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

Abstract

Polymorphonuclear leukocytes (PMNs) 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 PMNs declines over the course of infection. We found that the progressive inability of PMNs 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 PMNs to kill S. pneumoniae. In exploring the mechanisms by which CD73 controlled PMN function, we found that CD73 mediated its antimicrobial activity by inhibiting IL‐10 production. PMNs from wild‐type mice did not increase IL‐10 production in response to S. pneumoniae; however, CD73−/− PMNs up‐regulated IL‐10 production upon pneumococcal infection in vitro and during lung challenge. IL‐10 inhibited the ability of WT PMNs to kill pneumococci. Conversely, blocking IL‐10 boosted the bactericidal activity of CD73−/− PMNs 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 (ROS) production by PMNs. ROS contributed to PMN antimicrobial function as their removal or detoxification impaired the ability of PMNs to efficiently kill S. pneumoniae. This study demonstrates that CD73 controls PMN antimicrobial phenotype during S. pneumoniae infection.

A Murine Model for Enhancement ofStreptococcus pneumoniaePathogenicity Upon Viral Infection and Advanced Age

“…We previously found that PMNs were key determinants of disease during primary pneumococcal pneumonia and are required to initially control bacterial numbers (20,79). In this study we found that aging was associated with earlier influx of PMNs into the lungs of co-infected mice.…”

“…that IL-10 impairs PMN anti-bacterial function by inhibiting ROS production in response to infection(79). Blocking this cytokine boosted PMN anti-bacterial function and importantly restored resistance of vulnerable hosts to primary pneumococcal pneumonia(79).In summary, here we modified existing murine models to establish an experimental system that reflects the transition of S. pneumoniae from asymptomatic colonizer to invasive pulmonary pathogen upon IAV co-infection. In this model, IAV triggers the transition of a pathobiont from a commensal to a pathogenic state through modification of bacterial behavior in the nasopharynx, enhancement of bacterial colonization in the lung, and compromise of PMN-mediated anti-bacterial immunity.…”

Extracellular adenosine signaling reverses the age‐driven decline in the ability of neutrophils to kill Streptococcus pneumoniae

“…Mice that lacked CD73 suffered dramatically higher pulmonary bacterial numbers, systemic spread of the infection, and increased lethality upon S. pneumoniae lung infection (Bou Ghanem, Clark, Roggensack, et al, 2015). Importantly, CD73 controlled PMN antimicrobial activity (Siwapornchai et al, 2020). CD73 expression and EAD production by PMNs was required for their ability to kill and clear S. pneumoniae (Siwapornchai et al, 2020).…”

“…Importantly, CD73 controlled PMN antimicrobial activity (Siwapornchai et al, 2020). CD73 expression and EAD production by PMNs was required for their ability to kill and clear S. pneumoniae (Siwapornchai et al, 2020).…”

Gehua Jiecheng Decoction Inhibits Diethylnitrosamine-Induced Hepatocellular Carcinoma in Mice by Improving Tumor Immunosuppression Microenvironment

“…IL-10 participates in the inflammatory response by inhibiting the bactericidal ability of polymorphonuclear leukocytes (PMN). If IL-10 is blocked, the ability to kill pathogenic microorganisms is enhanced (Siwapornchai et al, 2020). Furthermore, IL-10 is considered an immunosuppressive cytokine, which promotes tumor immune escape by reducing the anti-tumor immune responses in the tumor microenvironment.…”