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1.
researchsquare; 2021.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-898487.v1

ABSTRACT

Background: The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, it remains unclear whether immune responses following natural infection can be sustained or potentially prove critical for long-term immune protection against SARS-CoV-2 reinfection. Here, we systematically mapped the phenotypic landscape of SARS-CoV-2-specific immune responses in peripheral blood samples of 4 healthy donors and 13 convalescent patients with COVID-19, including moderate and severe cases, by single-cell RNA sequencing. Results: : The relative percentage of the CD8+ effector memory subset was increased in both convalescent moderate and severe cases, but NKT-CD160 and maginal zone B clusters were decreased. Innate immune responses were attenuated reflected by decreased expression of genes involved in interferon-gamma, leukocyte migration and neutrophil mediated immune response in convalescent COVID-19 patients. Functions of T cell were strengthened in convalescent COVID-19 patients by clear endorsement of increased expression of genes involved in biological processes of regulation of T cell activation, differentiation and cell-cell adhesion. In addition, T cell mediated immune responses were enhanced with remarkable clonal expansions of TCR and increased transition of CD4+ effector memory and CD8+ effector-GNLY in severe subjects. B cell immune responses displayed sophisticated and dual functions during convalescence of COVID-19, providing a novel mechanism that B cell activation was observed especially in moderate while humoral immune response was weakened. Interestingly, HLA class I genes displayed downregulation while HLA class II genes upregulation in both T and B cell subsets in convalescent individuals. Notably, some unique IGV genes in severe patients may facilitate the design of vaccines. Conclusions: : Our collective dataset showed that innate immunity was declined but SARS-CoV-2-specific T cell responses were retained even strengthened whereas sophisticated and dual functions of B cells, including declined humoral immunity were presented at several months following infections, which provided insights into evaluation of possibility of reinfection of exposed individuals with COVID-19 and facilitation to design of effective therapeutics and vaccines.

2.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.29.360479

ABSTRACT

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19.

3.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.29.361261

ABSTRACT

The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

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