Adenosine 2B Receptor Signaling Impairs Vaccine-Mediated Protection Against Pneumococcal Infection in Young Hosts by Blunting Neutrophil Killing of Antibody-Opsonized Bacteria.

Neutrophils 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 that control the neutrophil responses in vaccinated hosts are not fully understood. The extracellular adenosine pathway is a known regulator of neutrophils in naïve hosts. The aim of this study was to test the role of this pathway in the function of neutrophils and their protection against infection upon vaccination as a function of the host's age. To 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 that were specific to the different adenosine receptors prior to pulmonary challenge with pneumococci and assessed the bacterial burden and clinical score post-infection. We found that signaling via the adenosine 2B (A2BR) receptor but not the A2A or A1 receptors diminished the intracellular pneumococcal killing following antibody-mediated uptake in young hosts. In vivo, the agonism of the A2BR receptor significantly worsened the pneumococcal infection outcomes in young, vaccinated mice. In contrast, A2BR signaling had no effect on the intracellular bacterial killing by neutrophils from aged mice. Further, in vivo A2BR inhibition had no effect on the pneumococcal disease progression in aged, vaccinated mice. A2BR signaling reduced pneumococcal vaccine-mediated protection by impairing the antimicrobial activity of neutrophils against antibody-opsonized bacteria in young hosts. However, inhibiting this pathway was not sufficient to boost responses in aged hosts.