Lung epithelium as a sentinel and effector system in pneumonia--molecular mechanisms of pathogen recognition and signal transduction

Abstract

Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and lung epithelium comprises a large surface between host and environment and is attacked as a primary target during lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the lung epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics.

Figure 1

Transmembraneous receptors involved in lung epithelial cell recognition of pathogens. Heterodimers composed of TLR2/TLR1 or TLR2/TLR6 recognize lipoproteins and lipoteichoic acid. TLR4 detects LPS and bacterial factors like pneumococcal pneumolysin (Ply). Flagellin, an integral structure of bacterial flagella, is recognized by TLR5. Although not acting as classical PRRs in principle, TNF receptor-1 (TNFR1) and platelet activating factor receptor (PAFR) displayed an important role in S. aureus induced pneumonia by recognition of staphylococci protein A or LTA, respectively. In addition, SARS causing coronavirus is detected by angiotensin converting enzyme 2 (ACE2) in the lung epithelium. Transmembraneous TLRs residing within the endosome of some cells detect dsRNA (TLR3), ssRNA (TLR7/8) or CpG DNA (TLR9).

Figure 2

Recognition of pathogens by cytosolic PRRs. (A) As an example, NOD1 is shown. NOD1 is activated by peptidoglycan-derived peptides. The carboxy-terminal LRR domain is involved in agonist recognition, whereas the central NOD (NACHT) domain has ATPase activity and facilitates self-oligomerization. At the amino-terminal a protein-protein interaction mediating caspase-recruitment domain (CARD) is localized (one CARD domain in NOD1, two in NOD2). Recruitment of the kinase-activity containing adaptor molecule RICK transmits the signal to the NF-κB pathway and it may also participate in MAPK stimulation. (B) The cytosolic PRRs MDA5 and RIG-I recognize dsRNA leading to a complex signalling pathway involving molecules like IPS-1, Rip, FADD promoting NF-κB activation, whereas IPS, TBK and IKKi mediate IRF3 activation.

Figure 3

TLRs mediate activation of NF-κB- and IRF-related gene transcription. (A) Examples of recruited adaptor molecules critical for TLR4 function. With the possible exception of TLR3, all TLRs share a MyD88-dependent pathway for the activation of NF-κB. A protein complex composed of TIRAP, MyD88, IRAK4, IRAK1 and TRAF6 mediates NF-κB stimulation. In addition, TRAM, TRIF as well as TRAF6 and TBK1 stimulate IRF3 activation. (B) Located in the endosomal membrane, TLR3 recognizes dsRNA. Whereas TRIF recruitment connects TLR3 via TBK1 to IRF3 activation, further recruitment of RIP1 and TRAF6 stimulates NF-κB.

Figure 4

Histone modifications regulate the accessibility of the DNA to transcription factors. (A) In most cases, hyperacetylation (Ac) of histones loosens DNA-histone interaction thereby making gene promoters amenable for the binding of transcription factors. After stimulation of transmembraneous (e.g. TLRs) or cytosolic (e.g. NODs) PRRs histone acetylases (HATs) may be recruited whereas histone deacetylases (HDACs) may disappear resulting in increased histone acetylation. (B) In addition, after binding of the transcription factors to the DNA further modification of the bound transcription factor by PRR-mediated MAPK-dependent phosphorylation may be necessary to induce recruitment of the basal transcription apparatus of the cell and subsequent gene transcription as shown for pneumococci infected pulmonary epithelial cells.