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.Keywords: DCs r Delayed Th1 immunity r FimH r Mycobacterium r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPulmonary mycobacterial infection is mainly caused by Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), and by other slow growing less virulent nontuberculous Correspondence: Dr. Zhou Xing e-mail: xingz@mcmaster.ca mycobacterial (NTM) species including M. avium and M. kasasii. The continuing high global incidence of and death due to tuberculosis infections [1] and the dramatic increase in pulmonary NTM disease globally over the past three decades [2] underscores the need to further understand the complex host immune responses to mycobacterial exposure in order to develop effective prophylactic and therapeutic strategies.Protective immunity against mycobacterial infection requires the presence of a robust adaptive Th1-type response at the site of Eur. J. Immunol. 2014Immunol. . 44: 1375Immunol. -1386 infection. Upon exposure to the bacterium, mycobacteria is taken up by sentinel APCs such as DCs and delivered to the draining lymph node (dLN) [3,4]. On arrival, these APCs present mycobacterial antigen to naive T cells within the dLN, thereby priming the antigen-specific T cells to a Th1 phenotype and stimulating their expansion [5]. The Th1 cells are then recruited back to the site of infection, and the secretion of Th1 cytokines such as IFN-γ by these cells is critical to activation of infected APCs to control bacterial growth [6]. However, one of the defining characteristics of host defense toward mycobacterial patho...

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

“…In contrast, delivery of FimH, a TLR4 ligand, improved T-cell responses and resulted in ∼1 log reduction in lung bacterial burden, following high-dose intranasal infection with Mtb H37Ra (ref. 53). To our knowledge, no published studies have manipulated early host responses in vaccinated Mtb -infected hosts, with resulting complete early Mtb control.…”

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“…Indeed, we have previously demonstrated that the inoculation of pro-inflammatory agonists, such as Toll-like receptor ligands, into the lung of intramuscularly immunised animals is able to draw antigen-specific T-cells from the peripheral sites into the airway lumen and provide protection against pulmonary TB [5,14]. Furthermore, we have recently demonstrated that a robust innate inflammatory response is key for the timely generation of anti-TB T-cell immunity in the lung following primary pulmonary M. tuberculosis infection [10].…”

“…Upon exposure to M. tuberculosis, the bacterium is deposited into the lung airway, and infects local macrophage and dendritic cells. After 8-9 days these cells migrate to the lung draining lymph node, where they prime naïve T-cells and provide the activation signals to generate a population of M. tuberculosis-specific T-cells [10]. These cells then travel through the lymphatic circulation into the venous blood circulation, eventually ending up in the pulmonary vasculature (pulmonary artery).…”

Developing aerosol vaccines for Mycobacterium tuberculosis: Workshop proceedings

“…By Day Dr. Zhou Xing described vaccination strategies to elicit enhanced protective immunity on the respiratory mucosal surface that will provide a more rapid immunological response to infection. Following Mtb infection of naïve mice, bacteria replicate rapidly in the lungs during the first 14 days of infection, and only begin to slow down when the adaptive immune response begins around 21 days post-infection [61][62][63]. Even animals that have received subcutaneous BCG vaccination demonstrate a delayed airway CD-4+ T-cell response, which only begins 14 days after the Mtb challenge, too late to protect against the initial rapid bacterial build up.…”