The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly ...understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.
SARS-CoV-2 is the pathogenic agent of COVID-19, which has evolved into a global pandemic. Compared with some other respiratory RNA viruses, SARS-CoV-2 is a poor inducer of type I interferon (IFN). ...Here, we report that SARS-CoV-2 nsp12, the viral RNA-dependent RNA polymerase (RdRp), suppresses host antiviral responses. SARS-CoV-2 nsp12 attenuated Sendai virus (SeV)- or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner. It also inhibited IFN promoter activation triggered by RIG-I, MDA5, MAVS, and IRF3 overexpression. Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3. Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12. Given these findings, our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.
During July 2007-June 2015, we enrolled 4,225 hospitalized children with pneumonia in a study to determine the seasonality of respiratory syncytial virus (RSV) infection in Beijing, China. We defined ...season as the period during which >10% of total PCRs performed each week were RSV positive. We identified 8 distinctive RSV seasons. On average, the season onset occurred at week 41 (mid-October) and lasted 33 weeks, through week 20 of the next year (mid-May); 97% of all RSV-positive cases occurred during the season. RSV seasons occurred 3-5 weeks earlier and lasted ≈6 weeks longer in RSV subgroup A-dominant years than in RSV subgroup B-dominant years. Our analysis indicates that monitoring such RSV subgroup shifts might provide better estimates for the onset of RSV transmission. PCR-based tests could be a flexible or complementary way of determining RSV seasonality in locations where RSV surveillance is less well-established, such as local hospitals throughout China.
We conducted a surveillance among acute respiratory tract infection (ARTI) cases to define the epidemiology, clinical characteristics and genetic variations of enterovirus D68 (EV-D68) in Beijing, ...China from 2015 to 2017. Nasopharyngeal swabs and sputum were collected from 30 sentinel hospitals in Beijing and subjected to EV and EV-D68 detection by real-time PCR. The VP1 gene region and complete genome sequences of EV-D68 positive cases were analyzed. Of 21816 ARTI cases, 619 (2.84%) were EV positive and 42 cases were EV-D68 positive. The detection rates of EV-D68 were 0 (0/6644) in 2015, 0.53% (40/7522) in 2016 and 0.03% (2/7650) in 2017, respectively. Two peaks of EV-D68 infections occurred in late summer and early-winter. Ten cases (23.81%) with upper respiratory tract infection and 32 cases (76.19%) presented with pneumonia, including 3 cases with severe pneumonia. The phylogenetic analysis suggested 15 subclade D3 strains and 27 subclade B3 strains of EV-D68 were circulated in China from 2016 to 2017. A total of 52 amino acid polymorphisms were identified between subclades D1 and D3. These data suggest an upsurge of EV-D68 occurred in Beijing in 2016, the new subclade D3 emerged in 2016 and co-circulated with subclade B3 between 2016 and 2017.
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system ...senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.
The transcription regulator ID2 plays an essential role in the development and differentiation of immune cells. Here, we report that ID2 also negatively regulates antiviral innate immune responses. ...During viral infection of human epithelial cells, ID2 bound to TANK-binding kinase 1 (TBK1) and to inhibitor of nuclear factor κB kinase ε (IKKε). These interactions inhibited the recruitment and activation of interferon (IFN) regulatory factor 3 (IRF3) by TBK1 or IKKε, leading to a reduction in the expression of IFN-β1 (
). IFN-β induced the nuclear export of ID2 to form a negative feedback loop. Knocking out ID2 in human cells enhanced innate immune responses and suppressed infection by different viruses, including SARS-CoV-2. Mice with a myeloid-specific deficiency of ID2 produced more IFN-α in response to viral infection and were more resistant to viral infection than wild-type mice. Our findings not only establish ID2 as a modulator of IRF3 activation induced by TBK1 and/or IKKε but also introduce a mechanism for cross-talk between innate immunity and cell development and differentiation.
During August 2006-April 2010, in Beijing, China, 2 rare human enterovirus serotypes, coxsackievirus A21 and enterovirus 68, were detected most frequently in human enterovirus-positive adults with ...acute respiratory tract infections. Thus, during some years, these 2 viruses cause a substantial proportion of enterovirus-associated adult acute respiratory tract infections.
Respiratory viruses may interfere with each other and affect the epidemic trend of the virus. However, the understanding of the interactions between respiratory viruses at the population level is ...still very limited. We here conducted a prospective laboratory-based etiological study by enrolling 14,426 patients suffered from acute respiratory infection (ARI) in Beijing, China during 2005 to 2015. All 18 respiratory viruses were simultaneously tested for each nasal and throat swabs collected from enrolled patients using molecular tests. The virus correlations were quantitatively evaluated, and the respiratory viruses could be divided into two panels according to the positive and negative correlations. One included influenza viruses (IFVs) A, B, and respiratory syncytial virus (RSV), while the other included human parainfluenza viruses (HPIVs) 1/3, 2/4, adenovirus (Adv), human metapneumovirus (hMPV), and enterovirus (including rhinovirus, named picoRNA), α and β human coronaviruses (HCoVs). The viruses were positive-correlated in each panel, while negative-correlated between panels. After adjusting the confounding factors by vector autoregressive model, positive interaction between IFV-A and RSV and negative interaction between IFV-A and picoRNA are still be observed. The asynchronous interference of IFV-A significantly delayed the peak of β human coronaviruses epidemic. The binary property of the respiratory virus interactions provides new insights into the viral epidemic dynamics in human population, facilitating the development of infectious disease control and prevention strategies.
Systematic quantitative assessment of the interactions between different respiratory viruses is pivotal for the prevention of infectious diseases and the development of vaccine strategies. Our data showed stable interactions among respiratory viruses at human population level, which are season irrelevant. Respiratory viruses could be divided into two panels according to their positive and negative correlations. One included influenza virus and respiratory syncytial virus, while the other included other common respiratory viruses. It showed negative correlations between the two panels. The asynchronous interference between influenza virus and β human coronaviruses significantly delayed the peak of β human coronaviruses epidemic. The binary property of the viruses indicated transient immunity induced by one kind of virus would play role on subsequent infection, which provides important data for the development of epidemic surveillance strategies.
Rhinovirus infections are common in all age groups world-wide, and they occur throughout the year. In this study, we examined 2,689 nasopharyngeal swabs collected in Mongolia during 2008–2013. Human ...rhinoviruses (HRVs) were detected in 295 (11.0%) samples, and 85 (28.8%) patients were co-infected with other respiratory viruses. HRV was co-detected with bocavirus, human coronavirus, and respiratory syncytial virus in 21 (24.7%), 17 (20.0%), and 14 (16.5%), respectively. We tested 170 (57.6%) of the 295 HRV-positive samples: 117 HRV strains were typed by using the VP4/VP2 method and 53 by using 5′ UTR method. We found HVR-A, HVR-C, and HVR-B infections in 80 (47.1%), 76 (44.7%), and 14 (8.2%) samples, respectively.
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