Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia

ABSTRACT

Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development. However, the role of pep27 gene, belonging to the vancomycin-resistance locus (vncRS operon), in virulence, is largely unknown. This study demonstrates that transferrin in the host serum reduces the survival of the host during S. pneumoniae infections in mice. The exposure of the pneumococcal D39 strain to lactoferrin induced the vncRS operon, lysis, and subsequent in vivo cytokine production, resulting in lung inflammation. However, these responses were significantly attenuated in pneumococci harboring a mutation in pep27. Mechanistically, the VncS ligand, identified as lactoferrin, induced the vncRS operon and increased the in vivo mortality rates. Thus, serum-induced activation of vncRS plays an essential role in inducing pneumonia.

KEYWORDS:

• Streptococcus pneumoniae
• VncRS
• Pep27
• lactoferrin
• pneumococcal pneumonia

Acknowledgments

This work was supported by the National Research Foundation (NRF-2015R1 A2 A1 A10052511) to DKR. The funding body played no role in designing the study, data collection and analysis, decision to publish, or manuscript preparation.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

The authors declare that all the relevant data pertaining to the experiments described herein are presented within the article and the supplementary data files, and relevant data are available from the authors on request.

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Additional information

Funding

This work was supported by the National Research Foundation of Korea [2015R1 A2 A1 A10052511].