Key Points
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The respiratory tract is a major portal of entry for viruses into the body. Infection of the respiratory tract can, if severe, induce life-threatening damage to the lungs. Various strategies to control virus replication and to limit immune-mediated inflammation and tissue injury have evolved in the respiratory tract.
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Multiple innate immune cell types, particularly dendritic cells (DCs), within the pulmonary interstitium and between airway epithelial cells are strategically poised to recognize and sample airway particulates, such as viruses.
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In response to respiratory virus infection, several distinct DC subsets are stimulated to migrate from the site of infection in the lungs to the draining lymph nodes. Here, these migrant DCs have a crucial role in initiating the antivirus adaptive immune response to the invading viruses.
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After entering the infected lungs, effector T cells that were generated in the lymph nodes undergo further modifications that are shaped by the inflammatory milieu.
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Co-stimulatory receptor–ligand interactions between effector T cells and various cell types presenting viral antigens in the infected lungs modulate the host adaptive immune response in situ.
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Effector T cells that produce pro-inflammatory mediators are also the major producers of regulatory (anti-inflammatory) cytokines, providing a fine-tuning mechanism of self-control by effector T cells responding to viruses in the inflamed tissue.
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The immune mechanisms that control virus replication and/or excessive inflammation in the virus-infected lungs can also predispose the individual recovering from a virus infection to bacterial superinfection. Therapeutic strategies should consider balancing the need to inhibit virus replication and excessive inflammation with the need to optimize the antibacterial functions of innate immune phagocytes, which are crucial for clearing the bacteria from the lungs.
Abstract
Recent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed.
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Acknowledgements
We thank the members of the Braciale laboratory for their editorial assistance and insightful discussions, and colleagues in the field who provided recent publications and personal communications. As a result of space limitations we apologize for being unable to cite many primary references relevant to the topic of this Review. This study was supported by grants to T.J.B. from the US National Institutes of Health (RO1 AI-15608, RO1 AI-37293, RO1 HL-33391 and U-19 AI-83024). T.S.K. and J.S. are recipients of Senior Research Training Fellowships from the American Lung Association.
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Supplementary information
Supplementary information S1 (table)
Viruses that induce infections in humans that are primarily localized to the respiratory tract (PDF 82 kb)
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Non-immune barriers and innate immune defence to virus infection in the lung (PDF 105 kb)
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Glossary
- Type I and type II alveolar epithelial cells
-
Type I alveolar epithelial cells (also known as squamous alveolar cells and type I pneumocytes) form the structure of the alveolar wall and are responsible for gas exchange in the alveoli. Type II alveolar epithelial cells (also known as great alveolar cells) continually secrete pulmonary surfactant to lower the surface tension of pulmonary fluids, thereby increasing gas exchange.
- Acute respiratory distress syndrome
-
(ARDS). A severe inflammatory disease of the lung that is usually triggered by another pulmonary pathology. The uncontrolled inflammation leads to impaired gas exchange, alveolar flooding and/or collapse, and systemic inflammatory response syndrome.
- Plasmacytoid DCs
-
(pDCs). A dendritic cell (DC) subtype defined by the expression of CD11c and B220 and the lack of CD8 and CD11b. pDCs are specialized to produce large amounts of type I interferons in response to viral infection, and they therefore have an important role in the immune response to viruses.
- Integrin
-
A member of a group of proteins that regulate the attachment of cells to one another (cell–cell adhesion) and to the surrounding network of proteins and other molecules (cell–matrix adhesion). Integrins also transmit chemical signals that regulate cell growth and the activity of certain genes.
- Sphingosine-1-phosphate
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(S1P). A sphingolipid that is involved in signalling. In the immune system, S1P induces the egress of lymphocytes from lymphoid organs by binding to S1P receptors on the cells.
- Cross-presentation
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A mechanism that can initiate a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.
- Efferocytosis
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The phagocytic clearance of apoptotic cells before they undergo secondary necrosis. The process usually triggers an anti-inflammatory response.
- Inflammatory DCs
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Dendritic cells (DCs) that are not normally present in the steady state but develop as a result of inflammation or microbial stimuli. For example, one such subset is tumour necrosis factor- and inducible nitric oxide synthase-producing DCs (TIP DCs). Inflammatory monocytes can also give rise to inflammatory DCs.
- Effector TReg cell
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A regulatory T (TReg) cell that expresses particular transcription factors, such as T-bet, and follows a differentiation pathway to acquire a phenotype or function for efficiently controlling a specific subset of effector T cells, such as TH1 cells.
- Alternatively activated macrophages
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(Also known as M2 macrophages). Macrophages that are stimulated by IL-4 or IL-13 and that express arginase 1, the mannose receptor CD206 and IL-4 receptor. There may be pathogen-associated molecular patterns expressed by helminths that can also drive the alternative activation of macrophages.
- Innate lymphoid cells
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(ILCs; also known as natural helper cells and nuocytes). Cells that combine innate and adaptive immune functions and are part of the first line of defence against mucosal infections. ILCs are distinguished from adaptive lymphocytes by their independence from recombination-activating genes and the resulting absence of specific antigen receptors. They produce large quantities of type 2 cytokines such as IL-5 and IL-13.
- Fibrocytes
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Mature fibroblasts that no longer produce fibres or intercellular substance in connective tissue. Fibroblasts are large, flat cells that form the collagenous and elastic fibres and intercellular substance of loose connective tissue.
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Braciale, T., Sun, J. & Kim, T. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol 12, 295–305 (2012). https://doi.org/10.1038/nri3166
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DOI: https://doi.org/10.1038/nri3166
