<i>Streptococcus suis</i> synthesizes deoxyadenosine and adenosine by 5’-nucleotidase to dampen host immune responses

<i>Streptococcus suis</i> is a major porcine bacterial pathogen and emerging zoonotic agent. <i>S. suis</i> 5ʹ-nucleotidase is able to convert adenosine monophosphate to adenosine, resulting in inhibiting neutrophil functions <i>in vitro</i> and it is an important virulence factor. Here, we show that <i>S. suis</i> 5ʹ-nucleotidase not only enables producing 2ʹ-deoxyadenosine from 2ʹ-deoxyadenosine monophosphate by the enzymatic assay and reversed-phase high performance liquid chromatography (RP-HPLC) analysis <i>in vitro</i>, but also synthesizes both 2ʹ-deoxyadenosine and adenosine in mouse blood <i>in vivo</i> by RP-HPLC and liquid chromatography with tandem mass spectrometry analyses. Cellular cytotoxicity assay and Western blot analysis indicated that the production of 2ʹ-deoxyadenosine by 5ʹ-nucleotidase triggered the death of mouse macrophages RAW 264.7 in a caspase-3-dependent way. The <i>in vivo</i> infection experiment showed that 2ʹ-deoxyadenosine synthesized by 5ʹ-nucleotidase caused monocytopenia in mouse blood. The <i>in vivo</i> transcriptome analysis in mouse blood showed the inhibitory effect of 5ʹ-nucleotidase on neutrophil functions and immune responses probably mediated through the generation of adenosine. Taken together, these findings indicate that <i>S. suis</i> synthesizes 2ʹ-deoxyadenosine and adenosine by 5ʹ-nucleotidase to dampen host immune responses, which represents a new mechanism of <i>S. suis</i> pathogenesis.