Probing and engineering the B cell response to the skin microbiota

Project Summary / Abstract
The development of vaccines is one of the greatest success stories of biomedical research. Vaccines exploit the
remarkable capability of the immune system to recognize pathogens, develop memory and upon re-exposure
quickly mount an immune response that culminates with elimination of the pathogen. Vaccines are typically
injected intramuscularly and provide long-term systemic immunity. However, they are less efficient at generating
immunity at the site of infection: mucosal surfaces. With poor mucosal immunity, vaccinated individuals can still
become infected and transmit disease, thereby reducing the herd immunity benefits of a vaccine program. The
microbial communities that inhabit our mucosal surfaces elicit precise immune responses upon colonization –
without inflammation, and across an intact tissue barrier. I propose to develop a novel and unconventional
mucosal vaccine strategy that leverages the extraordinary capability of the commensal microbiota to induce
precise and long-term immunity at mucosal surfaces. In addition to their efficacy, commensal vaccines promise
to be inexpensive and lend themselves to needle-free and cold-chain-free formulations that enable deployment
in low- and middle-income countries. Overall, this project will uncover the molecular mechanisms underpinning
the intimate relationship established between commensal microbes and their host over millions of years of
coevolution and harness this knowledge to develop new vaccine strategies against pathogens.
To achieve this goal, I will exploit commensal microbes that colonize the skin, where microbiome intervention is
much more accessible. To gain a broad understanding of the immune responses elicited by the microbiota in the
skin, I will study the B cell response to prevalent skin commensal microbes (Aim 1). I will profile the B cell
response to a newly identified B cell antigen derived from a ubiquitous skin commensal and generate a new
monoclonal mouse model to study the molecular interplay between the skin microbiota and B cells (Aim 2). I will
engineer skin commensal microbes to elicit potent B cell responses against pathogens (Aim 3). Overall, this
project will 1) uncover the B cell response to skin commensal microbes, 2) generate new technologies to probe
commensal-specific immunity at the skin barrier and 3) develop a new mucosal vaccination strategy.
To achieve my long-term career goal of developing novel technologies to study commensal-immune interactions
and creating commensal-based therapies, I have assembled an outstanding group of mentors who complement
my training in mucosal immunology and biochemistry: Dr. Michael Fischbach (primary mentor, microbiology and
bacterial genetics), Dr. Yasmine Belkaid (co-mentor, skin immunology and bacterial models of infection), Dr.
Gabriel Victora (advisor/collaborator, B cell biology and viral models of infection) and Dr. Christopher Barnes
(advisor/collaborator, vaccinology). The training I will receive during the K99/R00 award will accelerate my
transition into an independent position and allow me to establish a cutting-edge research group of my own.

Grant Number: 5K99AI180358-02
NIH Institute/Center: NIH
Principal Investigator: Djenet Bousbaine