The Airway Epithelium: Soldier in the Fight against Respiratory Viruses

In the paper

“Activation of epithelial cells results in immediate host defense responses that include production of antiviral substances as well as proinflammatory cytokines which recruit and activate other mucosal innate immune cells and initiate mechanisms of adaptive immunity (108).”

What the sources say

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In the paper

“Besides its role in maintaining the conduit for air to and from the alveoli, the airway epithelium is central to the defense of the lung against pathogens, through the combined function of ciliated epithelial and secretory cells maintaining efficient mucociliary clearance and through a variety of other host defense mechanisms (45, 65, 144).”

What the sources say

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In the paper

“The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions.”

In the paper

“Primary human airway epithelial cells and cell lines derived from them have been shown to express 10 TLRs (TLR1 to -10) (188, 260), and TLR expression has been documented for human biopsy tissue (101).”

What the sources say

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In the paper

“Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.”

In the paper

“While airway defense mechanisms efficiently fight respiratory viruses most of the time, resulting in rapid clearance of the virus with minimal clinical consequences, viruses have found ways of avoiding immune responses in the airways, with the potential consequence of severe respiratory disease.”

In the paper

“In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones.”

In the paper

“Innate immune responses of the epithelium allow for control of viral invasion and replication, and adaptive responses allow for effective viral clearance through cells of the adaptive immune system.”

In the paper

“However, mucin overproduction and excessive mucus formation can lead to airway obstruction and exacerbation of preexisting airway disease, turning a powerful innate cleaning defense system into a detrimental mechanism (see The Wounded Soldier) (239, 298).”

What the sources say

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In the paper

“These defense mechanisms usually result in rapid virus clearance.”

In the paper

“They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms.”

In the paper

“Type III IFNs possess antiviral properties similar to those of type I IFNs but appear to be expressed especially by epithelial cells and consequently exert host protection primarily at epithelial surfaces (8, 9, 335).”

What the sources say

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In the paper

“Binding of RNA species to RIG-I and MDA5 leads to interaction of CARDs within an adaptor protein called IPS-1, MAVS, VISA, or Cardif (222). This outer mitochondrial membrane protein mediates the recruitment and activation of protein kinases that phosphorylate the transcription factor IRF-3, leading to the synthesis of type I and type III IFNs (155).”

What the sources say

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In the paper

“For example, RSV induces replication-mediated activation of the IFN-β promoter via RIG-I signaling (253).”

What the sources say

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In the paper

“It has been shown that the RSV fusion protein interacts with TLR4, which then signals through MyD88 to induce immune responses in airway epithelial cells (28, 92, 103, 152), and a recent study demonstrated RSV interaction with TLR2 and TLR6, promoting a proinflammatory response (190).”

What the sources say

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In the paper

“Among them, IFNs, lactoferrin (LF), β-defensins (BDs), and nitric oxide (NO) are considered the most important epithelium-derived antiviral host defense molecules (Fig. 1).”

In the paper

“TLRs trigger activation predominantly of mitogen-activated protein (MAP) kinases and of several key transcription factors, including NF-κB, interferon regulatory factor 3 (IRF-3), and IRF-7, resulting in the induction of numerous proinflammatory cytokines and type I (α and β) and type III (λ) IFNs (120).”

What the sources say

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In the paper

“In contrast, RIG-I has been shown to detect negative-sense ssRNA viruses that bear a 5′-triphospho-RNA genome, such as influenza virus and RSV, and appears to play a crucial role in the antiviral response to infection with these viruses (138).”

What the sources say

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In the paper

“NLRP3 expression and production of IL-1β are induced in primary human airway epithelial cells in response to influenza A virus infection, but it has yet to be determined whether NLRP3 acts directly as a PRR for viral RNA or if it is activated only indirectly in response to PRR signaling (5).”

What the sources say

• Not checked yetcites [5] Allen, I. C., M. A. Scull, C. B. Moore, E. K. Holl, E. McElvania-TeKippe, D. J. Taxman, E. H. Guthrie, R. J. Pickles, and J. P. Ting. 2009. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30:556-565. [DOI] [PMC free article] [PubMed] [Google Scholar]

In the paper

“IFN-α and IFN-β were among the first antiviral agents to be characterized and are still seen as central to the early antiviral response of virus-infected cells.”

In the paper

“It prevents entry of virus into the host cell, either by blocking cellular receptors or by direct binding to virus particles (290).”

What the sources say

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In the paper

“MDA5 has been shown to detect small RNA viruses such as rhinoviruses and is critical in regulating IFN-β, IFN-λ, and proinflammatory cytokine transcription (138).”

What the sources say

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In the paper

“This defective IFN response may promote susceptibility to infection by impairing the ability of the infected host cell to undergo early apoptosis and by allowing increased virus replication and, ultimately, cytolysis of infected cells.”

In the paper

“Four hBDs (hBD-1 to -4) for airway mucosal defense have been identified in respiratory epithelial cells, but only hBD-2 and hBD-3 act against respiratory viruses (52, 73, 148, 267, 324).”

What the sources say

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In the paper

“Data for humans show that increased exhaled nitric oxide after rhinovirus infection is correlated with reduced airway hyperresponsiveness in asthmatic patients, suggesting a beneficial effect of NO in virus-induced asthma exacerbations (42).”

What the sources say

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In the paper

“Activation of NF-κB is common to many respiratory viruses, as demonstrated for rhinovirus (129, 203), RSV (24), and influenza virus (145).”

What the sources say

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In the paper

“The importance of nitric oxide production in antiviral defense of the airway epithelium is demonstrated by studies showing that increased virus (parainfluenza virus 3) replication in airway epithelial cells from CF patients is due at least partly to a lack of NOS-2 induction in response to virus and that NO donor or NOS-2 overexpression provides protection from virus infection (333, 334).”

What the sources say

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In the paper

“NOS-2 is induced and NO production increased after infection with respiratory viruses (136, 191, 246, 287).”

What the sources say

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In the paper

“Respiratory epithelial cells produce high levels of NO, as evidenced by detection of NO in exhaled breath and of NO reaction products (e.g., NO2− and NO3−) in bronchoalveolar lavage fluid from human lungs (77).”

What the sources say

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In the paper

“Bronchial biopsy specimens from subjects undergoing experimental rhinovirus infection show T-cell infiltration of the airway epithelium (69).”

What the sources say

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In the paper

“RSV strains have also been documented to induce different patterns and severities of inflammatory responses (173, 174, 271).”

What the sources say

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In the paper

“Airway epithelial cells have been shown to enhance cDC migration into the epithelium via MIP-3α/CCL20 production (232), and MIP-3α/CCL20 induction has been demonstrated in several viral infections, such as influenza virus infection (178, 308).”

What the sources say

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In the paper

“However, upon extrinsic and intrinsic stimuli such as viral infections, this complex regulatory mechanism is lost or shifts and proinflammatory immune responses are initiated (113, 301).”

What the sources say

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In the paper

“In contrast to cDCs, pDCs are not efficient antigen-presenting cells. Rather, their antiviral action is mediated by production of large amounts of IFN-α, which delivers a powerful innate response to limit viral replication.”

In the paper

“Upon viral infection, pDCs are recruited rapidly from the bone marrow, and within several days, they form the majority of DCs in the lung (300).”

What the sources say

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In the paper

“For instance, studies of mice presensitized by recombinant vaccinia viruses showed that after RSV infection, animals exhibiting mainly Th2 cytokine responses developed enhanced disease with severe symptoms, whereas those with Th1 responses had reduced immunopathology and enhanced viral clearance (6).”

What the sources say

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In the paper

“The appearance of antigen-specific effector T cells in the airways is observed around 6 to 7 days after infection with influenza and parainfluenza viruses (275).”

What the sources say

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In the paper

“For instance, pandemic influenza viruses, including H5N1 avian influenza virus and the H1N1 2009 California influenza virus strain, have been associated with more severe inflammation than seasonal influenza virus strains, and it is believed that the magnitude of inflammation is a major contributing factor to disease severity (17, 200, 209, 283, 319).”

What the sources say

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In the paper

“NK cells also play an important role in the innate immune response against respiratory viruses, with their function being the elimination of a variety of target cells, including virus-infected cells, and the modulation of adaptive immunity toward an efficient antiviral response (22).”

What the sources say

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In the paper

“Similarly, rhinovirus group C strains are thought to be associated with increased inflammation and morbidity compared with rhinovirus group A or B strains (10, 125).”

What the sources say

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In the paper

“Airway epithelial cells induce migration of Th1 cells into the mucosa via production of RANTES/CCL5 and IP-10/CXCL10 and that of Th2 cells via production of IL-1β (178).”

What the sources say

• Not checked yetcites [178] Message, S. D., and S. L. Johnston. 2004. Host defense function of the airway epithelium in health and disease: clinical background. J. Leukoc. Biol. 75:5-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

In the paper

“Airway epithelial cells not only mediate innate immune responses but also regulate adaptive immune responses through interactions with DCs and T and B lymphocytes.”

In the paper

“Interestingly, however, inhibition of neutrophil recruitment to the lung had no effect on virus clearance in a mouse model of influenza virus infection, suggesting only a minor role of neutrophils in this model of respiratory viral infection (309).”

What the sources say

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In the paper

“Using in vitro culture systems, some differences between susceptibilities to rhinovirus infection have been noted, with bronchial epithelium generating higher viral loads and more expression of virus-inducible mediators than those in bronchial epithelial cells cultured in the same manner (163).”

What the sources say

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In the paper

“Whereas rhinovirus-induced cytotoxicity was shown in bronchial epithelial cells after rhinovirus infection (27)”

What the sources say

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In the paper

“Cytotoxicity upon infection with certain viruses may depend on the virus strain, infection conditions, and infected cell type and density (27).”

What the sources say

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In the paper

“We further discuss how vRTIs can lead to perturbed inflammatory responses and to increased mucus production, which will be detrimental rather than protective to the host.”

In the paper

“However, considering that the airway epithelium is the main site of viral infection, it is likely to contribute significantly to the type and magnitude of the inflammatory response.”

In the paper

“For instance, TGF-β increases airway wound repair through MMP-2 upregulation (154).”

What the sources say

• Not checked yetcites [154] Lechapt-Zalcman, E., V. Pruliere-Escabasse, D. Advenier, S. Galiacy, C. Charriere-Bertrand, A. Coste, A. Harf, M. P. d'Ortho, and E. Escudier. 2006. Transforming growth factor-beta1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair? Am. J. Physiol. Lung Cell. Mol. Physiol. 290:L1277-L1282. [DOI] [PubMed] [Google Scholar]

In the paper

“Migrating basal airway epithelial cells repopulate damaged areas, proliferate, and differentiate until epithelial integrity has been restored (242).”

What the sources say

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In the paper

“MMPs play a crucial role in the remodeling of the matrix onto which cells migrate, and many pathways are involved in this process (294).”

What the sources say

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In the paper

“Most viruses have efficient ways to inhibit IFN synthesis, to bind and inactivate secreted IFN molecules, to block IFN-activated signaling, or to disturb the action of IFN-induced antiviral proteins.”

In the paper

“It is currently believed that NS2 prevents RIG-I signaling by interfering with the RIG-I-MAVS interaction, therefore severely limiting signaling mediated by the critical interaction between the sensor RIG-I and its specific adaptor, MAVS (161).”

What the sources say

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In the paper

“V proteins may be expressed at high levels during the initial stages of infection and therefore limit IRF3 activation by binding IKK-ɛ and preventing IRF-3 activation, and hence IFN induction (165).”

What the sources say

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In the paper

“Furthermore, they induce the production of proangiogenic molecules, including amphiregulin (a member of the epidermal growth factor [EGF] family) and vascular endothelial growth factor (VEGF), and therefore may lead to increased angiogenesis (156, 220).”

What the sources say

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In the paper

“The NS1 and NS2 proteins of RSV inhibit STAT-2 activation, thus blocking IFN-α/β function (161, 162).”

What the sources say

• Not checked yetcites [161] Ling, Z., K. C. Tran, and M. N. Teng. 2009. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J. Virol. 83:3734-3742. [DOI] [PMC free article] [PubMed] [Google Scholar]
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In the paper

“A role for airway epithelial cells in contributing to the Th2 phenotype is possible, as they have receptors for and respond to IL-4, IL-13, and IL-25 (68, 115).”

What the sources say

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In the paper

“In allergic asthmatic subjects, Th1 responses to rhinovirus are downregulated, as indicated by lower levels of IL-12 and IFN-γ, whereas Th2 responses are increased, with higher levels of IL-4, IL-5, and IL-13 (179).”

What the sources say

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In the paper

“Furthermore, RSV and rhinovirus can lead to induction of the pro-Th2 cytokine TSLP, suggesting a direct link between viral infection of the epithelium and an altered immune response toward a Th2 pattern (4, 157, 264).”

What the sources say

• Not checked yetcites [4] Allakhverdi, Z., M. R. Comeau, H. K. Jessup, B. R. Yoon, A. Brewer, S. Chartier, N. Paquette, S. F. Ziegler, M. Sarfati, and G. Delespesse. 2007. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J. Exp. Med. 204:253-258. [DOI] [PMC free article] [PubMed] [Google Scholar]
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In the paper

“This is illustrated by studies showing that influenza virus infection results in decreased tracheal mucociliary velocity and clearance of S. pneumoniae (172, 213).”

What the sources say

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In the paper

“For instance, rhinoviruses disrupt airway epithelial barrier functions and promote the paracellular migration of bacteria such as H. influenzae (244).”

What the sources say

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In the paper

“In addition, perturbation of the epithelial barrier upon virus infection may increase paracellular permeability and facilitate translocation of bacteria and their soluble products into the submucosa.”

What the sources say

• Not checked yetcites [244] Sajjan, U., Q. Wang, Y. Zhao, D. C. Gruenert, and M. B. Hershenson. 2008. Rhinovirus disrupts the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 178:1271-1281. [DOI] [PMC free article] [PubMed] [Google Scholar]

In the paper

“Mechanisms involved in ciliostasis are poorly understood but could be mediated by ion alterations during viral attachment and replication, by direct damage to the ciliary system, or by damage through the induction of NO, cyclic AMP, calmodulin, and inositol 1,4,5-triphosphate (InP3) production, which alters baseline ciliary beat frequency (33) or modulates hfh4 and mdnh5 gene expression, resulting”

What the sources say

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In the paper

“It also increases the expression of ICAM-1, which serves as a receptor both for itself and for H. influenzae (11, 316).”

What the sources say

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In the paper

“For instance, whereas RSV upregulates cellular receptors such as ICAM-1 and CEACAM-1, leading to an increase of bacterial adherence, influenza virus has no effect on the expression of these receptors (11).”

What the sources say

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In the paper

“Increased bacterial adherence facilitates biofilm formation and could represent a critical step in permanent airway colonization by P. aeruginosa in cystic fibrosis patients (98).”

What the sources say

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In the paper

“In addition, virus-induced cell death may expose new receptors for bacterial adherence or impair mechanical removal of attached pathogens (30, 41, 96).”

What the sources say

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In the paper

“Mechanisms responsible for the increased adherence to respiratory epithelial cells differ between viruses and also between cell types.”

In the paper

“For example, steroids are well established as suppressors of viral (56, 268, 296) and bacterial (100) inflammation and mucin production and may modulate epithelial damage, injury, and repair.”

What the sources say

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In the paper

“Impairment of TLR4 and TLR5 has been demonstrated after influenza virus infection, leading to reduced neutrophil recruitment and increased P. aeruginosa and S. pneumoniae adherence in airway epithelial cells (46).”

What the sources say

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In the paper

“They lead to more than 400,000 hospitalizations per year among children in the United States and are therefore a major burden on the health care system (105, 180, 194).”

What the sources say

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In the paper

“A recent study demonstrated effectiveness of the ketomacrolide telithromycin in asthma exacerbations (128).”

What the sources say

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In the paper

“a recent study found no protective effect of the above in a trial of post-RSV bronchiolitis in children (23).”

What the sources say

• Not checked yetcites [23] Bisgaard, H., A. Flores-Nunez, A. Goh, P. Azimi, A. Halkas, M. P. Malice, J. L. Marchal, S. B. Dass, T. F. Reiss, and B. A. Knorr. 2008. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Am. J. Respir. Crit. Care Med. 178:854-860. [DOI] [PubMed] [Google Scholar]

In the paper

“By use of in vitro culture systems, azithromycin was able to augment rhinovirus-induced IFNs and their inducible genes and to decrease virus replication (81).”

What the sources say

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In the paper

“vRTIs are an important cause of morbidity and, in some cases, mortality.”

What the sources say

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In the paper

“While a recent study demonstrated that children admitted to hospital with asthma-related symptoms were less likely to have used therapies, including leukotriene receptor antagonists (127)”

What the sources say

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In the paper

“However, respiratory viruses have evolved strategies to subvert epithelial defense mechanisms and can lead to complications such as loss of epithelial integrity, perturbed inflammatory responses, increased mucus production, and secondary bacterial infections.”