SARS-CoV primarily infects epithelial cells within the lung.
The virus is capable of entering macrophages and dendritic cells but only leads to an abortive infection. Despite this, infection of these cell types may be important in inducing pro-inflammatory cytokines that may contribute to disease. In fact, many cytokines and chemokines are produced by these cell types and are elevated in the serum of SARS-CoV infected patients. The exact mechanism of lung injury and cause of severe disease in humans remains undetermined. Viral titers seem to diminish when severe disease develops in both humans and in several animal models of the disease. Furthermore, animals infected with rodent-adapted SARS-CoV strains show similar clinical features to the human disease, including an age-dependent increase in disease severity. These animals also show increased levels proinflammatory cytokines and reduced T-cell responses, suggesting a possible immunopathological mechanism of disease.
SOURCE: Methods in Molecular Biology
[pdf_attachment file=”1″ name=”Fehr AR, Perlman S (article)”]
Coronavirus (CoV) infection is usually detected by cellular sensors, which trigger the activation of the innate immune system. Nevertheless, CoVs have evolved viral proteins that target different signaling pathways to counteract innate immune responses. Some CoV proteins act as antagonists of interferon (IFN) by inhibiting IFN production or signaling. After CoV infection, potent cytokines relevant in controlling virus infections and priming adaptive immune responses are also generated. However, an uncontrolled induction of these proinflammatory cytokines can lead to pathogenesis and disease severity as described for SARS-CoV and MERS-CoV.
The cellular pathways mediated by interferon regulatory factor (IRF)-3 and 7, activating transcription factor (ATF)-2/jun, activator protein (AP)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor of activated T cells (NF-AT), are the main drivers of the inflammatory response triggered after viral infections, with NF-κB pathway the most frequently activated.
The relatively small E protein elicits a strong influence on the interaction of SARS-CoV with the host. After infection with viruses in which this protein has been deleted, increased cellular stress and unfolded protein responses, apoptosis, and augmented host immune responses were observed. In contrast, the presence of E protein activated a pathogenic inflammatory response that may cause death in animal models and in humans.
The modification or deletion of different motifs within E protein is sufficient to attenuate the virus. A comprehensive collection of SARS-CoVs in which these motifs have been modified elicited full and long-term protection even in old mice, making those deletion mutants promising vaccine candidates.
The E protein affects virus morphogenesis, budding, assembly, intracellular trafficking, and virulence. In fact, E protein is responsible in a significant proportion of the inflammasome activation and the associated inflammation elicited by SARS-CoV in the lung parenchyma. This exacerbated inflammation causes edema accumulation, leading to acute respiratory distress syndrome (ARDS) and, frequently, to the death of infected animal models or human patients.
SOURCE: Virus Research
Chloroquine, a diprotic weak base that increases the pH of acidic vesicles, has been used for the treatment of malaria and inflammatory diseases, such as rheumatoid arthritis. Chloroquine has antimicrobial effects even against viruses, such as human immunodeficiency virus type 1 (HIV-1) and SARS-CoV.
Coronavirus, an enveloped virus, enters the cell cytoplasm by endocytosis and matures in the membrane transport system, such as the trans-Golgi network. Endoplasmic reticulum stress caused by virus infection induces the activation of p38 mitogen-activated protein kinase (MAPK) and [can trigger] host cell apoptosis [‘programmed cell death’].
Chloroquine [can] inhibit the activation of p38 MAPK and cytokine production. In this study, we examined the correlation between CQ and the activation of p38 MAPK in human coronavirus 229E (HCoV-229E) infection .
The amount of viral RNA incorporated into the cells was not significantly influenced by chloroquine (Fig. 1b). These data demonstrate that chloroquine has no influence on the process prior to the internalization of HCoV-229E into cells.
HCoV-229E infection induced the phosphorylation of p38 MAPK, which was inhibited by 25 μM chloroquine, [demonstrating] that chloroquine can neutralize the effect of HCoV-229E-infection on p38 MAPK.
SOURCE: Antiviral research
Severe acute respiratory syndrome (SARS) is a zoonotic infectious disease caused by a novel coronavirus (CoV). The tissue tropism of SARS-CoV includes not only the lung, but also the gastrointestinal tract, kidney and liver.
Angiotensin-converting enzyme 2 (ACE2), the C-type lectin CD209L (also known L-SIGN), and DC-SIGN bind SARS-CoV, but ACE2 appears to be the key functional receptor for the virus.
There is a prominent innate immune response to SARS-CoV infection, including acute-phase proteins, chemokines, inflammatory cytokines and C-type lectins such as mannose-binding lectin, which plays a protective role against SARS. By contrast there may be a lack of type 1 interferon response. Moreover, lymphopenia with decreased numbers of CD4+ and CD8+ T cells is common during the acute phase. Convalescent patients have IgG-class neutralizing antibodies that recognize amino acids 441-700 of the spike protein (S protein) as the major epitope.
SOURCE: Current Opinion in Immunology