cells; Th17 cells; chronic viral infection; coinfection; neutrophil.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Animals
Chronic Disease
Coinfection
Immunity, Innate
Lymphocytic Choriomeningitis / immunology*
Lymphocytic choriomeningitis virus / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mycobacterium tuberculosis / physiology*
Neutrophils / immunology*
Phagocytosis
Severity of Illness Index
Th1 Cells / immunology*
Th17 Cells / immunology*
Time Factors
Tuberculosis / immunology*

Abstract

Publication types

MeSH terms

Grants and funding