The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions about the possible role of a cytokine storm in its pathogenesis. Although ...recent studies showed that MERS-CoV infection is associated with an attenuated IFN response, no induction of inflammatory cytokines was demonstrated during the early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes TNF-α, IL-1β, IL-6, IL-8, IFN-β, monocyte chemotactic protein-1, transforming growth factor-β and IFN-γ-induced protein (IP)-10 in cell lysates of polarized airway epithelial Calu-3 cells infected with MERS-CoV or severe acute respiratory syndrome (SARS)-CoV up to 30 h post-infection. Among the eight cytokine genes, IL-1β, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, whilst TNF-α, IFN-β and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-β response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared with SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared with human HCoV-229E in embryonal lung fibroblast HFL cells, which also revealed higher IFN-β and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. Whilst our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.
The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery ...of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV's ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic.
Background. Given the apparent high mortality associated with the novel swine-origin influenza A/H1N1 virus (S-OIV) in Mexico, we aimed to study the cytokine profiles induced by S-OIV and the effect ...of immunomodulators. Methods. We assayed cytokines and their messenger RNA (mRNA) levels in culture supernatants of human macrophages infected with H5N1, S-OIV California/04/2009 (S-OIV-CA), S-OIV Hong Kong/415742 (S-OIV-HK), or seasonal H1N1 with or without celecoxib and mesalazine. Results. Among the 12 cytokines showing detectable levels, levels of 8 proinflammatory cytokines (interleukin IL 2R, IL-6, interferon IFN α, macrophage inflammatory protein MIP α, MIP-1b, IFN-induced protein 10, regulated on activation, normal T cell expressed and secreted RANTES, and monocyte chemotactic protein MCP 1) were higher in cells infected by H5N1 but similar among cells infected with H1N1, S-OIV-CA, or SOIV- HK. The levels of the other 4 cytokines were similar for H5N1, H1N1, S-OIV-CA and S-OIV-HK. Among the 8 cytokines induced by H5N1, 6 were suppressed by celecoxib and mesalazine. The mRNA levels of tumor necrosis factor a, IFN-γ, IL-6, and MCP-1 induced by H5N1 were higher than the levels of other cytokines at 12 and/or 24 h. Conclusions. No major cytokine storm, as seen in H5N1 infection, is associated with S-OIV infection of cell lines. The mainstay of treatment for uncomplicated S-OIV infections should be antiviral agents without immunomodulators. For individual S-OIV-infected patients with severe primary viral pneumonia, severe sepsis, and multiorgan failure, immunomodulators may be considered as an adjunctive therapy in clinical trials.
The Omicron variant is rapidly becoming the dominant SARS-CoV-2 virus circulating globally. It is important to define reductions in virus neutralizing activity in the serum of convalescent or ...vaccinated individuals to understand potential loss of protection against infection by Omicron. We previously established that a 50% plaque reduction neutralization antibody titer (PRNT
) ≥25.6 in our live virus assay corresponded to the threshold for 50% protection from infection against wild-type (WT) SARS-CoV-2. Here we show markedly reduced serum antibody titers against the Omicron variant (geometric mean titer (GMT) < 10) compared to WT virus 3-5 weeks after two doses of BNT162b2 (GMT = 218.8) or CoronaVac vaccine (GMT = 32.5). A BNT162b2 booster dose elicited Omicron PRNT
titers ≥25.6 in 88% of individuals (22 of 25) who previously received 2 doses of BNT162b2 and 80% of individuals (24 of 30) who previously received CoronaVac. However, few (3%) previously infected individuals (1 of 30) or those vaccinated with three doses of CoronaVac (1 of 30) met this threshold. Our findings suggest that countries primarily using CoronaVac vaccines should consider messenger RNA vaccine boosters in response to the spread of Omicron. Studies evaluating the effectiveness of different vaccines against the Omicron variant are urgently needed.
We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. Its genome is closest to that of severe acute respiratory syndrome-related coronaviruses from ...horseshoe bats, and its receptor-binding domain is closest to that of pangolin viruses. Its origin and direct ancestral viruses have not been identified.
Although human rhinoviruses (HRVs) are common causes of respiratory illness, their molecular epidemiology has been poorly investigated. Despite the recent findings of new HRV genotypes, their ...clinical disease spectrum and phylogenetic positions were not fully understood. In this study, 203 prospectively collected nasopharyngeal aspirates (NPAs), negative for common respiratory viruses (83 were human bocavirus HBoV positive and 120 HBoV negative), from hospitalized children during a 1-year period were subjected to reverse transcription-PCR for HRV. HRV was detected in 14 NPAs positive and 12 NPAs negative for HBoV. Upon VP4 gene analysis, 5 of these 26 HRV strains were found to belong to HRV-A while 21 belonged to a genetic clade probably representing a previously undetected HRV species, HRV-C, that is phylogenetically distinct from the two known HRV species, HRV-A and HRV-B. The VP4 sequences of these HRV-C strains were closely related to the newly identified HRV strains from the United States and Australia. Febrile wheeze or asthma was the most common presentation (76%) of HRV-C infection, which peaked in fall and winter. Complete genome sequencing of three HRV-C strains revealed that HRV-C represents an additional HRV species, with features distinct from HRV-A and HRV-B. Analysis of VP1 of HRV-C revealed major deletions in regions important for neutralization in other HRVs, which may be signs of a distinct species, while within-clade amino acid variation in potentially antigenic regions may indicate the existence of different serotypes among HRV-C strains. A newly identified HRV species, HRV-C, is circulating worldwide and is an important cause of febrile wheeze and asthmatic exacerbations in children requiring hospitalization.
Bats are a unique group of mammals of the order
. They are highly diversified and are the group of mammals with the second largest number of species. Such highly diversified cell types and receptors ...facilitate them to be potential hosts of a large variety of viruses. Bats are the only group of mammals capable of sustained flight, which enables them to disseminate the viruses they harbor and enhance the chance of interspecies transmission. This article aims at reviewing the various aspects of the global epidemiology of bat coronaviruses (CoVs). Before the SARS epidemic, bats were not known to be hosts for CoVs. In the last 15 years, bats have been found to be hosts of >30 CoVs with complete genomes sequenced, and many more if those without genome sequences are included. Among the four CoV genera, only alphaCoVs and betaCoVs have been found in bats. As a whole, both alphaCoVs and betaCoVs have been detected from bats in Asia, Europe, Africa, North and South America and Australasia; but alphaCoVs seem to be more widespread than betaCoVs, and their detection rate is also higher. For betaCoVs, only those from subgenera
,
,
and
have been detected in bats. Most notably, horseshoe bats are the reservoir of SARS-CoV, and several betaCoVs from subgenus
are closely related to MERS-CoV. In addition to the interactions among various bat species themselves, bat⁻animal and bat⁻human interactions, such as the presence of live bats in wildlife wet markets and restaurants in Southern China, are important for interspecies transmission of CoVs and may lead to devastating global outbreaks.
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