A virus-specific monocyte inflammatory phenotype is induced by SARS-CoV-2 at the immune-epithelial interface.

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.

Comparison of the Epidemiological and Clinical Characteristics of Hospitalized Children With Pneumonia Caused by SARS-CoV-2, Influenza A, and Human Adenoviruses: A Case-Control Study.

Background. This case-control study aims to investigate the clinical characteristics in pediatric patients with pneumonia infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, and human adenoviruses (HAdVs). Methods. Hospitalized pediatric patients with pneumonia infected with SARS-CoV-2 at Wuhan Children's Hospital and pneumonia infected with influenza A, and HAdVs at Qilu Children's Hospital were compared. Clinical manifestations, laboratory examinations, and imaging characteristics were analyzed. Results. The proportions of hyperpyrexia (54.3%, 33.9%), cough (100%, 99.2%), wheezing (45.7%, 53.7%), diarrhea (31.4%, 14.9%), and fever (100%, 75.2%) in patients with influenza A and HAdVs were higher than those of patients with SARS-CoV-2 (9.4%, P < .001; 48.5%, P < .001; 0%, P < .001; 8.8%, P = .002; 41.5%, P < .001; respectively). Laboratory examinations revealed the proportions of leukocytosis (37.1%, 52.9%), abnormal rates of neutrophils (40%, 40.5%), and lymphocytosis (42.9%, 65.3%) in influenza A and HAdV pneumonia groups were significantly higher than coronavirus disease 2019 (COVID-19) group (0%, P < .001; 0%, P < .001; 0%, P < .001; respectively). The proportion of elevated procalcitonin (5.7%, 14%) in patients with influenza A and HAdVs was significantly lower than those in patients with SARS-CoV-2 (64%, P < .001). In chest computed tomography, ground-glass opacities near the pleura were more common in patients with COVID-19 than those in patients with influenza A and HAdVs (32.7% vs 0% vs 0%, P < .001). Conclusion. Fever, cough, and wheezing are more common in the influenza A and HAdVs groups, whereas procalcitonin and computed tomography findings are likely to be pronounced in COVID-19 pneumonia. It provides a variety of methods except polymerase chain reaction for differentiating COVID-19 pneumonia from influenza A and HAdVs pneumonia.

Tetraspanins: Host Factors in Viral Infections.

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases.

A Biological Insight into the Susceptibility to Influenza Infection in Junior Rats by Comprehensive Analysis of lncRNA Profiles.

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.

Ceramide and Related Molecules in Viral Infections.

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.

Antiviral effect of fufang yinhua jiedu (FFYH) granules against influenza A virus through regulating the inflammatory responses by TLR7/MyD88 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-Yinhua-Jiedu Granules (FFYH) optimized from a Yin-Qiao-San, as traditional Chinese medicine (TCM), was used to treat influenza and upper respiratory tract infection and was recommended for the prevention and treatment of SARS in 2003 and current COVID-19 in Anhui Province in 2020. AIM OF STUDY: In the clinical studies, FFYH was very effective for the treatment of influenza, but the mechanism of action against influenza A virus remains unclear. In the present study, we investigated the antiviral effect of FFYH against influenza A virus in vitro and vivo. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was investigated for the first time. MATERIALS AND METHODS: CPE inhibition assay and HA assay were used to evaluate the in vitro antiviral effects of FFYH against influenza A virus H1N1, H3N2, H5N1, H7N9 and H9N2. Mice were used to evaluate the antiviral effect of FFYH in vivo with ribavirin and lianhuaqingwen as positive controls. RT-PCR was used to quantify the mRNA transcription of TNF-α, IL-6, IFN-γ, IP10, and IL-1ß mRNA. ELISA was used to examine the expression of inflammatory factors such as TNF-α, IL-6, IFN-γ, IP10, and IL-1ß in sera. The blood parameters were analyzed with auto hematology analyzer. Moreover, the potential mechanism of FFYH against influenza A virus in vivo was also investigated. RESULTS: FFYH showed a broad-spectrum of antiviral activity against H1N1, H3N2, H5N1, H7N9, and H9N2 influenza A viruses. Furthermore, FFYH dose-dependently increased the survival rate, significantly prolonged the median survival time of mice, and markedly reduced lung injury caused by influenza A virus. Also, FFYH significantly improve the sick signs, food taken, weight loss, blood parameters, lung index, and lung pathological changes. Moreover, FFYH could markedly inhibit the inflammatory cytokine expression of TNF-α, IL-6, IFN-γ, IP10, IL-10, and IL-1ß mRNA or protein via inhibition of the TLR7/MyD88/NF-κB signaling pathway in vivo. CONCLUSION: FFYH not only showed a broad-spectrum of anti-influenza virus activity in vitro, but also exhibited a significant protective effect against lethal influenza virus infection in vivo. Furthermore, our results indicated that the in vivo antiviral effect of FFYH against influenza virus may be attributed to suppressing the expression of inflammatory cytokines via regulating the TLR7/MyD88/NF-κB signaling pathway. These findings provide evidence for the clinical treatment of influenza A virus infection with FFYH.

Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1-dependent targeting of LC3 to single-membrane, non-autophagosome compartments - referred to as non-canonical autophagy - protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non-canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.

The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.

In this study, we performed a single-centered study of 307 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. It was found that co-infection of SARS-CoV-2 and influenza virus was common during COVID-19 outbreak. And patients coinfected with SARS-CoV-2 and influenza B virus have a higher risk of developing poor outcomes so a detection of both viruses was recommended during COVID-19 outbreak.

Innate Immunity and Influenza A Virus Pathogenesis: Lessons for COVID-19.

There is abundant evidence that the innate immune response to influenza A virus (IAV) is highly complex and plays a key role in protection against IAV induced infection and illness. Unfortunately it also clear that aspects of innate immunity can lead to severe morbidity or mortality from IAV, including inflammatory lung injury, bacterial superinfection, and exacerbation of reactive airways disease. We review broadly the virus and host factors that result in adverse outcomes from IAV and show evidence that inflammatory responses can become damaging even apart from changes in viral replication per se, with special focus on the positive and adverse effects of neutrophils and monocytes. We then evaluate in detail the role of soluble innate inhibitors including surfactant protein D and antimicrobial peptides that have a potential dual capacity for down-regulating viral replication and also inhibiting excessive inflammatory responses and how these innate host factors could possibly be harnessed to treat IAV infection. Where appropriate we draw comparisons and contrasts the SARS-CoV viruses and IAV in an effort to point out where the extensive knowledge existing regarding severe IAV infection could help guide research into severe COVID 19 illness or vice versa.

Comparison of influenza type A and B with COVID-19: A global systematic review and meta-analysis on clinical, laboratory and radiographic findings.

We compared clinical symptoms, laboratory findings, radiographic signs and outcomes of COVID-19 and influenza to identify unique features. Depending on the heterogeneity test, we used either random or fixed-effect models to analyse the appropriateness of the pooled results. Overall, 540 articles included in this study; 75,164 cases of COVID-19 (157 studies), 113,818 influenza type A (251 studies) and 9266 influenza type B patients (47 studies) were included. Runny nose, dyspnoea, sore throat and rhinorrhoea were less frequent symptoms in COVID-19 cases (14%, 15%, 11.5% and 9.5%, respectively) in comparison to influenza type A (70%, 45.5%, 49% and 44.5%, respectively) and type B (74%, 33%, 38% and 49%, respectively). Most of the patients with COVID-19 had abnormal chest radiology (84%, p < 0.001) in comparison to influenza type A (57%, p < 0.001) and B (33%, p < 0.001). The incubation period in COVID-19 (6.4 days estimated) was longer than influenza type A (3.4 days). Likewise, the duration of hospitalization in COVID-19 patients (14 days) was longer than influenza type A (6.5 days) and influenza type B (6.7 days). Case fatality rate of hospitalized patients in COVID-19 (6.5%, p < 0.001), influenza type A (6%, p < 0.001) and influenza type B was 3%(p < 0.001). The results showed that COVID-19 and influenza had many differences in clinical manifestations and radiographic findings. Due to the lack of effective medication or vaccine for COVID-19, timely detection of this viral infection and distinguishing from influenza are very important.

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.

Convalescent plasma treatment for COVID-19: Tempering expectations with the influenza experience.

The COVID-19 pandemic caused by the zoonotic coronavirus, SARS-CoV-2 has swept the world in 5 months. A proportion of cases develop severe respiratory tract infections progressing to acute respiratory distress syndrome and a diverse set of complications involving different organ systems. Faced with a lack of coronavirus-specific antiviral drugs and vaccines, hundreds of clinical trials have been undertaken to evaluate repurposed drugs. Convalescent plasma from recovered patients is an attractive option because antibodies can have direct or indirect antiviral activity and immunotherapy works well in principle, in animal models, and in anecdotal reports. However, the benefits of convalescent plasma treatment can only be clearly established through carefully designed randomized clinical trials. The experience from investigations of convalescent plasma products for severe influenza offers a cautionary tale. Despite promising pilot studies, large multicenter randomized controlled trials failed to show a benefit of convalescent plasma or hyperimmune intravenous globulin for the treatment of severe influenza A virus infection. These studies provide important lessons that should inform the planning of adequately powered randomized controlled trials to evaluate the promise of convalescent plasma therapy in COVID-19 patients.

Clinical features of COVID-19 and influenza: a comparative study on Nord Franche-Comte cluster.

Clinical descriptions about influenza-like illnesses (ILI) in COVID-19 seem non-specific. We aimed to compare the clinical features of COVID-19 and influenza. We retrospectively investigated the clinical features and outcomes of confirmed cases of COVID-19 and influenza in Nord Franche-Comté Hospital between February 26th and March 14th 2020. We used SARS-CoV-2 RT-PCR and influenza virus A/B RT-PCR in respiratory samples to confirm the diagnosis. We included 124 patients. The mean age was 59 (±19 [19-98]) years with 69% female. 70 patients with COVID-19 and 54 patients with influenza A/B. Regarding age, sex and comorbidities, no differences were found between the two groups except a lower Charlson index in COVID-19 group (2 [±2.5] vs 3 [±2.4],p = 0.003). Anosmia (53% vs 17%,p < 0.001), dysgeusia (49% vs 20%,p = 0.001), diarrhea (40% vs 20%,p = 0.021), frontal headache (26% vs 9%,p = 0.021) and bilateral cracklings sounds (24% vs 9%,p = 0.034) were statistically more frequent in COVID-19. Sputum production (52% vs 29%,p = 0.010), dyspnea (59% vs 34%,p = 0.007), sore throat (44% vs 20%,p = 0.006), conjunctival hyperhemia (30% vs 4%,p < 0.001), tearing (24% vs 6%,p = 0.004), vomiting (22% vs 3%,p = 0.001) and rhonchi sounds (17% vs 1%,p = 0.002) were more frequent with influenza infection. We described several clinical differences which can help the clinicians during the co-circulation of influenza and SARS-CoV-2.

Comparative review of respiratory diseases caused by coronaviruses and influenza A viruses during epidemic season.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to sweep the world, causing infection of millions and death of hundreds of thousands. The respiratory disease that it caused, COVID-19 (stands for coronavirus disease in 2019), has similar clinical symptoms with other two CoV diseases, severe acute respiratory syndrome and Middle East respiratory syndrome (SARS and MERS), of which causative viruses are SARS-CoV and MERS-CoV, respectively. These three CoVs resulting diseases also share many clinical symptoms with other respiratory diseases caused by influenza A viruses (IAVs). Since both CoVs and IAVs are general pathogens responsible for seasonal cold, in the next few months, during the changing of seasons, clinicians and public heath may have to distinguish COVID-19 pneumonia from other kinds of viral pneumonia. This is a discussion and comparison of the virus structures, transmission characteristics, clinical symptoms, diagnosis, pathological changes, treatment and prevention of the two kinds of viruses, CoVs and IAVs. It hopes to provide information for practitioners in the medical field during the epidemic season.

Collateral Benefit of COVID-19 Control Measures on Influenza Activity, Taiwan.

Taiwan has strictly followed infection control measures to prevent spread of coronavirus disease. Meanwhile, nationwide surveillance data revealed drastic decreases in influenza diagnoses in outpatient departments, positivity rates of clinical specimens, and confirmed severe cases during the first 12 weeks of 2020 compared with the same period of 2019.

Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020.

Since December 2019, China has been experiencing a large outbreak of a novel coronavirus (2019-nCoV) which can cause respiratory disease and severe pneumonia. We estimated the basic reproduction number R0 of 2019-nCoV to be around 2.2 (90% high density interval: 1.4-3.8), indicating the potential for sustained human-to-human transmission. Transmission characteristics appear to be of similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and pandemic influenza, indicating a risk of global spread.