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Principal Investigator: Sarah E Webster
Organization: WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $74,084
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Lower respiratory tract infections such as pneumonia claims the lives of approximately 4 million people worldwide
each year, making these infections fourth on the list of global causes of death. Streptococcus pneumoniae is the
most common cause of pneumonia leading to death in individuals over the age of 65 eight times more frequently
than those aged 5-49, despite the long-standing availability of a vaccine for this age group (approved in 1983).
In both murine and human systems, there is a greater incidence of, and susceptibility to, pneumococcal infection
in males; nevertheless, the factors contributing to this difference between males and females are unknown.
Therefore, the long-term goal of this study is to gain a greater understanding of the immune system in the context
of sex. Specifically, the goal of this proposal is to determine whether sex and/or anatomical location influences
a specific subset of B cells, B1 cells, which provide essential protection and therefore survival from S.
pneumoniae infection through production of natural antibodies.
Antibodies provide defense against infection by binding the pathogen and preventing infection of host cells.
Natural antibodies are present in the absence of infection or intentional immunization. B1 cells’ unique ability to
provide protection against S. pneumoniae is attributed to their production of natural antibodies, which have
unique structural characteristics resulting from their fetal development. Fetal derived B1 cells maintain their
population through a self-renewal process, which is unlike the B cell subset, B2 cells, generated from
hematopoietic stem cells. Therefore, self-renewal is essential for the maintenance of natural antibodies
protective against infection, though little is known about how sex influences self-renewal of B1 cells into old age.
We have demonstrated natural antibody from aged male mice does not provide protection against S.
pneumoniae infection whereas, natural antibody from aged females maintains its protective capacity.
We hypothesize that maintenance of B1 cells through self-renewal is influenced by sex during aging. We
postulate that female B1 cells maintain more productive B1 self-renewal allowing for the differences seen in
susceptibility to infection with sex and age. To test this hypothesis, we will perform the following aims: 1) elucidate
the sex-specific developmental differences regulating B1 cells by examining cell cycle maintenance through a
unique transgenic reporter line combined with examination of self-renewal to determine the functional
consequence of sex, age, and cell cycle activity on the production of protective antibody and 2) determine how
maintenance of self-renewal in humans may mirror the murine system and influence production of natural
antibody. This project will determine how sex influences the maintenance of B1 cell self-renewal and the
subsequent impact on the production of natural antibodies during aging. This further understanding of the
immune system in context to sex will likely suggest new prevention and/or treatment strategies of S. pneumoniae
infection in both male and female aging populations.
Terms: <19S Gamma Globulin><21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><Ab response><Adult><Adult Human><Age><Aged 65 and Over><Aging><Anatomic Sites><Anatomic structures><Anatomy><Antibodies><Antibody Formation><Antibody Production><Apoptotic><Autoimmune Diseases><Autoregulation><B blood cells><B cell><B cells><B-Cell Development><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><Bacteria><Binding><Blood Precursor Cell><Blood Serum><Blood Vessels><Bone Marrow><Bone Marrow Reticuloendothelial System><CD25><CD86><CD86 gene><Cause of Death><Cell Aging><Cell Body><Cell Cycle><Cell Division Cycle><Cell Growth and Maintenance><Cell Maintenance><Cell Senescence><Cells><Cellular Aging><Cellular Senescence><Cessation of life><Characteristics><D pneumoniae><D. pneumoniae><DNA Nucleotidylexotransferase><Data><Death><Deoxynucleotidyl Transferase><Deoxynucleotidyltransferase><Desoxynucleotidyl Transferase><Desoxynucleotidyltransferase><Developing fetus><Development><Differences between sexes><Differs between sexes><Diplococcus pneumoniae><Disease><Disorder><Encapsulated><Enzyme Gene><Enzymes><Female><Fetal Development><Frequencies><Generations><Genes><Germ Lines><Goals><Greater sac of peritoneum><Hematopoietic Progenitor Cells><Hematopoietic stem cells><History><Homeostasis><Human><IL2R><IL2RA><IL2RA gene><Ig Genes><IgA><IgM><Immune><Immune response><Immune system><Immunes><Immunization><Immunoglobulin A><Immunoglobulin Genes><Immunoglobulin M><Immunological response><Incidence><Individual><Infection><Infection prevention><Innate Immunity><Life><Location><Lower Respiratory Tract Infection><Lower respiratory infection><Lymphatic cell><Lymphocyte><Lymphocytic><Maintenance><Mediating><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Native Immunity><Natural Immunity><Neonatal><Non-Specific Immunity><Nonspecific Immunity><Peritoneal Cavity><Persons><Phenotype><Physiological Homeostasis><Play><Pneumococcal Infections><Pneumococcus><Pneumonia><Population><Predisposition><Prevent infection><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Productivity><Recording of previous events><Regulation><Replicative Senescence><Reporter Genes><Role><S pneumoniae><S. pneumoniae><Serum><Sex Differences><Sexual differences><Source><Spleen><Spleen Reticuloendothelial System><Streptococcus pneumoniae><Streptococcus pneumoniae Infections><Structure><Susceptibility><System><TCGFR><Terminal Addition Enzyme><Terminal Deoxynucleotidyl Transferase><Terminal Deoxynucleotidyltransferase><Terminal Deoxyribonucleotidyl Transferase><Terminal Deoxyribonucleotidyltransferase><Testing><Time><Transgenic Organisms><Vaccines><Vulnerable Populations><Work><above age 65><adulthood><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated alterations><age associated changes><age associated effects><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age effect><age group><age of 65 years onward><age related alterations><age related changes><age related effects><age specific alterations><age specific changes><aged><aged 65 and greater><aged 65+><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aged ≥65><ages><aging effect><aging population><alterations with age><antibody biosynthesis><autoimmune condition><autoimmune disorder><autoimmunity disease><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><changes with age><developmental><expression cloning><fetal><fighting><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><histories><host response><human old age (65+)><immune system response><immunoglobulin biosynthesis><immunoresponse><impact of age><influence of age><lymph cell><male><microbial><natural antibodies><old age><over 65 years><pathogen><pneumococcal disease><pneumococcus infection><population aging><progenitor cell function><progenitor cell niche><progenitor function><progenitor niche><response><self-renew><self-renewal><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social role><stem><stem and progenitor cell function><stem and progenitor cell niche><stem and progenitor function><stem cell function><stem cell niche><transgenic><treatment strategy><vascular><vulnerable group><vulnerable individual><vulnerable people><≥65 years>