Adenosine 2B receptor signaling impairs vaccine-mediated protection against pneumococcal infection in young hosts by blunting neutrophil killing of antibody opsonized bacteria

Abstract

Background/ObjectiveNeutrophils are essential for vaccine-mediated protection against pneumococcal infection and impairment in their antibacterial function contributes to reduced vaccine efficacy during aging. However, the signaling pathways controlling neutrophil responses in vaccinated hosts are not fully understood. The extracellular adenosine pathway is a known regulator of neutrophils in naive hosts. The aim of this study was to test the role of this pathway in neutrophil function and protection against infection upon vaccination across host age. MethodsTo test the role of adenosine in the antimicrobial activity of neutrophils against antibody-opsonized pneumococci, we used bone marrow derived neutrophils isolated from wild type or specific adenosine receptors knock-out mice. To measure the effect of adenosine receptor signaling in vivo, we treated vaccinated mice with agonists or antagonists specific to the different adenosine receptors prior to pulmonary challenge with pneumococci and assessed bacterial burden and clinical score post infection. ResultsWe found that signaling via the adenosine 2B (A2BR) but not A2A or A1 receptor diminished intracellular pneumococcal killing following antibody-mediated uptake in young hosts. In vivo, agonism of A2BR significantly worsened pneumococcal infection outcome in young, vaccinated mice. In contrast, A2BR signaling had no effect on intracellular bacterial killing by neutrophils from aged mice. Further, in vivo A2BR inhibition had no effect on pneumococcal disease progression in aged, vaccinated mice. ConclusionsA2BR signaling reduced pneumococcal vaccine-mediated protection by impairing neutrophil antimicrobial activity against antibody-opsonized bacteria in young hosts. However, inhibiting this pathway was not sufficient to boost responses in aged hosts.