Dynamic Innate Immune Responses of Human Bronchial Epithelial Cells to Severe Acute Respiratory Syndrome-Associated Coronavirus Infection

Yoshikawa, Tomoki; Hill, Terence E.; Yoshikawa, Naoko; Popov, Vsevolod L.; Galindo, Cristi L.; Garner, Harold R.; Peters, C. J.; Tseng, Chien-Te K.

doi:10.1371/journal.pone.0008729

Cited by 185 publications

(201 citation statements)

References 77 publications

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“…Both of these interferons have been reported to be elevated in experimental SARS-CoV infections in primates and in cell lines infected with SARS-CoV (15, 24, 41). IL-29 is important in the innate immune response and may help control SARS-CoV infection (29,41,42).…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome–Coronavirus

Qian

Travanty

Oko

et al. 2013

Am J Respir Cell Mol Biol

286

266

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Severe acute respiratory syndrome (SARS)-coronavirus (CoV) produces a devastating primary viral pneumonia with diffuse alveolar damage and a marked increase in circulating cytokines. One of the major cell types to be infected is the alveolar type II cell. However, the innate immune response of primary human alveolar epithelial cells infected with SARS-CoV has not been defined. Our objectives included developing a culture system permissive for SARS-CoV infection in primary human type II cells and defining their innate immune response. Culturing primary human alveolar type II cells at an airliquid interface (A/L) improved their differentiation and greatly increased their susceptibility to infection, allowing us to define their primary interferon and chemokine responses. Viral antigens were detected in the cytoplasm of infected type II cells, electron micrographs demonstrated secretory vesicles filled with virions, virus RNA concentrations increased with time, and infectious virions were released by exocytosis from the apical surface of polarized type II cells. A marked increase was evident in the mRNA concentrations of interferon-b and interferon-l (IL-29) and in a large number of proinflammatory cytokines and chemokines. A surprising finding involved the variability of expression of angiotensin-converting enzyme-2, the SARS-CoV receptor, in type II cells from different donors. In conclusion, the cultivation of alveolar type II cells at an air-liquid interface provides primary cultures in which to study the pulmonary innate immune responses to infection with SARS-CoV, and to explore possible therapeutic approaches to modulating these innate immune responses.Keywords: lung innate immune response; cytokine responses to SARS coronavirus; lung cell differentiation; air-liquid interface culturesSevere acute respiratory syndrome-associated coronavirus (SARSCoV) produces devastating viral pneumonia (1, 2). Pathologic changes are most prominent in the lungs, with disruptions of the epithelium in gas exchange areas and conducting airways (2-4). The epithelial cells of the alveoli and the conducting airways are the primary targets of SARS-CoV in the human lung, and they express the SARS receptor, angiotension-converting enzyme-2 (ACE2) (5-8). In autopsies of patients with SARS, coronavirus RNA and proteins have been detected in type II cells via immunocytochemisty and in situ hybridization (7,(9)(10)(11)(12)(13)(14). In the aged macaque model of SARS, in which the initial site of infection in the lung can be studied, virus infection was detected in both alveolar type I and type II cells (11,15). In human SARS autopsy specimens, the infection of alveolar macrophages was also suggested because they contained SARS antigens and formed multinucleated giant cells (2, 11). However, in vitro human alveolar macrophages, monocyte-derived dendritic cells, and monocytes are not readily susceptible to SARS-CoV, and these cell types show only very modest cytokine and interferon responses upon exposure to SARS-CoV (16-21).One of the major...

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Section: Discussionmentioning

confidence: 99%

Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome–Coronavirus

Qian

Travanty

Oko

et al. 2013

Am J Respir Cell Mol Biol

286

266

View full text Add to dashboard Cite

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“…After 24 h, samples were processed to examine viral RNA levels by quantitative RT-PCR, released viral particles in cell supernatants by plaque assay, and the auophagic pathway (LC3 I and LC3 II expression) by Western blot. IFN-β and IFN-λ1 concentrations were chosen based on previous publications in human lung epithelial cell cultures (Spurrell et al 2005, Suh et al 2007, Yoshikawa et al 2010) and our preliminary IFN dose (1, 3, and 10 ng/ml) and time course (4 and 24 h) optimization experiments in which 3 ng/ml of IFN-β and 10 ng/ml of IFN-λ1 demonstrated the maximal inhibitory effect on HRV-16 replication at 24 h.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway

Dyk

Jiang

et al. 2013

Virology

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Human rhinovirus (HRV) is the most common viral etiology in acute exacerbations of asthma. However, the exact mechanisms underlying HRV infection in allergic airways are poorly understood. IL-13 increases interleukin-1 receptor associated kinase M (IRAK-M) and subsequently inhibits airway innate immunity against bacteria. However, the role of IRAK-M in lung HRV infection remains unclear. Here, we provide the first evidence that IRAK-M over-expression promotes lung epithelial HRV-16 replication and autophagy, but inhibits HRV-16-induced IFN-β and IFN-λ1 expression. Inhibiting autophagy reduces HRV-16 replication. Exogenous IFN-β and IFN-λ1 inhibit autophagy and HRV-16 replication. Our data indicate the enhancing effect of IRAK-M on epithelial HRV-16 infection, which is partly through the autophagic pathway. Impaired anti-viral interferon production may serve as a direct or an indirect (e.g., autophagy) mechanism of enhanced HRV-16 infection by IRAK-M over-expression. Targeting autophagic pathway or administrating anti-viral interferons may prevent or attenuate viral (e.g., HRV-16) infections in allergic airways.

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“…Perhaps more than at any other site, excessive inflammation (i.e., acute pneumonia) is associated with respiratory compromise and must be tightly controlled. Thus, a major component of mucosal immunity is the activation of the regulatory components of the innate immune system, which includes expression of NF-kB, activator protein 1, IFN regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) (1,2).…”

mentioning

confidence: 99%

Innate Immunity in the Respiratory Epithelium

Parker

Prince

2011

Am J Respir Cell Mol Biol

393

404

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The airway epithelium represents the first point of contact for inhaled foreign organisms. The protective arsenal of the airway epithelium is provided in the form of physical barriers and a vast array of receptors and antimicrobial compounds that constitute the innate immune system. Many of the known innate immune receptors, including the Toll-like receptors and nucleotide oligomerization domain-like receptors, are expressed by the airway epithelium, which leads to the production of proinflammatory cytokines and chemokines that affect microorganisms directly and recruit immune cells, such as neutrophils and T cells, to the site of infection. The airway epithelium also produces a number of resident antimicrobial proteins, such as lysozyme, lactoferrin, and mucins, as well as a swathe of cationic proteins. Dysregulation of the airway epithelial innate immune system is associated with a number of medical conditions that can result in compromised immunity and chronic inflammation of the lung. This review focuses on the innate immune capabilities of the airway epithelium and its role in protecting the lung from infection as well as the outcomes when its function is compromised.

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Dynamic Innate Immune Responses of Human Bronchial Epithelial Cells to Severe Acute Respiratory Syndrome-Associated Coronavirus Infection

Cited by 185 publications

References 77 publications

Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome–Coronavirus

Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome–Coronavirus

Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway

Innate Immunity in the Respiratory Epithelium

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