Interferon-γ and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells

Lang, Anna de; Osterhaus, Albert D. M. E.; Haagmans, Bart L.

doi:10.1016/j.virol.2006.06.011

Cited by 125 publications

(110 citation statements)

References 41 publications

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“…De Lang and colleagues reported that IL-4 and IL-13 decreased ACE2 expression in Vero E6 cells (32). However, as shown in Figure 1, we found that IL-4/IL-13 actually increased ACE2 expression in our primary human alveolar type II cells.…”

Section: Discussioncontrasting

confidence: 54%

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

281

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: Discussioncontrasting

confidence: 54%

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

281

266

View full text Add to dashboard Cite

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“…Pretreatment of cells with interferon before infection prevents SARS-CoV replication in these cells [53]. Interestingly, it has been demonstrated that IFN-γ downregulates expression of ACE2, the cellular SARS-CoV receptor, on the cell surface, resulting in decreased infection in these cells [54]. In addition, Haagmans and coworkers showed that IFN-α protects type-I pneumocytes from SARS-CoV infection in macaques [55].…”

Section: Future Perspectivementioning

confidence: 99%

Unraveling the Complexities of the Interferon Response During Sars-Cov Infection

et al. 2008

Self Cite

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Viruses employ different strategies to circumvent the antiviral actions of the innate immune response. SARS coronavirus (SARS-CoV), a virus that causes severe lung damage, encodes an array of proteins able to inhibit induction and signaling of type-I interferons. However, recent studies have demonstrated that interferons are produced during SARS-CoV infection in humans and macaques. Furthermore, nuclear translocation of activated STAT1 and a range of interferon-stimulated genes could be demonstrated in the lungs of SARS-CoV-infected macaques. In line with these observations, plasmacytoid dendritic cells have been shown to produce interferons upon SARS-CoV infection in vitro. Given the pivotal role of interferons during viral infections, (differential) induction of interferons may affect the outcome of the infection. Therefore, the functional implication of interferon production during SARS-CoV infection remains to be re-investigated. Rapid spread of the virus owing to air travel, immediate media coverage all over the world and the globalization of the economy contributed to the high impact of the epidemic. The emergence of this new highly pathogenic virus led to a quick response from the scientific world; only a few months after the first emergence of SARS, a newly discovered coronavirus (CoV) was identified as its etiological agent [1][2][3][4]. Many of the people that were infected with SARS-CoV early during the epidemic had been in close contact with live animals on Chinese wet markets, suggesting that the virus came from an animal source [5]. The current hypothesis is that bats are the main natural reservoirs of SARS-CoV-like viruses, and virus transmission to humans most likely occurred via civet cats, which are common trade animals on these wet markets [6]. KeywordsInfection with SARS-CoV in humans initially causes lower respiratory tract disease with clinical symptoms that include fever, malaise and lymphopenia [7][8][9][10]. Approximately 20-30% of SARS patients suffered from severe disease and needed to be transferred to intensive care units. Ultimately, the overall fatality rate approached 10-20% in adults, while children seemed to be relatively resistant to SARS [11]. The clinical course of SARS follows three phases. The first phase is characterized by active viral replication and patients experience the first symptoms of disease, such as fever and malaise. Virus levels start to decrease while antibodies, which are effective in controlling infection, increase in the second phase. Nonetheless, pneumonia and immunopathological injury also develop in this phase. Eventually, in the third phase, fatal cases of SARS develop severe pneumonia and acute respiratory distress syndrome (ARDS), characterized by the presence of diffuse alveolar damage [7]. Although a wide range of animal species are susceptible to experimental infection with SARS-CoV, nonhuman primates are the only animals in which pathology similar to that of human SARS patients has been observed so far. ARDS is characterized by massive in...

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“…Although the Vero E6 cell line lacks the ability to transcribe type I IFNs as these cells possess a genetic deletion, research has indicated that the cells mount a weak initial IRF3-dependent response to various ligands, inducing a weak innate response to viruses [19]. With respect to coronaviruses, upon IFNs binding to the corresponding receptors, a downstream signaling is initiated and acts to block one or more steps in the virus life cycle [20]. Mammalian target of rapamycin (mTOR) plays a vital role in monitoring the availability of nutrients, mitogenic signals and cellular energy, and is a necessary part of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway [21].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

Zhang

Liu

et al. 2018

Microbial Pathogenesis

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PEDV remains one of the most important swine diseases that infects pigs of all ages. It causes devastating viral enteric disease in piglets with a high mortality rate, leading to significant threats and huge economic loss to the pork industry. In this study, a transcriptomic shotgun sequencing (RNA-Seq) procedure was used to study gene responses against PEDV infection. Genome-wide analysis of differentially expressed genes (DEGs) was performed in Vero E6 cells post-PEDV infection. mTOR signaling pathway activator-MHY1485, and inhibitor-PP242 were used to study the antiviral function. Results revealed that the IRF3 was significantly up-regulated post-PEDV infection. Although most of the IFN-regulatory and -related genes evaluated in this study were either down-regulated or remained unchanged, IL11 behaved significantly up-regulated, with the peak at 16 hpi. Nearly 90% of PEDV infections were suppressed in the PP242 pretreated cells whereas the reverse effect was observed in the MYH1485 pretreated cells. Results indicated that the mTOR signaling pathway played a vital role in the PEDV antiviral regulation in the Vero E6 cells. Future studies will contribute to better understand the cellular antiviral mechanism against PEDV.

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Interferon-γ and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells

Cited by 125 publications

References 41 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

Unraveling the Complexities of the Interferon Response During Sars-Cov Infection

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

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