Epitopes screening and vaccine molecular design of SADS-CoV based on immunoinformatics.

The regional outbreak of the Swine acute diarrhea syndrome coronavirus (SADS-CoV) has seriously threatened the swine industry. There is an urgent need to discover safe and effective vaccines to contain them quickly. The coronavirus spike protein mediates virus entry into host cells, one of the most important antigenic determinants and a potential vaccine target. Therefore, this study aims to conduct a predictive analysis of the epitope of S protein B cells and T cells (MHC class I and class II) by immunoinformatics methods by screening and identifying protective antigenic epitopes that induce major neutralized antibodies and activate immune responses to construct epitope vaccines. The study explored primary, secondary, and tertiary structures, disulfide bonds, protein docking, immune response simulation, and seamless cloning of epitope vaccines. The results show that the spike protein dominant epitope of the screening has a high conservativeness and coverage of IFN-γ, IL-4-positive Th epitope, and CTL epitope. The constructed epitope vaccine interacts stably with TLR-3 receptors, and the immune response simulation shows good immunogenicity, which could effectively activate humoral and cellular immunity. After codon optimization, it was highly likely to be efficiently and stably expressed in the Escherichia coli K12 expression system. Therefore, the constructed epitope vaccine will provide a new theoretical basis for the design of SADS-CoV antiviral drugs and related research on coronaviruses such as SARS-CoV-2.

Negative Immune Checkpoint Protein, VISTA, Regulates the CD4+ Treg Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival

Sepsis is a systemic immune response to infection that is responsible for ~35% of in-hospital deaths and over 24 billion dollars in annual treatment costs. Strategic targeting of non-redundant negative immune checkpoint protein pathways can cater therapeutics to the individual septic patient and improve prognosis. B7-CD28 superfamily member V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an ideal candidate for strategic targeting in sepsis. We hypothesized that immune checkpoint regulator, VISTA, controls T-regulatory cells (Treg), in response to septic challenge, thus playing a protective role/reducing septic morbidity/mortality. Further, we investigated if changes in morbidity/mortality are due to a Treg-mediated effect during the acute response to septic challenge. To test this, we used the cecal ligation and puncture model as a proxy for polymicrobial sepsis and assessed the phenotype of CD4+ Tregs in VISTA-gene deficient (VISTA-/-) and wild-type mice. We also measured changes in survival, soluble indices of tissue injury, and circulating cytokines in the VISTA-/- and wild-type mice. We found that in wild-type mice, CD4+ Tregs exhibit a significant upregulation of VISTA which correlates with higher Treg abundance in the spleen and small intestine following septic insult. However, VISTA-/- mice have reduced Treg abundance in these compartments met with a higher expression of Foxp3, CTLA4, and CD25 compared to wild-type mice. VISTA-/- mice also have a significant survival deficit, higher levels of soluble indicators of liver injury (i.e., ALT, AST, bilirubin), and increased circulating proinflammatory cytokines (i.e., IL-6, IL-10, TNFα, IL-17F, IL-23, and MCP-1) following septic challenge. To elucidate the role of Tregs in VISTA-/- sepsis mortality, we adoptively transferred VISTA-expressing Tregs into VISTA-/- mice. This adoptive transfer rescued VISTA-/- survival to wild-type levels. Taken together, we propose a protective Treg-mediated role for VISTA by which inflammation-induced tissue injury is suppressed and improves survival in early-stage murine sepsis. Thus, enhancing VISTA expression or adoptively transferring VISTA+ Tregs in early-stage sepsis may provide a novel therapeutic approach to ameliorate inflammation-induced death.

A Mini-Review on Cell Cycle Regulation of Coronavirus Infection.

Coronaviruses are widespread in nature and infect humans, mammals and poultry. They cause harm to humans and animals. Virus-mediated cell cycle arrest is an essential strategy for viral survival and proliferation in the host cells. A clarification system of the mechanisms of virus-induced cell cycle arrest is highly desirable to promote the development of antiviral therapies. In this review, molecular mechanisms of coronavirus-induced cell cycle arrest were systematically summarized. Moreover, the common features of coronavirus-mediated cell cycle arrest were discussed. This review will provide a theoretical basis for further studies on the infection mechanisms and prevention of coronaviruses.