Age-associated changes in B cell and antibody effector responses to Streptococcus pneumoniae

Wake Forest University Health Sciences, Winston-Salem NC

Investigators

Abstract

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.