Cellular and humoral mechanisms involved in the control of tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs). We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB.

Figure 1

Pathogenesis of tuberculosis. TB pathogenesis can be divided in four well-defined events. Inhalation of the mycobacteria is followed by its interaction with resident macrophages through cellular receptors and its internalization. Macrophage bactericidal mechanisms are then activated, including RNI and ROI generation. The efficient killing of mycobacteria depends on pathogen and host factors. Inflammatory cell recruitment: survived mycobacteria proliferate within macrophages inducing the production of proinflammatory cytokines. The local inflammatory environment induces the recruitment of several cell types including monocytes, neutrophils, and dendritic cells to the site of infection. High levels of TNF-α contribute to control Mtb growth and granuloma formation. Control of mycobacteria proliferation: arrival of immune cells to the site of infection including T cells, which become organized in characteristic structures called granulomas efficiently stop mycobacteria proliferation and contain the mycobacteria within the granuloma walls preventing its spread. Characteristic of this structure is the presence of foam cells resulting from the differentiation of chronically activated macrophages. Mycobacteria containment eventually becomes stable (latent) infection. Postprimary TB: mycobacteria persistence associated with a failure in the immunosurveillance system increases the risk that latent disease becomes reactivated, inducing the damage of nearby bronchi and conditioning the spreading of the Mtb to other areas of the lung and the transmission of the disease.

Figure 2

TLRs signaling pathways involved in the recognition of Mtb structures.TLR receptors can recognize several conserved molecular patterns of the mycobacteria cell wall. Diacylated or triacylated proteins as well as LPS are recognized by membrane receptors (TLR1, TLR2, TLR6, and TLR4), whereas bacterial unmethylated CpG DNA can be recognized by endosomal TLR9. MyD88 adaptor is a central component in TLR signaling whose downstream signaling cascade leads to the activation of NF-kB and AP-1 transcription factors and to the production of inflammatory cytokines. Signaling through TRIF adaptor molecule activates IRF-3 transcription factor inducing IFN-β secretion.