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1.
J Inflamm Res ; 14: 3781-3795, 2021.
Article in English | MEDLINE | ID: covidwho-1360681

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus which caused a global respiratory disease pandemic beginning in December 2019. Understanding the pathogenesis of infection and the immune responses in a SARS-CoV-2-infected animal model is urgently needed for vaccine development. Methods: Syrian hamsters (Mesocricetus auratus) were intranasally inoculated with 105, 5×105, and 106 TCID50 of SARS-CoV-2 per animal and studied for up to 14 days. Body weight, viral load and real-time PCR amplification of the SARS-CoV-2 N gene were measured. On days 3, 6 and 9, lung, blood, liver, pancreas, heart, kidney, and bone marrow were harvested and processed for pathology, viral load, and cytokine expression. Results: Body weight loss, increased viral load, immune cell infiltration, upregulated cytokine expression, viral RNA, SARS-CoV-2 nucleoprotein, and mucus were detected in the lungs, particularly on day 3 post-infection. Extremely high expression of the pro-inflammatory cytokines MIP-1 and RANTES was detected in lung tissue, as was high expression of IL-1ß, IL-6, IL-12, and PD-L1. The glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) ratio in blood was significantly increased at 6 days post-infection, and plasma amylase and lipase levels were also elevated in infected hamsters. Conclusion: Our results provide new information on immunological cytokines and biological parameters related to the pathogenesis and immune response profile in the Syrian hamster model of SARS-CoV-2 infection.

2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Article in English | MEDLINE | ID: covidwho-1350316

ABSTRACT

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.


Subject(s)
Amyloid beta-Peptides/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Peptide Fragments/metabolism , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Animals , COVID-19/complications , COVID-19/metabolism , Chlorocebus aethiops , Humans , Interleukin-6/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/chemistry , Protein Subunits/chemistry , Protein Subunits/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Internalization
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Article in English | MEDLINE | ID: covidwho-1335101

ABSTRACT

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.


Subject(s)
Amyloid beta-Peptides/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Peptide Fragments/metabolism , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Animals , COVID-19/complications , COVID-19/metabolism , Chlorocebus aethiops , Humans , Interleukin-6/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/chemistry , Protein Subunits/chemistry , Protein Subunits/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Internalization
4.
PLoS Negl Trop Dis ; 15(5): e0009374, 2021 05.
Article in English | MEDLINE | ID: covidwho-1264204

ABSTRACT

The development of efficient vaccines against COVID-19 is an emergent need for global public health. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major target for the COVID-19 vaccine. To quickly respond to the outbreak of the SARS-CoV-2 pandemic, a nucleic acid-based vaccine is a novel option, beyond the traditional inactivated virus vaccine or recombinant protein vaccine. Here, we report a DNA vaccine containing the spike gene for delivery via electroporation. The spike genes of SARS-CoV and SARS-CoV-2 were codon optimized for mammalian cell expression and then cloned into mammalian cell expression vectors, called pSARS-S and pSARS2-S, respectively. Spike protein expression was confirmed by immunoblotting after transient expression in HEK293T cells. After immunization, sera were collected for antigen-specific antibody and neutralizing antibody titer analyses. We found that both pSARS-S and pSARS2-S immunization induced similar levels of antibodies against S2 of SARS-CoV-2. In contrast, only pSARS2-S immunization induced antibodies against the receptor-binding domain of SARS-CoV-2. We further found that pSARS2-S immunization, but not pSARS-S immunization, could induce very high titers of neutralizing antibodies against SARS-CoV-2. We further analyzed SARS-CoV-2 S protein-specific T cell responses and found that the immune responses were biased toward Th1. Importantly, pSARS2-S immunization in hamsters could induce protective immunity against SARS-CoV-2 challenge in vivo. These data suggest that DNA vaccination could be a promising approach for protecting against COVID-19.


Subject(s)
COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/standards , Animals , Chlorocebus aethiops , Cricetinae , Electroporation , HEK293 Cells , Humans , Mesocricetus , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Plasmids , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, DNA/immunology , Vero Cells
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