Expression of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐infected ACE2<sup>+</sup> cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

He, Li; Ding, Yan‐Qing; Zhang, Q; Che, Xin; He, Yuxian; Shen, Hong; Wang, H; Li, Z; Zhao, Laura; Geng, Jian Guo; Deng, Yongzhi; Yang, Lan; Li, J; Cai, Junjie; Qiu, Li-wen; Wen, Kai; Xu, Xiao-Ning; Jiang, Shibo

doi:10.1002/path.2067

Cited by 373 publications

(415 citation statements)

References 46 publications

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“…CXCL10 may be responsible for the infiltration of activated T cells and monocytes or macrophages, which is a pathologic finding in SARS patients (41)(42)(43). It has been reported that elevated expression of monocyte or macrophage activation factors (CCL2 and CCL3) was observed in SARS patients (8,44). Furthermore, the highest expression of IL-6 in mOrVVNHis-immunized mice is reasonable (Fig.…”

Section: Discussionmentioning

confidence: 66%

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Yasui¹,

Kai

Kitabatake³

et al. 2008

The Journal of Immunology

248

240

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The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7–8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-β), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.

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Section: Discussionmentioning

confidence: 66%

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Yasui¹,

Kai

Kitabatake³

et al. 2008

The Journal of Immunology

248

240

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“…He and colleagues suggested that resident ACE2-expressing lung epithelial cells, and not the subsequently recruited inflammatory cells, constitute the primary source of elevated cytokines in patients infected with SARS-CoV, and that these epithelial-derived cytokines play an important role in the acute lung injury and pathogenesis of SARS (27). Our data show that type II alveolar cells likely contribute to the high concentrations of cytokines and chemokines detected in the gas-exchange portion of the lungs in patients with SARS.…”

Section: Discussionmentioning

confidence: 99%

“…Based on in situ hybridization and immunocytochemistry, He and colleagues suggested that ACE2-positive infected cells in lungs of patients with SARS are the source of proinflammatory cytokines (27).…”

Section: Clinical Relevancementioning

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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“…Cellular infiltration by macrophages has been observed, as has a combination of macrophages and lymphocytes, with or without neutrophils. 6,8,[17][18][19]48,58,69 Large multinucleated cells identified as macrophages and pneumocytes by immunohistochemistry are frequently observed in the lungs of SARS patients. Bronchiolitis obliterans organizing pneumonia, 48 hemophagocytosis in the mononuclear cells residing in pulmonary tissues, 48 and apoptosis of epithelial cells, monocytes/macrophages, lymphocytes and pneumocytes 17 are also seen.…”

Section: Pathologic Changesmentioning

confidence: 99%

“…6,19 In situ hybridization and immunohistochemistry studies have identified viral nucleic acid and/or antigen in epithelial cells from bronchi, bronchioles, trachea, and alveoli and in multinucleated cells and alveolar macrophages. 16,17,47,58,66,75 Investigation of the cytokine and chemokine profiles of SARS patients has suggested that severe SARS-related lung injury might be attributed to an excessive host immune response-particularly, the deregulation of proinflammatory cytokine production. 48,50,68,77 Wild Animals and Domestic Animals in the Market…”

Section: Pathologic Changesmentioning

confidence: 99%

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

2010

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During the severe acute respiratory syndrome (SARS) outbreak of 2003, approximately 10% of SARS patients developed progressive respiratory failure and died. Since then, several animal models have been established to study SARS coronavirus, with the aim of developing new antiviral agents and vaccines. This short review describes the pathologic features of SARS in relation to their clinical presentation in human cases. It also looks at animal susceptibility after experimental infection, animal models of SARS, and the pathogenesis of this disease. It seems that adaptation of the virus within the host animal and the subsequent abnormal immune responses may be key factors in the pathogenesis of this new and fatal respiratory disease. The proteases produced in the lung during inflammation could also play an important role for exacerbation of SARS in animals.

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Expression of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐infected ACE2⁺ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

Cited by 373 publications

References 46 publications

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

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

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

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Expression of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

Cited by 373 publications

References 46 publications

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

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

Studies of Severe Acute Respiratory Syndrome Coronavirus Pathology in Human Cases and Animal Models

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Product

Resources

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Expression of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐infected ACE2⁺ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS