COVID-19 - Coronavirus disease 2019

Potential HLA class I associations with COVID-19 control – HLACOVID19

Submission summary

Whether host genetic determinants influence the susceptibility to and severity of COVID-19 is unknown. Cytotoxic T cells recognize virus-infected cells after presentation of short viral peptides within the binding groove of HLA class 1 (HLA-1) molecules. NK cells also recognize virus-infected cells using activating and inhibitory receptors, many of which interact with HLA-1 molecules. Functional diversity of the highly polymorphic HLA-1 (A, B and C) genes underlies successful immunologic control of viral diseases through multiple mechanisms, including: i) influence of specific alleles/ aminoacid positions on disease progression through presentation of virus-derived immunogenic peptides to CD8 T cells; ii) HLA heterozygous advantage, conferring a higher probability of triggering a specific immune response upon infection; iii) HLA allelic divergence advantage; iv) variation in HLA expression levels; v) HLA interactions with NK cell receptors. As the best example, the HLA-1 locus is the most robust correlate of HIV disease outcome through these different mechanisms.
Aim of our project is to determine the impact of HLA-1 polymorphisms on SARS-CoV-2 control, by comparing COVID-19 patients to SARS-CoV2-infected but asymptomatic subjects, high-risk subjects that have been exposed but not infected, and healthy controls. We will benefit from the access to DNA samples from the well-annotated French multicentric cohorts of COVID-19 patients (French CoVID-19) and contacts (CoV-CONTACT / Cov-CONTACT-SERO) (promoter INSERM) to address the following aims:
Aim 1: To identify specific HLA-1 alleles/amino acids associated with risk to progress to COVID-19. We will use computational methods to predict 9-mer peptides derived from the SARS-CoV-2 spike (S), membrane (M), nucleocapsid (N) and envelope (E) structural proteins potentially bound by the HLA-1 alleles, and identify immmunogenic epitopes. We will test whether the patient-specific repertoire of predicted SARS-CoV-2 epitopes is associated with COVID-19 control. Among COVID-19 patients, particular attention will be paid to those severe with hyperinflammatory cytokine storm syndrome, as they may represent a subset of patients with uncontrolled T cell responses to viral antigens.
Aim 2: To determine the advantage of HLA-1 heterozygosity (defined as carrying two different homologous alleles at a given HLA-1 locus) and of HLA-1 allelic divergence (defined by the physiochemical sequence divergence between HLA-1 alleles of each patient's genotype) on SARS-CoV-2 control.
Aim 3: To determine the impact of increased HLA-1 expression levels on disease severity, in particular in patients with uncontrolled cytokine storm.
This study may help understand why some subjects progress to severe and fatal COVID-19, and provide useful information to map immunogenic epitopes on viral structural proteins for designing vaccine candidates.

Project coordination

Sophie Caillat (INSERM DR PARIS 7)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM DR PARIS 7

Help of the ANR 108,324 euros
Beginning and duration of the scientific project: - 12 Months

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