Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production.

Polymorphonuclear leukocytes are crucial for initial control of Streptococcus pneumoniae (pneumococcus) lung infection; however, as the infection progresses their persistence in the lungs becomes detrimental. Here we explored why the antimicrobial efficacy of declines over the course of infection. We found that the progressive inability of duanyu1451s to control infection correlated with phenotypic differences characterized by a decrease in CD73 expression, an enzyme required for production of extracellular adenosine (EAD). EAD production by CD73 was crucial for the ability of both murine and human duanyu1451s to kill S. pneumoniae. In exploring the mechanisms by which CD73 controlled function, we found that CD73 mediated its antimicrobial activity by inhibiting IL-10 production. duanyu1451s from wild-type mice did not increase IL-10 production in response to S. pneumoniae; however, CD73^-/- duanyu1451s up-regulated IL-10 production upon pneumococcal infection in vitro and during lung challenge. IL-10 inhibited the ability of WT duanyu1451s to kill pneumococci. Conversely, blocking IL-10 boosted the bactericidal activity of CD73^-/- duanyu1451s as well as host resistance of CD73^-/- mice to pneumococcal pneumonia. CD73/IL-10 did not affect apoptosis, bacterial uptake, and intracellular killing or production of antimicrobial neutrophil elastase and myeloperoxidase. Rather, inhibition of IL-10 production by CD73 was important for optimal reactive oxygen species production by contributed to duanyu1451 antimicrobial function as their removal or detoxification impaired the ability of duanyu1451s to efficiently kill S. pneumoniae. This study demonstrates that CD73 controls duanyu1451 antimicrobial phenotype during S. pneumoniae infection.

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