# The B cell repertoire as a window into the nature and impact of the lung virome

> **NIH NIH R33** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $798,456

## Abstract

Project summary
Respiratory viruses have a major impact on human health. Pneumonia is the primary cause of hospitalizations
of the very young and a leading cause of death in older adults, and is most often caused by respiratory viruses.
There is considerable variation in the susceptibility of humans to severe infection caused by these commonly
encountered viruses, poorly understood at mechanistic levels. Further, the etiology of pneumonia remains
enigmatic, with many infections caused by unidentified microbes other than the current suspects. Repeated
exposures to respiratory viruses have a lasting impact on populations of memory lymphocytes that reside
within the lung, contributing to the control of this local dynamic virome. This includes memory B cells. The
shaping of B-cell memory through clonal selection and affinity maturation together leaves a signature of the
individual's natural history of virome interactions. This imprint can be detected by sequencing the
immunoglobulin variable-region gene (IgVRG) repertoire of lung B cells and analyzing their clonal structure
statistically. We propose that identifying viruses recognized by lung B cells with the greatest affinity maturation
will provide an unbiased window into the virome exerting immunological pressure on the lung. We will study
lung B cells using a suite of specialized approaches including IgVRG repertoire analyses, an innovative Nojima
culture system for growing B cell clones out of lung samples, and the newly developed multiplex VirScan
technology for detecting viral specificity, in order to identify the virome that has exerted the most severe,
recurrent, or chronic local immunological pressure on the human lung. These human lung virome analyses will
be complemented by studies of how lung B cells and respiratory viruses interact causally, to test whether there
are differences in memory B cells across compartments or conditions that determine the efficacy of local
immune control of viruses in the lung. In the R61 phase, we will 1) use a mouse model to test the hypothesis
that respiratory virome dynamics remodel lung B cells; 2) establish the Nojima B cell culture system for human
lung B cells; 3) determine if human lungs contain virome-reactive B cells that can be detected by VirScan
technology. If these proof-of-concept experiments are successful, then in the R33 phase we will test the
hypotheses: 4) that the population-dynamic system comprising the human lung virome and lung-resident B
cells is distinctive from other anatomical sites; 5) that there is heterogeneity within the human lung, such that
central, conducting airway-rich regions of the lung recognize different viral antigens than do those from more
peripheral regions of the same lung; 6) that long-term interactions between the human lung virome and
resident B cells contribute to pneumonia susceptibility; 7) that lung memory B cells have a unique and
specialized phenotype that provides rapid local antibody-mediated control of...

## Key facts

- **NIH application ID:** 9928493
- **Project number:** 5R33HL137081-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Rachel Fearns
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $798,456
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928493

## Citation

> US National Institutes of Health, RePORTER application 9928493, The B cell repertoire as a window into the nature and impact of the lung virome (5R33HL137081-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9928493. Licensed CC0.

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