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Nat Methods ; 18(6): 627-630, 2021 06.
Article in English | MEDLINE | ID: covidwho-1550331


We introduce the TRUST4 open-source algorithm for reconstruction of immune receptor repertoires in αß/γδ T cells and B cells from RNA-sequencing (RNA-seq) data. Compared with competing methods, TRUST4 supports both FASTQ and BAM format and is faster and more sensitive in assembling longer-even full-length-receptor repertoires. TRUST4 can also call repertoire sequences from single-cell RNA-seq (scRNA-seq) data without V(D)J enrichment, and is compatible with both SMART-seq and 5' 10x Genomics platforms.

Algorithms , Receptors, Immunologic/genetics , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, T-Cell/genetics , V(D)J Recombination
Viruses ; 13(10)2021 10 13.
Article in English | MEDLINE | ID: covidwho-1470992


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the coronavirus disease 2019 (COVID-19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS-CoV-2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID-19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS-CoV-2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS-CoV-2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.

Adaptive Immunity/immunology , COVID-19/pathology , DNA Repair/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , V(D)J Recombination/genetics , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , BRCA1 Protein/antagonists & inhibitors , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Cell Line , DNA Damage/genetics , HEK293 Cells , Humans , Immunity, Humoral/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors
J Biol Chem ; 296: 100745, 2021.
Article in English | MEDLINE | ID: covidwho-1213326


Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.

Adaptive Immunity , Antibodies, Viral/chemistry , Antigens, Viral/chemistry , Immunity, Innate , Receptors, Antigen, T-Cell/chemistry , Receptors, Cytokine/chemistry , SARS-CoV-2/immunology , Allergy and Immunology/history , Animals , Antibodies, Viral/genetics , Antibodies, Viral/immunology , Antibody Specificity , Antigen Presentation , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/immunology , COVID-19/virology , Crystallography/history , Crystallography/methods , History, 20th Century , History, 21st Century , Humans , Protein Folding , Protein Interaction Domains and Motifs , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Cytokine/genetics , Receptors, Cytokine/immunology , SARS-CoV-2/pathogenicity , V(D)J Recombination