Streptococcus suis synthesizes deoxyadenosine and adenosine by 5'-nucleotidase to dampen host immune responses

Virulence. 2018;9(1):1509-1520. doi: 10.1080/21505594.2018.1520544.

Abstract

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

Keywords: 2ʹ-deoxyadenosine; 5ʹ-nucleotidase; Streptococcus suis; adenosine; immune response; monocytopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / metabolism*
  • Adenosine / biosynthesis*
  • Animals
  • Bacterial Proteins / metabolism
  • Deoxyadenosines / biosynthesis*
  • Female
  • Gene Expression Profiling
  • Host-Pathogen Interactions / immunology*
  • Macrophages / microbiology
  • Macrophages / pathology
  • Mice
  • Neutrophils / microbiology
  • RAW 264.7 Cells
  • Streptococcal Infections / immunology*
  • Streptococcus suis / enzymology*
  • Streptococcus suis / pathogenicity*
  • Virulence Factors

Substances

  • Bacterial Proteins
  • Deoxyadenosines
  • Virulence Factors
  • 5'-Nucleotidase
  • Adenosine
  • 2'-deoxyadenosine

Grants and funding

This work was supported by grants from the National Key Research and Development Program of China [2017YFD0500102]; the Fundamental Research Funds for the Central Universities [KYZ201847]; the National Natural Science Foundation of China [31572544 and 31872469]; the State Key Laboratory of Veterinary Etiological Biology [SKLVEB2016KFKT005]; the Shanghai Agriculture Applied Technology Development Program, China [G2016060201]; the Priority Academic Program Development of Jiangsu Higher Education Institutions [PAPD].