title: Restoration of innate immune activation accelerates Th1-cell priming and protection following pulmonary mycobacterial infection.
abstract: The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.
authors: McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: Rocky
authors: R
authors: Lai
authors: Mangalakumari
authors: M
authors: Jeyanathan
authors: Christopher R
authors: CR
authors: Shaler
authors: Daniela
authors: D
authors: Damjanovic
authors: Amandeep
authors: A
authors: Khera
authors: Carly
authors: C
authors: Horvath
authors: Ali A
authors: AA
authors: Ashkar
authors: Zhou
authors: Z
authors: Xing
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology
keywords: DCs; Delayed Th1 immunity; FimH; Mycobacterium; Tuberculosis