Outlining the Role of IgA in Memory Instruction

Descripción del proyecto

El papel de los linfocitos B IgA+ durante las infecciones víricas respiratorias

Los virus respiratorios (con el virus de la gripe H1N1 y el coronavirus del síndrome respiratorio agudo grave de tipo 2) se propagan con rapidez y pueden resultar letales. Inducen la producción de anticuerpos IgA implicados en la protección pulmonar. Sin embargo, las vacunas no generan cantidades suficientes de IgA. Tras la infección por el virus de la gripe, los linfocitos B IgA+ se diferencian mayoritariamente en células plasmáticas de vida larga en lugar de convertirse en linfocitos B de memoria. El proyecto ORIgAMI, financiado por el Consejo Europeo de Investigación, tiene por objeto estudiar cómo el receptor de linfocitos B IgA modula los linfocitos B de los centros germinales a través de programas transcripcionales y epigenéticos específicos. Los resultados de este estudio podrían favorecer la extracción de antígenos, el reclutamiento de linfocitos T y la señalización de linfocitos B. El equipo del proyecto empleará el virus de la gripe H1N1 como modelo, ratones transgénicos, secuenciación de ARN de célula única, ATAC, y espectrometría de masas. Comprender el papel de los linfocitos B IgA+ durante las infecciones víricas respiratorias podría contribuir al desarrollo de nuevas estrategias de vacunación.

Objetivo

Several times in human history, we faced sudden outbreaks of respiratory viruses that rapidly spread over the world before we could design broadly protective vaccines. Such was the case of the H1N1 influenza virus that killed 50 million people during the 1918 Spanish flu and SARS-CoV-2 that led to at least 5 million deaths during the current COVID-19 pandemics. Influenza and SARS-CoV-2 elicit robust humoral immune responses, including production of virus-specific antibodies of the IgM, IgG, and IgA types. In particular, IgA plays a crucial role in protecting lung mucosal surfaces by neutralizing respiratory viruses and impeding their attachment to epithelial cells. Despite its protective role, current vaccines against influenza and SARS-CoV-2 fail to produce significant levels of IgA in the respiratory tract. Then, a deeper understanding of the biology of IgA+ cells during respiratory infection is of utmost interest. ORIgAMI is based on recent unexpected findings from my team showing that germinal center B cells expressing IgA are mostly recruited towards the long-lived plasma cell compartment rather than to the memory B cell one upon influenza infection. In this frame, we will determine if the IgA BCR biases cell fate by:
1-Imprinting germinal center B cells with specific transcriptional/epigenetic programs.
2-Favoring antigen extraction and recruitment of T cell help within germinal centers.
3-Enhancing downstream B cell signalling pathways.
To to this end, we will use influenza H1N1 virus as respiratory infection model combined with a series of complementary innovative tools and methodologies: de novo-generated transgenic mice, single-cell RNA/ATAC-seq, 3D imaging, DNA-based force sensors, phospho- and imaging- flow cytometry, and mass-spectrometry. A deep understanding of the biology of IgA+ B cells during respiratory viral infection is of fundamental interest and may provide clues towards the design of future vaccination approaches against air-borne pathogens.