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

Abstract

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...

Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures

“…Until the outbreak of severe acute respiratory syndrome (SARS) caused by severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, there was limited research on the tissue tropism and host response following human infection with coronaviruses. In comparison to human betacoronavirus 229E (HCoV-229E), SARS-CoV was found to be deficient at eliciting beta interferon (IFN-␤) innate immune responses in primary human macrophages and dendritic cells (1, 2) since SARS-CoV encodes several antagonists of innate immune-sensing and signaling pathways (3,4). The tropism of SARS-CoV in the respiratory tract was primarily restricted to differentiated human airway epithelium (5) and alveolar type II pneumocytes (6)(7)(8), with limited tropism for alveolar type I pneumocytes (9).…”

Infection of human alveolar macrophages by human coronavirus strain 229E

“…As AMs are considered to be an important source of type I IFNs following infection by RNA viruses (Kumagai et al , 2007), our results suggest that HCoV-229E may have a mechanism to block the IFN pathway in AMs. Several SARS-CoV gene products may downregulate or inhibit the IFN-signalling pathway during SARS-CoV infection (de Lang et al , 2009; Kopecky-Bromberg et al , 2006, 2007; Minakshi et al , 2009; Narayanan et al , 2008). Similar gene products of HCoV-229E may be able to inhibit IFN during infection of AMs and should be the subject of additional studies.…”

Nsp1 proteins of group I and SARS coronaviruses share structural and functional similarities

“…Surprisingly, few viral particles are isolated from lung tissues of SARS-CoV infected patients, but levels of inflammatory cytokines and chemokines are greatly elevated in the lung. A hyperinflammatory response is presumed to be the key determinant of the high pathogenicity of SARS-CoV, rather than rapid viral spread (De Lang et al, 2009). The specific mechanism for SARS-CoV pathogenicity is not known, but a number of viral coding proteins may be involved (Weiss and Navas-Martin, 2005).…”