Early humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are dominated by IgM and IgA antibodies, which greatly contribute to virus neutralization at mucosal sites. Given the essential roles of IgM and IgA in the control and elimination of SARS-CoV-2 infection, the mucosal immunity could be exploited for therapeutic and prophylactic purposes. However, almost all neutralizing antibodies that are authorized for emergency use and under clinical development are IgG antibodies, and no vaccine has been developed to boost mucosal immunity for SARS-CoV-2 infection. In addition to IgM and IgA, bispecific antibodies (bsAbs) combine specificities of two antibodies in one molecule, representing an important alternative to monoclonal antibody cocktails. Here, we summarize the latest advances in studies on IgM, IgA and bsAbs against SARS-CoV-2. The current challenges and future directions in vaccine design and antibody-based therapeutics are also discussed.
Oridonin Inhibits SARS‐CoV‐2 Oridonin, a natural product extracted from Rabdosia rubescens , possesses a wide range of pharmacological properties, including anti‐inflammatory, anti‐cancer, anti‐microbial, neuroprotection, immunoregulation, etc. In article number 2100124 , Baisen Zhong, Litao Sun, and co‐workers demonstrate that Oridonin targets the SARS‐CoV‐2 3CL protease by covalently binding to cysteine145 in its active pocket to exert an anti‐SARS‐CoV‐2 effect, which provides a novel candidate for the treatment of COVID‐19. Permissions: © 2022 WILEY‐VCH GmbH
The current COVID‐19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is an enormous threat to public health. The SARS‐CoV‐2 3C‐like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (–)‐Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS‐CoV‐2 3CLpro. Further, blocking SARS‐CoV‐2 infectivity by Oridonin is confirmed in cell‐based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C—S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID‐19.
Background Understanding the transmission source, pattern, and mechanism of infectious diseases is essential for targeted prevention and control. Though it has been studied for many years, the detailed transmission patterns and drivers for the seasonal influenza epidemics in China remain elusive. Methods In this study, utilizing a suite of epidemiological and genetic approaches, we analyzed the updated province-level weekly influenza surveillance, sequence, climate, and demographic data between 1 April 2010 and 31 March 2018 from continental China, to characterize detailed transmission patterns and explore the potential initiating region and drivers of the seasonal influenza epidemics in China. Results An annual cycle for influenza A(H1N1)pdm09 and B and a semi-annual cycle for influenza A(H3N2) were confirmed. Overall, the seasonal influenza A(H3N2) virus caused more infection in China and dominated the summer season in the south. The summer season epidemics in southern China were likely initiated in the “Lingnan” region, which includes the three most southern provinces of Hainan, Guangxi, and Guangdong. Additionally, the regions in the south play more important seeding roles in maintaining the circulation of seasonal influenza in China. Though intense human mobility plays a role in the province-level transmission of influenza epidemics on a temporal scale, climate factors drive the spread of influenza epidemics on both the spatial and temporal scales. Conclusion The surveillance of seasonal influenza in the south, especially the “Lingnan” region in the summer, should be strengthened. More broadly, both the socioeconomic and climate factors contribute to the transmission of seasonal influenza in China. The patterns and mechanisms revealed in this study shed light on the precise forecasting, prevention, and control of seasonal influenza in China and worldwide.
Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor receptors (EGFRs). Although small molecule inhibitors and monoclonal antibodies have been developed to target EGFRs, few EGFR-targeted therapeutics are approved for clinical use. Ferroptosis is a new kind of programmed death induced by the iron catalyzed excessive peroxidation of polyunsaturated fatty acids. A growing body of evidence suggests that ferroptosis plays a pivotal role in inhibiting the tumor process. However, whether and how ferroptosis-inducers (FINs) play roles in hindering HNSCCs are unclear. In this study, we analyzed the sensitivity of different HNSCCs to ferroptosis-inducers. We found that only tongue squamous cell carcinoma cells and laryngeal squamous cell carcinoma cells, but not nasopharyngeal carcinoma cells, actively respond to ferroptosis-inducers. The different sensitivities of HNSCC cells to ferroptosis induction may be attributed to the expression of KRAS and ferritin heavy chain (FTH1) since a high level of FTH1 is associated with the poor prognostic survival of HNSCCs, but knocked down FTH1 can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody Cetuximab to inhibit the survival of nasopharyngeal carcinoma cells (CNE-2), which are insensitive to both ferroptosis induction and EGFR inhibition due to a high level of FTH1 and a low level of EGFR, respectively. Our findings prove that FTH1 plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition.
In late December 2019, a cluster of pneumonia cases caused by a novel coronavirus (CoV) was reported in Wuhan, China (1-3). Genomic sequencing showed that this pathogenic coronavirus is 96.2% identical to a bat coronavirus and shares 79.5% sequence identify to SARS-CoV (4-6). This novel coronavirus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses, and the pneumonia was designated as COVID-19 by the World Health Organization (WHO) on February 11, 2020 (7). The epidemic spread rapidly to more than 212 countries and was announced as a global health emergency by WHO (8). No clinically effective vaccines or specific antiviral drugs are currently available for the prevention and treatment of COVID-19 infections. The combination of α-interferon and the anti-HIV drugs Lopinavir/Ritonavir (Kaletra®) has been used, but the curative effect remains very limited and there can be toxic side effects (9). Remdesivir, a broad-spectrum antiviral drug developed by Gilead Sciences, Inc., is also being explored for the treatment of COVID-19, but more data are needed to prove its efficacy (10-12). Specific anti-SARS-CoV-2 drugs with efficiency and safety are urgently needed. A maximum likelihood tree based on the genomic sequence showed that the virus falls within the subgenus Sarbecovirus of the genus Betacoronavirus (6). Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs is approximately 30 k nt in length with a 5′-cap structure and 3′-poly-A tail, and contains at least 6 open reading frames (ORFs) (13, 14). The first ORF (ORF 1a/b), about two-third of genome length, directly translates two polyproteins: pp1a and pp1ab, because there is an a-1 frameshift between ORF1a and ORF1b. These polyproteins are processed by a main protease (M pro), also known as the 3C-like protease (3CL pro), and one or two papain-like proteases (PLPs), into 16 non-structural proteins (nsps). These nsps engage in the production of subgenomic RNAs that encode four main structural proteins (envelope (E), membrane (M), spike (S), and nucleocapsid (N) pro
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