Divergent functions of Toll-like receptors during bacterial lung infections

Abstract

Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD4(+) T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs.

Keywords: Toll-like receptor; bacterial infection; evasion of Toll-like receptor signaling; lung.

Figure 1.

Signaling cascades on activation of pattern recognition receptors by pulmonary pathogens. Plasma membrane-bound Toll-like receptors (TLRs) (TLR1, 2, 4, 5) and endosome membrane-bound TLRs (TLR9) recognize bacteria in the lungs. After bacterial recognition, TLR2 (with TLR1 or 6), TLR4 (in association with MD-2 and CD14), TLR5, and TLR9 recruit MyD88, whereas TLR2 and TLR4 recruit both MyD88 and Toll-IL-1R domain-containing adapter protein (TIRAP). All of these TLRs activate IL-1 receptor-associated kinase (IRAK) after MyD88 recruitment, followed by recruitment of tumor necrosis factor receptor–associated factor 6 (TRAF6), ultimately resulting in activation of the transcription factor nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). MAPK activation, in turn, results in the induction of transcription factors AP-1 and c-fos. In addition, TLR3 and TLR4 recruit the adaptor TIR-domain–containing adapter-inducing IFN-β (TRIF), ultimately leading to IRF3-mediated IFN-α/β and inducible nitric oxide synthase (iNOS) production through the intermediate signaling molecule TRAM, which is the bridging adaptor for TRIF-mediated signaling. In addition, pulmonary bacterial pathogens release ligands during infection that are recognized by nucleotide-binding oligomerization domains (NODs) and activate subsequent signaling pathways leading to NF-кB activation. Furthermore, when stimulated by ligands, the NOD-like receptor proteins (NLRP) induce activation of effector caspase-1, which cleaves the pro forms of IL-1β and IL-18. In turn, cytokine activation results in differentiation of naive T cells into Th1, Th17, or regulatory T cells (Tregs), thereby leading to pulmonary host defense or, in the case of Treg accumulation, resulting in host pathology. A. baumannii = Acinetobacter baumannii; E. coli = Escherichia coli; F. tularensis = Francisella tularensis; H. influenzae = Haemophilus influenzae; K. pneumoniae = Klebsiella pneumoniae; L. pneumophila = Legionella pneumophila; M. tuberculosis = Mycobacterium tuberculosis; P. aeruginosa = Pseudomonas aeruginosa; S. pneumoniae = Streptococcus pneumoniae.

Figure 2.

Regulation of Toll-like receptor (TLR) signaling during bacterial lung infections. Negative regulators of TLRs (shown in red in pale green ellipses), IL-1 receptor-associated kinase-M (IRAK-M), suppressor of cytokine signaling 1 (SOCS-1), SOCS-3, cylindromatosis (CYLD), and A20, target different molecules within the TLR signaling pathway to inhibit their expression or activation. Positive regulators (shown in blue in darker green ellipses), triggering receptor expressed on myeloid cell 1 (TREM-1), receptor for advanced glycation end products (RAGE), secretory molecules of bacterial secretion system, amplify the TLR signaling response by activating nuclear factor (NF)-кB and/or mitogen-activated protein kinases (MAPKs). B. pseudomallei = Burkholderia pseudomallei; C. pneumoniae = Chlamydophila pneumoniae; F. tularensis = Francisella tularensis; H. influenzae = Haemophilus influenzae; K. pneumoniae = Klebsiella pneumoniae; L. pneumophila = Legionella pneumophila; P. aeruginosa = Pseudomonas aeruginosa; S. aureus = Staphylococcus aureus; S. pneumoniae = Streptococcus pneumoniae.