[F31] Age-associated changes in B cell and antibody effector responses to Streptococcus pneumoniae
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-06-30
Importo max: 50.114 EUR
Paese: US
Descrizione
ABSTRACT
Streptococcus pneumoniae is an opportunistic human pathogen that causes pneumococcal pneumonia, an
infection of the lower respiratory tract, as well as life-threatening bloodstream infections and meningitis. Despite
the availability and widespread administration of pneumococcal vaccines, these infections continue to
disproportionately affect people over the age of 65. Due to the diversity in pneumococcal exposures over the
lifespan, vaccine responses, and comorbidities observed in elderly patient cohorts, it is difficult to assess the
extent to which vaccine responsiveness versus aging-associated changes in the lung contribute to failures in
vaccine-elicited protection. This project proposes the use of an aged mouse model to circumvent these
confounding factors so that underlying mechanisms that affect vaccine-induced protection against pneumonia in
aged individuals can be determined. Our preliminary data show aged male mice mount significantly higher
antibody (Ab) responses to Pneumovax23, a non-adjuvanted vaccine consisting of 23 serotypes of
pneumococcal capsular polysaccharide (PPS), than younger mice. Consistent with this, aged male mice have
significantly increased expansion and activation of PPS-specific innate-like B cells after immunization. Even
though these aged male mice make 5 to 10-fold greater antibody responses than their younger counterparts and
are highly protected against bacteremia, they have significantly increased lung bacterial burden and lower
survival than younger mice in response to respiratory pneumococcal challenge. Therefore, the central hypothesis
of this proposal is that increased PPS-specific Ab responses in aged male mice are due to intrinsic differences
that occur in B cell populations with aging. Nonetheless, we hypothesize these Abs have little effect on protection
against pneumonia due to failed complement-dependent Ab effector mechanisms in the aging lung. In Aim 1, I
will test the hypothesis that intrinsic differences in B cell subsets occur as a result of aging and contribute to
heightened T cell independent antibody responses. I will also determine the extent to which the aged male
environment contributes to increased antibody responses. In Aim 2, I will examine mechanisms contributing to
the susceptibility of Pneumovax23-immune aged male mice to pneumococcal lung infection. I will test the primary
hypothesis that aging compromises complement-dependent effector functions in the lung. I will examine whether
Fc-dependent effector functions are similarly impaired or if they can be leveraged to improve protection.
Collectively, this project will reveal basic mechanisms contributing to altered vaccine responses and susceptibility
to pneumococcal infections that occur with aging.
Istituzione: WAKE FOREST UNIVERSITY HEALTH SCIENCES
PI: Alexis Adams-Sims
Progetto: 5F31AI194729-02
Settori: National Institute of Allergy and Infectious Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.