ABSTRACT
Background: Depression and dysosmia have been regarded as the main neurological symptoms in COVID-19 patients, the mechanism of which remains unclear. Current studies have demonstrated that SARS-CoV-2 envelope protein served as a pro-inflammatory factor as sensed by Toll like receptor 2 (TLR2), suggesting the viral infection independent pathological feature of E protein. In this study, we aim to determine the role of E protein in depression, dysosmia and associated neuroinflammation in central nervous system (CNS). Methods: Depression and olfactory function were observed in both female and male mice as receiving intracisternal injection of envelope protein. Immunohistochemistry was applied in conjunction with RT-PCR to assess the glial activation, blood-brain barrier status and mediators synthesis in cortex, hippocampus and olfactory bulb. TLR2 was pharmacologically blocked to determine its role in E protein related depression and dysosmia. Results: Intracisternal injection of envelope protein evoked depression and dysosmia in both female and male mice. Immunohistochemistry suggested that envelope protein upregulated IBA1 and GFAP in cortex, hippocampus and olfactory bulb, while ZO-1 was downregulated. Moreover, IL-beta, TNF-alpha, IL-6, CCL2, MMP2 and CSF1 were upregulated in both cortex and hippocampus, whereas IL-beta, IL-6 and CCL2 were upregulated in olfactory bulb. Furtherly, inhibiting microglia, but not astrocyte, alleviated depression and dysosmia induced by envelope protein. Finally, RT-PCR and immunohistochemistry suggested that TLR2 was upregulated in cortex, hippocampus and olfactory bulb, the blocking of which mitigated depression and dysosmia induced by envelope protein. Conclusions: Our study demonstrates that envelope protein could directly induce depression and dysosmia together with obvious neuroinflammation in CNS. TLR2 mediated depression and dysosmia induced by envelope protein, which could serve as a promising therapeutic target for neurological manifestation in COVID-19 patients.
Subject(s)
Depressive Disorder , Olfaction Disorders , COVID-19ABSTRACT
The widespread SARS-CoV-2 in humans results in the continuous emergence of new variants. Recently emerged Omicron variant with multiple spike mutations sharply increases the risk of breakthrough infection or reinfection, highlighting the urgent need for new vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x), which showed high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine comprised of STFK and STFK1628x elicited high titers of broad-spectrum antibodies to neutralize all 14 circulating SARS-CoV-2 variants, including Omicron; and fully protected vaccinees from intranasal SARS-CoV-2 challenges of either the ancestral strain or immune-evasive Beta variant. Strikingly, the vaccination of hamsters with the bivalent vaccine completely blocked the within-cage virus transmission to unvaccinated sentinels, for either the ancestral SARS-CoV-2 or Beta variant. Thus, our study provides new insights and antigen candidates for developing next-generation COVID-19 vaccines.
Subject(s)
COVID-19 , Breakthrough PainABSTRACT
Background: Public health measures against COVID-19 may influence other disease epidemics. Many countries have reported significant reductions in influenza activity in 2020–2021, but the prevalence of other respiratory pathogens during the COVID-19 pandemic has rarely been reported, especially in China.Methods: Data from the Respiratory Pathogen Surveillance System in Beijing were analyzed to compare pathogen infection rates before the COVID-19 (from 1 February 2015 to 31 January 2020) and during the COVID-19 (from 1 February 2020 to 31 January 2021).Findings: Among 41630 acute respiratory tract infections 13630 had at least one pathogen positive result, which decreased from 32·16% (95% CI 31·69%, 32·64%) before the COVID-19 to 10·97% (95% CI 10·03%, 11·96%) during the COVID-19, representing a 65·90% decrease (P<0·001). The positivity rate fluctuated with the strictness of public health measures. Before the COVID-19 epidemic, the top five of the pathogenic spectrums were IFV (26·27%), MP (19·30%), HPIV (11·80%), HRV (9·38%), and EV (8·38%), while during the COVID-19, the top five were seasonal HCoV (21·10%), HRV (18·99%), HPIV (14·98%), IFV (13·08%), and RSV (10.76%).Interpretation: The prevalence of respiratory pathogens decreased significantly during the COVID-19, closely relating to public health measures against COVID-19; these measures can serve as useful strategies for the prevention and control of other respiratory tract infections.Funding Statement: The National Major Science and Technology Project for Control and Prevention of Major Infectious Diseases in China (2017ZX10103004).Declaration of Interests: FH received funds from the National Major Science and Technology Project for Control and Prevention of Major Infectious Diseases in China (2017ZX10103004). All other authors declare no competing interests.Ethics Approval Statement: Ethics approval for the protocol of this study was obtained from the Ethics Committee of the BJCDC. Written informed consent was obtained.