ABSTRACT
Butyrate, produced by gut microbe during dietary fiber fermentation, plays anti-inflammatory and antioxidant effects in chronic inflammation diseases, yet it remains to be explored whether butyrate has protective effects against viral infections. Here, we demonstrated that butyrate alleviated tissue injury in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected golden hamsters with supplementation of butyrate before and during the infection. Butyrate-treated hamsters showed augmentation of type I interferon (IFN) response and activation of endothelial cells without exaggerated inflammation. In addition, butyrate regulated redox homeostasis by enhancing the activity of superoxide dismutase (SOD) to inhibit excessive apoptotic cell death. Therefore, butyrate exhibited an effective prevention against SARS-CoV-2 by upregulating antiviral immune responses and promoting cell survival.
Subject(s)
Inflammation , Severe Acute Respiratory SyndromeABSTRACT
Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.
Subject(s)
Coronavirus Infections , Weight Loss , COVID-19ABSTRACT
Background: The pandemic of SARS-CoV-2 has turned into a global public health crisis. Acute SARS-CoV-2 infection is associated with severe pneumonia, multiple-organ failures and deaths. Currently, treatment for SARS-CoV-2 infection and severe pneumonia is largely lacking. Several clinical trials demonstrated that glucocorticoid dexamethasone is effective to reduce disease severity and mortality. However, whether dexamethasone is clinically sufficient to treat COVID-19 is unknown.Methods: We tested the therapeutic effect of dexamethasone on SARS-CoV-2 infection and pneumonia in a Syrian hamster model. Survival rate, body weight loss, viral RNA, antibody responses, severity of lung inflammation and injury were measured in a 7-day acute infection course.Findings: Dexamethasone reduces body weight loss and relieves the diffusion of lung injury in SARS-CoV-2-infected hamster by inhibiting the excessive proinflammatory cytokines including IL-4, IL-6, IL-10, IL-13, TNF-α and IFN-γ. Dexamethasone rescues hamsters from the lethal infection of SARS-CoV-2 variant D614G. Dexamethasone attenuates serum neutralizing antibody and RBD-specific antibody titers, and slightly increases viral RNA level in lung tissues.Interpretation: Overall, using the hamster model, this study improves our understanding of the therapeutic mechanisms and drawbacks of dexamethasone treatment of COVID-19, and suggests that an antiviral is needed to accompany the dexamethasone treatment regimen.Funding: National Science Key Research and Development Project of China, National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences and China Postdoctoral Science Foundation.Declaration of Interest: The authors declare no competing interests.Ethical Approval: All the animal experiments were approved by the Medical Ethics Committee(SUCM2021-112).
Subject(s)
COVID-19 , Lung Injury , Pneumonia , Wounds and InjuriesABSTRACT
A safe and effective SARS-CoV-2 vaccine is essential to avert the on-going COVID-19 pandemic. Here, we developed a subunit vaccine, which is comprised of CHO-expressed spike ectodomain protein (StriFK) and nitrogen bisphosphonates-modified zinc-aluminum hybrid adjuvant (FH002C). This vaccine candidate rapidly elicited the robust humoral response, Th1/Th2 balanced helper CD4 T cell and CD8 T cell immune response in animal models. In mice, hamsters, and non-human primates, 2-shot and 3-shot immunization of StriFK-FH002C generated 28- to 38-fold and 47- to 269-fold higher neutralizing antibody titers than the human COVID-19 convalescent plasmas, respectively. More importantly, the StriFK-FH002C immunization conferred sterilizing immunity to prevent SARS-CoV-2 infection and transmission, which also protected animals from virus-induced weight loss, COVID-19-like symptoms, and pneumonia in hamsters. Vaccine-induced neutralizing and cell-based receptor-blocking antibody titers correlated well with protective efficacy in hamsters, suggesting vaccine-elicited protection is immune-associated. The StriFK-FH002C provided a promising SARS-CoV-2 vaccine candidate for further clinical evaluation.
Subject(s)
COVID-19 , Weight Loss , PneumoniaABSTRACT
COVID-19, which has resulted a worldwide health crisis with more than 74.9 million confirmed cases worldwide by December 2020, is caused by a newly emerging coronavirus identified and named SARS-CoV-2 in February in Wuhan, China. Experiences in defeating SARS, which infested during 2002-2003, can be used in treating the new disease. However, comparative genomics and epidemiology studies have shown much difference between SARS-CoV and SARS-CoV-2, which underlies the different clinical features and therapies in between those two diseases. Further studies comparing transcriptomes infected by these two viruses to uncover the differences in host responses would be necessary. Here we conducted a comprehensive transcriptome analysis of SARS-CoV and SARS-CoV-2-infected human cell lines, including Caco-2, Calu-3, H1299. Clustering analysis and expression of ACE2 show that SARS-CoV-2 has broader but weaker infection, where the largest discrepancy occurs in the epithelial lung cancer cell, Calu-3. SARS-CoV-2 genes also show less tissue specificity than SARS-CoV genes. Furthermore, we detected more general but moderate immune responses in SARS-CoV-2 infected transcriptomes by comparing weighted gene co-expression networks and modules. Our results suggest a different immune therapy and treatment scheme for COVID-19 patients than the ones used on SARS patients. The wider but weaker permissiveness and host responses of virus infection may also imply a long-term existence of SARS-CoV-2 among human populations.