Project Summary
Bats host many viruses, seemingly without disease, that cause lethal infections in humans and other non-bat
species, including rabies, Marburg fever virus and SARS-related coronaviruses. A greater understanding of the
bat immune system – how it responds to viruses, how it differs from the human immune system – could lead to
improved approaches for treating or even avoiding infection in humans. The immune response consists of two
major branches: the nonspecific innate response and the pathogen-specific adaptive response. Although
numerous studies have investigated innate immunity in bats, very little is known about their adaptive immune
system. The long-term objective of the proposed research is to enhance understanding of adaptive immunity in
bats. A key feature of adaptive immunity is humoral immunity; this immune response is mediated by antibodies,
also known as immunoglobulins. The hyper-diverse immunoglobulin repertoire is generated through a
combination of gene recombination, DNA insertions and deletions, and somatic mutation of the antibody
sequence. While immunoglobulins have been detected in several serological studies of bats, the true extent of
the diversity of bat immunoglobulin repertoires, the degree to which bats rely on gene rearrangement vs. somatic
mutation to generate these repertoires, how mutation of the immunoglobulins correlates with neutralization of
pathogens, or the B cell subsets that arise in response to infection remain unknown. The proposed study will
use rabies virus vaccination followed by rabies virus infection in Jamaican fruit bats to generate the most
comprehensive understanding of B cell-mediated adaptive immunity in bats to date. Jamaican fruit bats are
common across Central and South America, where rabies remains a serious threat, and are naturally infected
by rabies virus. This research will use long-read sequencing to characterize the germline genes that provide the
starting diversity for the immunoglobulin repertoire. Next generation genomic techniques will be used to track
the development of rearranged immunoglobulin repertoires, monitor expansion of specific B cell clones, and
quantify the degree of somatic mutation in antigen-exposed antibodies across vaccination and challenge with
rabies. Single-cell transcriptomics will be used to characterize the B cell subsets that arise in response to immune
challenges, and binding assays and rabies neutralization tests will facilitate an understanding of how antibody
maturation correlates with function. Comparison of the immune responses of bats to vaccination and infection
will be used to investigate immunity in controlled and natural contexts. This research will provide important
information on the adaptive immune system of bats that is currently lacking. These data will provide insight into
the differences in immune responses between bats and humans to a shared pathogen and can be used to
develop new rabies prevention or intervention approaches. The framework and immunological data generated
by this project will also allow for specific investigations of B-cell mediated immunity to any infection.