Disease caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains a major health threat, causing an estimated 8 million new cases and 2 million deaths annually. The current vaccine, BCG, is not reliable, ranging in efficacy from no protection to 80% protection. There is an urgent need for a more effective vaccine against Mtb, and understanding all aspects of the host immune response that come into play during Mtb infection is necessary for vaccine development. It is known that the immune response to Mtb is initiated in the lung by Mtb interaction with Toll like receptors (TLRs) on the surface of antigen presenting cells (APCs), including macrophages and dendritic cells (DCs). Following interaction with Mtb, DCs migrate to the draining lymph node to generate a protective Th1 response, which is sufficient to contain, but not to eliminate, the bacteria. The reason behind the failure of the immune response to completely eradicate the bacteria is unknown, but the host mechanisms involved may include release of anti-inflammatory cytokines that inhibit antigen presentation or Th1 cell responses, negative feedback within the APCs or effector cells themselves, or the activation of regulatory T cells (Tregs). Indeed, both Tregs and the anti-inflammatory cytokines IL-10 and TGF-beta have been observed at higher frequencies in the circulation of TB patients as compared to healthy individuals, and may down-modulate host immunity. The overall goal of this project is to examine potential immune regulatory mechanisms in the context of Mtb interaction with its host receptors, TLRs. Our laboratory has previously demonstrated a TLR2-dependence for IL-10 production by APCs, and we have obtained preliminary data suggesting a TLR2-dependent mechanism for Treg induction during Mtb infection. In this proposal we will use a mouse model of Mtb infection in conjunction with flow cytometric techniques, immunohistochemistry, real time RT-PCR, and ELISPOT assay to fully evaluate immunosuppressive mechanisms resulting from Mtb interaction with TLR2. We will also assess the effects of TLR2 signaling on the magnitude of the Mtb-specific Th1 response, as well as the effects on the development of immunological memory to Mtb. The results of these studies will indicate whether TLR2 may be a useful target in novel vaccine design and may unveil other potential targets. The goals of this proposal will be addressed in the following aims:
Aim1 we will determine the effects of TLR2 signaling on DC ability to generate an efficient Th1 response;
Aim 2 we will determine the effects of TLR2 signaling on Treg induction;
Aim 3 we will determine the effects of TLR2 signaling in the development of effective immunological memory to Mtb. ? ? ?
| McBride, Amanda; Konowich, Jill; Salgame, Padmini (2013) Host defense and recruitment of Foxp3? T regulatory cells to the lungs in chronic Mycobacterium tuberculosis infection requires toll-like receptor 2. PLoS Pathog 9:e1003397 |
| McBride, Amanda; Bhatt, Kamlesh; Salgame, Padmini (2011) Development of a secondary immune response to Mycobacterium tuberculosis is independent of Toll-like receptor 2. Infect Immun 79:1118-23 |
