CE15 - Immunologie, Infectiologie et Inflammation

Mapping BCR repertoires against polyoma- and papillomaviruses to epitopes on viral capsids – Rep2Eps

Submission summary

Papillomaviruses (PV) and polyomaviruses (PyVs) are small nonenveloped, icosahedral DNA viruses that cause persistent infections. Some of these viruses, such as high risk HPVs (eg. HPV16, HPV18...) cause cervical cancer, while others, like BKPyV and JCPyV, cause severe disease in immunosuppressed patients.
Antibody responses against these viruses are key to the protective effects of vaccines against high-risk HPVs and also play a role in the emergence of overt BKPyV- and JCPyV-associated pathologies. However, most of what we know about antiviral antibodies comes from the study of enveloped viruses like HIV, influenza, and SARS-CoV2. The overarching aim of the Rep2Eps project is to increase the breadth of studied pathogens to include nonenveloped viruses, in order to deepen our understanding of host antiviral responses. Within this framework, we aim to answer specific questions related to each viral infection:
1. Are virus-specific antibody repertoires distinct between clinically relevant patient groups?
In BKPyV and JCPyV infections, severe pathology is associated with neutralization escape variants that emerge in some patients but not in others. We aim to determine whether there are qualitative differences in the humoral response that could explain why escape variants only emerge in some patients. To do this we will sort virus-specific B-cells, and analyze their B-cell receptors (BCR) by scRNAseq, map the epitopes recognized by antibodies, and cluster BCR sequences bioinformatically. We will then compare A) BKPyV-specific repertoires in kidney transplant recipients who control BKPyV DNAemia compared to those who experience persistent high-level DNAemia, and B) JCPyV-specific antibody repertoires in JCPyV seropositive MS patients who develop PML, and in a control group of JCPyV seropositive MS patients under Natalizumab therapy without PML. This work may lead to better stratification and monitoring of MS patients at risk for PML, and KTx recipients with BKPyV.
2. Why do some viruses induce a memory IgM response?
We recently found that memory B-cells specific for BKPyV in kidney transplant recipients were dominated by cells expressing IgM antibodies, which is unusual for an antiviral reponse. We hypothesize that the regular array of epitopes presented by the PyV capsid, typical of Type 2 T-independent antigens, is what leads to the emergence of a strong memory IgM response. To understand how this occurs, we propose to combine structural and bioinformatics approaches to compare the distribution of epitopes recognized by IgG clonotypes and memory IgM clonotypes on the capsid surface. A key objective is to determine the structure of virus capsids complexed with a full IgM antbody by cryo-EM. This will be the first high-resolution structure of an IgM molecule complexed with a viral antigen and will provide a mechanistic explanation of why some types of virus infection engage memory IgM responses.
3. What epitopes are targeted by antibodies that cross-neutralize different HPV types?
Vaccination with bi- and tetra-valent vaccines induces some serological cross-reactivity and clinical protection against closely related HPV types that are not represented in the vaccine. The structural basis for this cross-protection is not known. We aim to identify HPV16-HPV31 cross-reactive antibodies by analyzing the BCR repertoire in women with active infection with either HPV16 or HPV31. To do this, HPV-specific BCR repertoires will be determined by applying the LibraSeq approach, which can directly identify cross-reactive antibodies. Epitopes recognized by these cross-reactive antibodies will be analyzed functionally, and structurally by cryo-EM. A better understanding of serological cross-reactivity between HPV types would help to optimize next-generation HPV vaccines and thereby help to eradicate HPV-associated cancers.

Project coordinator

Monsieur Dorian McIlroy (Nantes Université)

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

CRT2I Nantes Université
Research Institute for Microbial Diseases, Osaka
PHU 7 PHU 7 - Biologie
CIRB Collège de France Paris
IBS IBS
CRCI2NA Institut national de la sante et de la recherche medicale

Help of the ANR 543,586 euros
Beginning and duration of the scientific project: January 2023 - 48 Months

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