课题基金 / 基金详情

Investigating the development and clonal dynamics of broadly neutralizing B cells against influenza viruses

Investigating the development and clonal dynamics of broadly neutralizing B cells against influenza viruses
研究针对流感病毒的广泛中和 B 细胞的发育和克隆动态
批准号:
10660297
负责人:
Jenna Guthmiller
金额:
$24.9万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-08-08 至 2023-07-31

项目摘要

项目成果

Jenna Guthmiller的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT Broadly neutralizing antibodies against the influenza virus surface glycoprotein hemagglutinin (HA) can provide protection from nearly all influenza viruses. However, broadly neutralizing antibodies are rarely induced by vaccination and instead, most antibodies target variable epitopes of the influenza virus HA head domain that only provide narrow protection against a few influenza virus strains. The fundamental mechanisms dictating B cell immunodominance, which B cell specificities are recalled upon virus exposure, remain largely unknown. We identified that first exposure to a novel influenza virus robustly induced antibodies against four broadly neutralizing epitopes of HA. However, repeated exposure to the same virus preferentially drove the recruitment of antibodies targeting variable epitopes of the HA head. Notably, my studies identified that antibodies targeting broadly neutralizing epitopes are enriched for polyreactivity, the ability of a single antibody to bind to multiple molecularly distinct antigens, including foreign and self-antigens. Furthermore, polyreactive naïve B cells targeting broadly neutralizing epitopes are preferentially selected into the memory B cell pool to provide defense against novel pandemic-threat influenza viruses. Based on my preliminary data, I hypothesize that HA epitope specificity influences B cell development, differentiation, and inter-clonal competition, which leads to differences in B cell immunodominance. B cell immunodominance may be dictated by three independent processes: 1) B cells targeting broadly neutralizing epitopes may undergo clonal deletion or become anergic as a result of being polyreactive (Aim 1), 2) B cells targeting broadly neutralizing epitopes differentiate into short-lived B cell subsets as opposed to long-lived B cell subsets (Aim 2), and 3) B cells targeting variable epitopes outcompete B cells targeting broadly neutralizing epitopes (Aim 3). To test these aims, I will use CRISPR/Cas9 to generate B cell receptor knock-in mice expressing the germline version of human monoclonal antibodies targeting four broadly neutralizing epitopes of HA and two variable epitopes of HA. To test Aim 1, I will evaluate B cell development and B cell signaling potential of each B cell receptor knock-in line by generating mixed bone marrow chimeras. In Aim 2, I will determine if epitope specificity shapes B cell differentiation potential by immunizing mice that receive a B cell adoptive transfer from each B cell receptor knock-in line and tracking B cell differentiation and affinity maturation. In Aim 3, I will determine whether B cells targeting a variable epitope outcompete B cells targeting a broadly neutralizing epitope within the germinal center by tracking germinal center responses in HA- immunized mice that have received adoptively transferred B cells targeting each epitope. Knowledge gained from this research will provide critical insight into how broadly neutralizing B cells can be induced, which will aid in the development of a universal influenza virus vaccine that can provide broad protection against all influenza viruses. The additional training afforded by this mentored award will enable me to expand my scientific and professional skillsets, leading to my research independence and successful transition into a faculty position.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Shifting immunodominance of humoral immunity against influenza viruses
  • 批准号:
    10720359
  • 项目类别:
  • 资助金额:
    $44.99万
  • 财政年份:
    2023
  • 负责人:
    Jenna Guthmiller
  • 依托单位:
Investigating the development and clonal dynamics of broadly neutralizing B cells against influenza viruses
  • 批准号:
    10191161
  • 项目类别:
  • 资助金额:
    $10.35万
  • 财政年份:
    2021
  • 负责人:
    Jenna Guthmiller
  • 依托单位:
海外基金