Viral infection of the lung: host response and sequelae

Abstract

Because of its essential role in gas exchange and oxygen delivery, the lung has evolved a variety of strategies to control inflammation and maintain homeostasis. Invasion of the lung by pathogens (and in some instances exposure to certain noninfectious particulates) disrupts this equilibrium and triggers a cascade of events aimed at preventing or limiting colonization (and more importantly infection) by pathogenic microorganisms. In this review we focus on viral infection of the lung and summarize recent advances in our understanding of the triggering of innate and adaptive immune responses to viral respiratory tract infection, mechanisms of viral clearance, and the well-recognized consequences of acute viral infection complicating underlying lung diseases, such as asthma.

Keywords: AIM2; APC; ASC; Absent in melanoma 2; Antigen-presenting cell; Apoptosis-associated speck-like protein containing CARD; B-cell immunity; CTL; Cytotoxic CD8(+) T-cell; DAMP; DC; Damage-associated molecular pattern; Dendritic cell; Follicular helper T; GC; Germinal center; HMGB1; High-mobility group box 1; IAV; ILC; ILC-II; IRF; Influenza A virus; Innate lymphoid cell; Interferon regulatory factor; LAPC; Late activator antigen-presenting cell; MAVS; MLN; Mediastinal lymph node; Mitochondrial anti-viral signaling; NK; NLRP3; Natural killer; Nod-like receptor family protein 3; PAMP; PRR; Pathogen-associated molecular pattern; Pattern recognition receptor; RIG-I; RIG-I–like receptor; RLR; RSV; Regulatory T; Respiratory syncytial virus; Retinoic acid–inducible gene I; T(FH); T-cell immunity; TLR; Toll-like receptor; Treg; Type II innate lymphoid cell; Viral sensor molecules; adaptive immunity; innate immunity; stem cells; tissue repair; viral clearance.

Fig 1

Innate recognition of viral pathogen–associated pattern molecules. Interferon (types I and III) production in response to viral respiratory tract infection can be triggered by recognition of (1) double-stranded RNA (dsRNA) by the cytosolic receptors melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) or (2) dsDNA (B-DNA) by DAI or as yet unknown cytosolic DNA receptors (DNA-RX; not depicted). This recognition leads to the activation of interferon regulatory transcription factor (IRF)-3 through the kinase TANK-binding kinase (TBK)-1 (or IKKi) and stimulates the production of interferons (types I and III) at the site of infection. RIG-I is also triggered by 5′-pppRNA transcribed from dsDNA by using RNA polymerase III. In addition, ligation of TLR3, TLR4, TLR7, and TLR9 by respective viral molecules triggers type I interferon production by means of signaling through adaptor molecules, including MyD88, Toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP), TRIF-related adaptor molecule (TRAM) and TIR-domain-containing adapter-inducing interferon-β (TRIF). The association of these adaptors with TBK1 ultimately results in the activation of the IRF family members (ie, IRF3/5/7) and, in some instances, nuclear factor κB, leading to the transcription of interferon genes (types I and III) and proinflammatory cytokines, such as pro–IL-1β, pro–IL-18, and IL-6. Of note, the production of interferons (types I and III) can be amplified by a positive feedback loop in which the interferons produced early trigger transcription in both autocrine and paracrine fashions.

Fig 2

Proposed pathway for NLRP3 inflammasome activation during viral respiratory tract infection. Respiratory tract viruses can trigger both signal 1 and signal 2 for NLRP3 inflammasome activation. Sensing of viral pathogen–associated pattern molecules induces the transcription of pro–IL-1β/pro–IL-18 and NLRP3 along with additional proinflammatory cytokines. The purinergic receptors, such as P2X7 receptor, an ATP-gated ion channel that causes potassium (K⁺) efflux when activated, are partially required for M2-induced inflammasome activation. In the case of influenza virus infection, virus-encoded M2 ion channel protein transports protons (H⁺) out of the lumen and triggers M2-mediated inflammasome activation. Phagolysosomal maturation and the activity of reactive oxygen species (ROS) and cathepsin B also play a role in virus-induced inflammasome activation, although the underlying mechanisms remain to be explored. The activation of the inflammasome in DCs and macrophages leads to the activation of caspase-1, which mediates the processing of pro–IL-1β/pro–IL-18 to mature IL-1β/IL-18 and its subsequent release into the extracellular space. RAGE, Receptor for advanced glycation end-products.