MECHANISMS OF MYCOBACTERIUM INHIBITION OF HOST ANTIGEN PRESENTATION

In order to make progress in the fight against Mycobacterium infections, there is an urgent need to develop new immunization strategies that provide robust and durable protection. TB and bovine TB, caused by Mycobacterium tuberculosis and Mycobacterium bovis, continue to impact the world and put both human health and domesticated livestock production in peril. Unfortunately, we continue to lack an understanding of the mechanisms by which Mycobacterial infections directly and indirectly modulate host immune responses. Without understanding how Mycobacterium inhibit host responses, it will remain challenging to effectively develop protective vaccines that bypass virulence mechanisms.Central to Mycobacterial immune evasion is the inhibition of T cell responses. Following Mycobacterial infection of macrophages, CD4+ T cells are required to control bacterial growth and prevent deleterious tissue damage. Activation of Mycobacterium-specific CD4+ T cells requires both antigen presentation and co-stimulation of T cells by the antigen presenting cells (APCs). These processes are regulated by the expression of surface molecules such as the major histocompatibility complex II (MHCII). Mycobacterial infections can inhibit the induction and surface expression of MHCII which is suggested to drive ineffective immune activation. However, the specific host pathways that are modulated during infection and the bacterial mechanisms that are responsible remain unclear. The goal of this research, is to understand how Mycobacterial infections manipulate critical aspects of the APC T-cell interface, and devise methods to subvert them.Specific AimsAim 1. Define the host pathways altered by M. tuberculosis and M. bovis that result in decreased MHCII expression during infection.1.1 Identify regulators of MHCII during Mycobacterial infection.1.2 Classify priority candidates that control MHCII surface expression during Mycobacterial infection1.3 Determine how modulation of MHCII alters Mycobacteria-Specific CD4+ T Cell function.Aim 2. Define M. tuberculosis and M. bovis genes that are responsible for decreased MHCII expression during infection.2.1 Identify Mycobacterial genes that influence MHCII surface expression during infection2.2 Identify high priority Mycobacterial genes that control MHCII surface2.3 Determine how loss of candidate Mycobacterial genes alters CD4+ T responses and disease progression.