Biology subjects

Huckaby, A. B.

Publications and source records attributed to Huckaby, A. B..

3 recordsLinked to original sources

bioRxiv2023

Addition of adjuvant to DTaP modulates vaccine-induced immunological responses but is insufficient to improve protection in CD-1 mice

3.1Pertussis is a vaccine-preventable respiratory disease caused by the Gram-negative bacterium Bordetella pertussis. While vaccination rates remain high in developed countries, incidence of pertussis has increased following the transition from wP vaccines to aP vaccines. The reemergence of pertussis is attributed, in part, to waning immunity induced by aP vaccination. Therefore, the objective of this work was to determine if addition of adjuvant to DTaP can modulate the immune response and improve protection compared to DTaP alone. In this study we immunized outbred, female CD-1 mice with 1/320th the human dose of vehicle control, DTaP, and DTaP supplemented with adjuvant. Markers of early vaccine-induced memory were measured using a chemokine assay or by flow cytometry. Protection was assessed by measuring serological responses and quantifying bacterial burden in the respiratory tract at day 3 post-challenge. From this work we identified a partially protective aP vaccine dose to use for vaccination and challenge studies. We observed that MPLA and SWE promote robust anti-B. pertussis antibody responses and stimulate significant increases in early markers of vaccine-induced memory such as CXCL13, FDCs, and TFH cells. Quil-A induced Th1 responses compared to DTaP alone, but none of the adjuvants improved protection against challenge with B. pertussis. Overall, the data suggests that addition of adjuvant modulates the protective immune responses induced by aPs. Further studies are needed to evaluate the B cell compartment and longevity of protection.

immunology↗

bioRxiv2021

Long-term analysis of pertussis vaccine immunity uncovers a memory B cell response to whole cell pertussis immunization that is absent from acellular immunized mice

Over two decades ago acellular pertussis vaccines (aP) replaced whole cell pertussis vaccines (wP) in several countries. Since then, a resurgence in pertussis has been observed, which is hypothesized to be linked to waning immunity. To better understand why waning immunity occurs, we developed a long-term outbred CD1 mouse model to conduct the longest murine pertussis vaccine studies to date, spanning out to 532 days post primary immunization. Vaccine-induced memory results from follicular responses and germinal center formation; therefore, cell populations and cytokines involved with memory were measured alongside protection from challenge. Both aP and wP immunization elicit protection from intranasal challenge and generation of pertussis specific antibody responses in mice. Responses to wP vaccination were characterized by a significant increase in T follicular helper cells in the draining lymph nodes and CXCL13 levels in sera compared to aP mice. In addition, a population of B. pertussis+ memory B cells was found to be unique to wP vaccinated mice. This population peaked post-boost, and was measurable out to day 365 post-vaccination. Anti-B. pertussis and anti-pertussis toxoid antibody secreting cells increased one day after boost and remained high at day 532. The data suggest that follicular responses, and in particular CXCL13 levels in sera, should be monitored in pre-clinical and clinical studies for the development of the next-generation pertussis vaccines.

immunology↗

bioRxiv2019

Elevated levels of interleukin-27 in early life compromise protective immunity during neonatal sepsis

Neonates are at increased risk for bacterial sepsis as a result of immature immunity. We established that the immune suppressive cytokine interleukin (IL)-27 is elevated in early life. In the present work, we hypothesized that increased levels of IL-27 may predispose the neonatal population to more severe infection during sepsis. In a neonatal sepsis model, systemic IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1 and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in WSX-1-/- mice that lack a functional IL-27 receptor. Infected WSX-1-/- pups exhibited improved weight gain and reduced morbidity. IL-27 signaling in WT mice promoted increased bacterial burdens and systemic inflammation compared to WSX-1-/- neonates. This was consistent with more efficient bacterial killing by Ly6B.2+ myeloid cells and macrophages from WSX-1-deficient compared to wild-type neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early life IL-27 on the host response in neonates while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 promotes inflammation during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.\n\nIMPORTANCEA number of differences in the neonatal immune response compared with adults have been well described. However, a mechanistic understanding of what needs to be overcome in the neonate to generate a more protective immune response during acute bacterial infection has been limited. The work described here helps fill the gap of what is necessary to overcome in order to achieve improved host response to infection. To further the novelty, IL-27 has not previously been attributed to dysfunction or deficiency in neonatal immunity. Our results enhance the understanding of IL-27 biology in the neonatal population while providing evidence that elevated IL-27 levels limit a protective immune response and are detrimental during neonatal sepsis. Strategies aimed at targeting circulating IL-27 concentrations early in life have the potential to improve control of bacterial infection in neonates.

immunology↗