Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use 4 strains, time course, lungs
Project description:Epidemiological models of COVID-19 transmission assume that recovered individuals have a fully protected immunity. To date, there is no definite answer about whether people who recover from COVID-19 can be reinfected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the absence of a clear answer about the risk of reinfection, it is instructive to consider the possible scenarios. To study the epidemiological dynamics with the possibility of reinfection, I use a Susceptible-Exposed-Infectious-Resistant-Susceptible model with the time-varying transmission rate. I consider three different ways of modeling reinfection. The crucial feature of this study is that I explore both the difference between the reinfection and no-reinfection scenarios and how the mitigation measures affect this difference. The principal results are the following. First, the dynamics of the reinfection and no-reinfection scenarios are indistinguishable before the infection peak. Second, the mitigation measures delay not only the infection peak, but also the moment when the difference between the reinfection and no-reinfection scenarios becomes prominent. These results are robust to various modeling assumptions.
Project description:Epidemiological models of COVID-19 transmission assume that recovered individuals have a fully pro- tected immunity. To date, there is no definite answer about whether people who recover from COVID-19 can be reinfected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the absence of a clear answer about the risk of reinfection, it is instructive to consider the possible scenarios. To study the epidemiological dynamics with the possibility of reinfection, I use a Susceptible-Exposed-Infectious- Resistant-Susceptible model with the time-varying transmission rate. I consider three different ways of modeling reinfection. The crucial feature of this study is that I explore both the difference between the reinfection and no-reinfection scenarios and how the mitigation measures affect this difference. The principal results are the following. First, the dynamics of the reinfection and no-reinfection scenarios are in- distinguishable before the infection peak. Second, the mitigation measures delay not only the infection peak, but also the moment when the difference between the reinfection and no-reinfection scenarios becomes prominent. These results are robust to various modeling assumptions.
Project description:This experiment aims to profile polyclonal antibody binding profiles in serum from vaccinated animals relative to antibody function in a virus neutralization assay. Rabbits received three vaccinations with a DNA vaccine encoding the spike protein of the SARS-CoV-2 index strain. Serum samples were selected based on a three-tier (low, intermediate, and high) capacity to cross-neutralize SARS-CoV-2 strains with known neutralization resistance. Following normalization of total anti-spike IgG levels, serum of each animal (n=3) were evaluated for antibody binding to 10mer cyclic constrained peptides spanning the entire spike protein and regions with known SARS-CoV-2 variant of concern spike mutations.
Project description:A recombinant SARS-CoV lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major virulence determinant in vivo. Elimination of SARS-CoV E protein PBM by using reverse genetics led to attenuated viruses (SARS-CoV-mutPBM) and to a reduction in the deleterious exacerbate immune response triggered during infection with the parental virus (SARS-CoV-wt). Cellular protein syntenin bound E protein PBM during SARS-CoV infection. Syntenin activates p38 MAPK leading to overexpression of inflammatory cytokines, and we have shown that active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM (SARS-CoV-mutPBM) as compared with the parental virus (SARS-CoV-wt), leading to a decreased expression of inflammatory cytokines and to viral attenuation. Therefore, E protein PBM is a virulence factor that activates pathogenic immune response most likely by using syntenin as a mediator of p38 MAPK induced inflammation. Three biological replicates were independently hybridized (one channel per slide) for each sample type (SARS-CoV-wt, SARS-CoV-mutPBM, Mock). Slides were Sure Print G3 Agilent 8x60K Mouse (G4852A-028005)
Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.
Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.
Project description:Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing transmission of SARS-CoV-2. We found that a single intranasal dose of serotype 5-based adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) secretory and serum anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and in respiratory secretions, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of wild-type mice from a challenge with the SARS-CoV-2 beta variant. Our data confirm and extend previous studies reporting promising preclinical results on vector-based intranasal SARS-CoV-2 vaccination, and support the potential of this approach to elicit mucosal immunity for preventing reinfection and transmission of SARS-CoV-2 more effectively than the currently available vaccines.
Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use
Project description:Severe acute respiratory syndrome virus (SARS-CoV) that lacks the envelope (E) gene (rSARS-CoV-ΔE) is attenuated in vivo [1,2]. To identify factors that contribute to rSARS-CoV-ΔE attenuation, gene expression in cells infected by SARS-CoV with or without E gene was compared. Twenty-five stress response genes were preferentially upregulated during infection in the absence of the E gene. In addition, genes involved in signal transduction, transcription, cell metabolism, immunoregulation, inflammation, apoptosis and cell cycle and differentiation were differentially regulated in cells infected with rSARS-CoV with or without the E gene. Administration of E protein in trans reduced the stress response in cells infected with rSARS-CoV-ΔE, with respiratory syncytial virus, or treated with drugs, such as tunicamycin and thapsigarcin that elicit cell stress by different mechanisms. In addition, SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. Overall, the activation of the IRE-1 pathway was not able to restore cell homeostasis, and apoptosis was induced probably as a meassure to protect the host by limiting virus production and dissemination. The expression of proinflammatory cytokines was reduced in rSARS-CoV-ΔE-infected cells compared to rSARS-CoV-infected cells, suggesting that the increase in stress responses and the reduction of inflammation in the absence of the E gene contributed to the attenuation of rSARS-CoV-ΔE. We used Affymetrix microarrays (Human Genome U133 plus 2.0) to compare global gene expression between SARS-CoV-infected, mock-infected and SARS-CoV-ΔE-infected cells. For ech type of sample three hybridizations were carried-out (independent biological replicates).