Biology subjects

Betadpur, A.

Publications and source records attributed to Betadpur, A..

3 recordsLinked to original sources

bioRxiv2025

Neutrophils induce effective antibody responses to the pneumococcal conjugate vaccine by inhibiting regulatory T cells

Neutrophils are required for production of protective antibodies in response to the pneumococcal conjugate vaccine (PCV), however, the mechanisms behind that are not known. Here, in exploring mechanisms, we found that depletion of neutrophils at the time of vaccination in female mice led to increased regulatory T cells (Tregs) in the spleen that was accompanied by a dysregulated cytokine environment. Following vaccination, neutrophils homed into secondary lymphoid organs where they increased expression of T cell engaging/inhibiting markers. Depletion of Tregs in neutrophil deficient mice restored antibody function against pneumococcal infection. Importantly, PCV vaccination of human female participants altered neutrophil phenotype and in vitro coculture of donor neutrophils with PBMCs at one week following vaccination resulted in lower percentage and proliferation of FOXP3+ T cells, showing the clinical relevance of this phenotype. This work reveals a new mechanism by which neutrophils ensure protective antibody responses to vaccination by suppressing Tregs.

immunology↗

bioRxiv2025

Host aging induces a senescent-like phenotype in neutrophils and altered transcriptional responses to Streptococcus pneumoniae

Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with S. pneumoniae. We observed significant transcriptomic differences across host age. Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Analysis of potential transcription factors controlling these changes indicated differential regulation by E2f2 in aged mice, which was linked to lower PMN differentiation resulting in more immature PMNs in the lungs of aged mice compared to young controls. Conversely, PMNs in aged mice displayed a higher senescence-associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow-up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL-10, TNF, and ROS, had lower incidence of apoptosis, and had a higher proportion of cells positive for senescence-associated {beta}-galactosidase, features of a senescent-like phenotype. In conclusion, host aging is associated with altered PMN phenotypes, including a shift toward senescent-like energy-deficient cells, which may contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.

immunology↗

bioRxiv2024

Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine

Vaccine-mediated protection and susceptibility to Streptococcus pneumoniae (pneumococcus) infections are influenced by biological sex. The incidence of invasive pneumococcal disease remains higher in males compared to females even after the introduction of the pneumococcal conjugate vaccine (PCV). However, sex-based differences in the immune response to this conjugate vaccine remain unexplored. To investigate those differences, we vaccinated adult male and female mice with PCV and assessed cellular and humoral immune responses. Compared to females, male mice displayed lower levels of T follicular helper cells, germinal center B cells and plasmablasts, which are all required for antibody production following vaccination. This was linked to lower IgG and IgM levels against pneumococci and lower isotype switching to IgG3 in vaccinated males. Additionally, sera of vaccinated male mice had lower efficacy in several anti-pneumococcal functions including neutralization of bacterial binding to pulmonary epithelial cells as well as direct cytotoxicity against S. pneumoniae. Importantly, while the vaccine was highly protective in females, vaccinated males succumbed to infection more readily and were more susceptible to both lung-localized infection and systemic spread following S. pneumoniae challenge. These findings identify sex-based differences in immune responses to PCV that can inform future vaccine strategies.

immunology↗