Chemokines in tuberculosis: the good, the bad and the ugly

Abstract

Mycobacterium tuberculosis (Mtb) infects about one-third of the world's population, with a majority of infected individuals exhibiting latent asymptomatic infection, while 5-10% of infected individuals progress to active pulmonary disease. Research in the past two decades has elucidated critical host immune mechanisms that mediate Mtb control. Among these, chemokines have been associated with numerous key processes that lead to Mtb containment, from recruitment of myeloid cells into the lung to activation of adaptive immunity, formation of protective granulomas and vaccine recall responses. However, imbalances in several key chemokine mediators can alter the delicate balance of cytokines and cellular responses that promote mycobacterial containment, instead precipitating terminal tissue destruction and spread of Mtb infection. In this review, we will describe recent insights in the involvement of chemokines in host responses to Mtb infection and Mtb containment (the good), chemokines contributing to inflammation during TB (the bad), and the role of chemokines in driving cavitation and lung pathology (the ugly).

Keywords: Chemokines; Lung; Mycobacterial infections.

Figure 1. “The good”: mechanisms that mediate lung Mtb containment

Upon Mtb entry into the lungs, alveolar macrophages become infected, leading to secretion of cytokines and chemokines, which drive additional innate cell recruitment (1). Infected DCs migrate into the lung draining lymph nodes (dLN) (2), carrying antigen that can be subsequently taken up by other APCs to activate naïve T cells (3). After activation, T cells (along with B cells) regulate their chemokine receptor expression, which guide their exit from the lymph node (4), homing to the infected lung (5), and subsequent migration. These responses are mediated by differential expression of chemokines, a process that enables ectopic lymphoid follicle formation (6). Additional innate cells, such as monocytes and neutrophils are also recruited into the lung (7). Together, interactions between innate and adaptive cells lead to granuloma formation and Mtb containment (8). Dashed blue lines represent chemokine-driven mechanisms.

Figure 2. “The bad”: transition to a dysregulated proinflammatory granuloma

An imbalance between anti-inflammatory and pro-inflammatory factors can lead to dysregulated inflammation in TB, a feature of which is accumulation of large numbers of neutrophils in the lungs. Through the secretion of numerous chemokines and molecules, such as S100A8/A9 proteins, neutrophils can perpetuate inflammation during TB.

Figure 3. “The ugly”: TB necrosis, cavitation and spread

The hallmark of active TB in humans and in several animal models is cavitation, which is a product of persistent inflammation and tissue destruction. Central to this process are matrix metalloproteinases, which can degrade the extracellular matrix that maintains lung structure, and cleave chemokines. These novel chemokine variants can be more or less active than their native counterparts, and their production likely alters the balance of cells that are recruited into the lung. This overwhelming inflammation and matrix destruction communicates Mtb-rich granulomas with the airways, facilitating Mtb spread.