Innate immune response to viral infection of the lungs - PubMed (original) (raw)

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Innate immune response to viral infection of the lungs

Hayley See et al. Paediatr Respir Rev. 2008 Dec.

Abstract

Viral respiratory tract infections are the most common infectious illnesses, though they are usually self-limiting and confined to the respiratory tract. The rapid identification of viruses and their effective elimination with minimal local and systemic inflammation is a testament to the efficiency of the innate immune response within the airways and lungs. A failure of this response appears to occur in those with asthma and chronic obstructive pulmonary disease, where viral infection is an important trigger for acute exacerbations. The innate immune response to viruses requires their early detection through pathogen recognition receptors and the recruitment of the efficient antiviral response that is centred around the release of type 1 interferons. The airway epithelium provides both a barrier and an early detector for viruses, and interacts closely with cells of the innate immune response, especially macrophages and dendritic cells, to eliminate infection and trigger a specific adaptive immune response.

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Figure 1

Figure 1

RNA helicases, retinoic-acid-inducible protein (RIG)-I and melanoma-differentiation-associated gene (MDA)-5 detect viral replication in the cytosol. RIG-I detects negative-sense RNA from DNA viruses and MDA-5 detects positive-sense RNA from RNA viruses. RIG-I and MDA-5 signal through interferon response factor (IRF)-3 and IRF-7 to induce interferon (IFN)-β and NF-κB, leading to the transcription of pro-inflammatory mediators. TLR-3 is expressed in intracellular endosomes and responds to the presence of double-stranded RNA (dsRNA) which forms as a product of the replication of the majority of RNA viruses. TLR-3 is dependent on binding with the Toll/IL-1 receptor domain-containing adaptor (TRIF). This leads to phosphorylation of IRF-3 which forms a homodimer and translocates to the nucleus, resulting in the expression of IFN-β. Signalling can also occur that leads to the translocation of NF-κB. TLR-4 is expressed on the surface of cells and recognizes bacterial endotoxin, lipopolysaccharide and the F protein of respiratory syncytial virus (RSV). TLR-4 is able to signal via both MyD88-dependent and -independent pathways and is able to activate a response via IRF-3, NF-κB and activating protein (AP)-1. TLR-7 is found within endosomes and is activated by single-stranded RNA (ssRNA). TLR-9 is also found within endosomes and is activated by unmethylated CpG dsRNA. Both TLR-7 and -9 signal through a MyD88-dependent pathway, leading to the translocation of NF-κB, AP-1 and IRF-7, and the latter is responsible for release of IFN-α. The IFNs mediate their effects through the induction of hundreds of IFN stimulated genes (ISGs), the actions of many of which remain unknown. Induction of IFN-β and IFN-α4 occurs early after virus infection and is regulated by phosphorylation of IRF-3. The other IFN-α genes require synthesis of IRF-7 to lead to their activation and this occurs as a more delayed response requiring a positive feedback signal via the early release of IFN-β/α4 to lead to the full induction of ISGs. Release of type 1 IFNs can be recognized by infected and neighbouring cells and type 1 IFNs exert their actions through specific receptors (IFN receptor-α1/α2). Receptor engagement leads to activation of the IFN stimulated regulatory factor (ISGF)-3 comprised of members of the signal transducers and activators of transcription (STAT)-1 and -2, as well as IRF-9. This complex can directly bind in the nucleus to the IFN stimulated response element, leading to transcription of type 1 IFNs as well as ISGs, especially the antiviral proteins: protein kinase receptor (PKR), RNAse-I and 2′,5′′′ oligoadenylate synthetase, and myxovirus resistance proteins (MxA).

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