Tolerating the Unwelcome Guest; How the Host Withstands Persistent Mycobacterium tuberculosis

Abstract

Our understanding of the host response to infections has historically focused on "resistance" mechanisms that directly control pathogen replication. However, both pathogen effectors and antimicrobial immune pathways have the capacity to damage host tissue, and the ability to tolerate these insults can also be critical for host survival. These "tolerance" mechanisms may be equally as important as resistance to prevent disease in the context of a persistent infection, such as tuberculosis, when resistance mechanisms are ineffective and the pathogen persists in the tissue for long periods. Host tolerance encompasses a wide range of strategies, many of which involve regulation of the inflammatory response. Here we will examine general strategies used by macrophages and T cells to promote tolerance in the context of tuberculosis, and focus on pathways, such as regulation of inflammasome activation, that are emerging as common mediators of tolerance.

Keywords: Mycobaterium tuberculosis; immunometabolism; inflammasome; persistent infections; tolerance.

Figure 1

Nos2 and Phox control tolerance during Mtb infection by negatively regulating inflammasome activation. During Mtb infection in macrophages, Nos2 and Phox produce NO and ROS respectively. While these molecules are antimicrobial against many pathogens, Mtb is mostly resistant. Persistent Mtb then activates the NLRP3 inflammasome to produce active IL1β. Prolonged inflammasome activation leads to increased IL1β secretion and neutrophil recruitment that damages the lungs. In order to tolerate persistent infections with Mtb, the NO and ROS produced by macrophages also suppresses inflammasome activation to limit the damage caused by recurring neutrophil recruitment. NO directly nitrosylates NLRP3 while the mechanisms of ROS inhibition remain unknown.

Figure 2

Host metabolic networks modulate tolerance to Mtb infections. Distinct metabolic networks control the inflammatory response during Mtb infection. Small molecule activation of Sirt1 with SRT1720 inhibits NF-κβ signaling and activates AMPK and promote tolerance to Mtb. This is similar to treatment with the diabetes drug Metformin that activates AMPK to inhibit inflammation and allow the host to better tolerate persistent Mtb infections. An alternative metabolic network activated by Irg1, produces the metabolite Itaconate. Itaconate can directly restrict Mtb replication, but in vivo robustly controls tolerance by modulating the inflammatory response to persistent infection. Together these metabolic networks directly and indirectly control tolerance to Mtb infection.