Fighting Persistence: How Chronic Infections with Mycobacterium tuberculosis Evade T Cell-Mediated Clearance and New Strategies To Defeat Them

Abstract

Chronic bacterial infections are caused by pathogens that persist within their hosts and avoid clearance by the immune system. Treatment and/or detection of such pathogens is difficult, and the resulting pathologies are often deleterious or fatal. There is an urgent need to develop protective vaccines and host-directed therapies that synergize with antibiotics to prevent pathogen persistence and infection-associated pathologies. However, many persistent pathogens, such as Mycobacterium tuberculosis, actively target the very host pathways activated by vaccination. These immune evasion tactics blunt the effectiveness of immunization strategies and are impeding progress to control these infections throughout the world. Therefore, it is essential that M. tuberculosis immune evasion-related pathogen virulence strategies are considered to maximize the effectiveness of potential new treatments. In this review, we focus on how Mycobacterium tuberculosis infects antigen-presenting cells and evades effective immune clearance by the adaptive response through (i) manipulating antigen presentation, (ii) repressing T cell-activating costimulatory molecules, and (iii) inducing ligands that drive T cell exhaustion. In this context, we will examine the challenges that bacterial virulence strategies pose to developing new vaccines. We will then discuss new approaches that will help dissect M. tuberculosis immune evasion mechanisms and devise strategies to bypass them to promote long-term protection and prevent disease progression.

T Cell Immunity to Bacterial Pathogens: Mechanisms of Immune Control and Bacterial Evasion

“…A key characteristic of many pathogens is persistence—the continued presence of pathogen in environments that are considered stressful or hostile conditions, which might have limited nutrients and might be shared with antimicrobial regents or threatening immune cells. During persistence, the pathogen is non-infectious, having stopped progressive activities, such as cell development and reproduction, and thus remains undetected by the host, while it ‘hides’ in a non-replicating state [ 212 ]. Until a more comfortable environment can be secured, such persistence will continue where the pathogen remains viable but does not thrive.…”

“…This is accomplished by M. tuberculosis changing its composition, as the structure of the cell wall and specific molecules on its surface serve as a barrier that allows the macrophages to maintain a neutral pH [ 217 ]. This mechanism allows the pathogen to avoid exposure to lysosomal hydrolases, unfavorable low pH conditions produced by the immune response, and other bactericidal lysosomal components [ 212 ]. Additionally, M. tuberculosis is capable of producing factors that modulate the expression of pro-apoptotic and anti-apoptotic genes in macrophages [ 218 ], which has implications for innate immune responses.…”

“…M. tuberculosis possesses antigens that are recognised by FoxP3 + CD4 + regulatory T cells, which expand in patients with an active infection and act to suppress the effector T cell responses against the bacterium, enabling the infection to expand and prolonging the bacterial burden [ 225 , 226 ]. M. tuberculosis does not evolve rapidly and, as a result, the antigens that drive M. tuberculosis -specific T cell responses are conserved across the human population [ 227 ]—a striking contrast to influenza or HIV that actively evades T cell immunity by mutating antigens to avoid detection [ 212 ]. It is also thought that defective interactions between T cells and cells harbouring M. tuberculosis contribute to the failure of T cells to remove infection.…”

A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

“…In non-inflammatory conditions, macrophages express low levels of MHCII that is uniquely dependent on NFAT5 (15). While basal MHCII expression on macrophages plays a role in graft rejection, it is insufficient to control intracellular bacterial pathogens, which require IFNg-activation to propagate protective CD4 + T cell responses (28)(29)(30). Many pathogens including Mycobacterium tuberculosis and Chlamydia trachomatis inhibit IFNg-mediated MHCII induction to evade CD4 + T cell-mediated control and drive pathogen persistence (31)(32)(33).…”

“…Overcoming these pathogen immune evasion tactics is essential to develop new treatments or immunization strategies that provide long-term protection (28). Without a full understanding of the global mechanisms controlling IFNg-mediated MHCII regulation in macrophages, it has proven difficult to dissect the mechanisms related to MHCII expression that cause disease or lead to infection susceptibility.…”