Role of innate cytokines in mycobacterial infection

Abstract

Cells of the innate immune system produce cytokines and lipid mediators that strongly influence the outcome of mycobacterial infection. In the case of Mycobacterium tuberculosis, the lung is a critical site for this interaction. Here, we review current information on the role of the major innate cytokine pathways both in controlling initial infection as well as in promoting and maintaining adaptive T-cell responses that mediate host resistance or immunopathology. Understanding this important feature of the host-pathogen interaction can provide major insights into the mechanisms of virulence and can lead to new approaches for immunological intervention in tuberculosis and other mycobacterial diseases.

Figure 1. Innate cytokines act during the initiation, expansion and chronic stages Mtb infection

The exposure of lung phagocytes to invading Mtb results in binding of the bacteria and/or bacterial products to specific receptors which then induce innate cytokine production by the infected cell. TNF and LT are produced by bacterially exposed phagocytes and promote the expression of chemokines that recruit inflammatory cells to the lung. Mtb can modulate the level of TNF and inflammation induced by altering the structure of glycolipids and mycolates on their surface. IL-12p80 promotes migration of bacteria- and antigen-bearing dendritic cells from the lung to the lymph node to start the acquired response. Virulent bacteria modulate the response of the phagocytes by induction of LTB4 and promote necrotic death of infected cells. Expression of innate cytokines within the lymph node defines the effector function of the T cells. Within the inflammatory site, infected phagocytes control bacterial growth in an IFN-γ, TNF and IL-1R1 dependent manner. ESX-1 related activity by the bacteria can promote the protective IL-1β response while increasing the detrimental type I IFN response. Mononuclear inflammation is promoted by IFN-γ and IL-12p70 while granulocytic and damaging inflammation is driven by IL-23 and IL-17 during the chronic phase of disease. IL-10 and IL-27 regulate protective responses but also limit inflammatory responses. A high dose of bacteria or infection in the absence of acquired immunity illustrates the potential protective role of innate cytokines that do not show a role in low dose aerosol infections.