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.


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*