A temperate Siphoviridae bacteriophage isolate from Siberian tiger enhances the virulence of methicillin-resistant Staphylococcus aureus through distinct mechanisms

ABSTRACT

The emergence and worldwide spread of Methicillin-resistant Staphylococcus aureus (MRSA) pose a threat to human health. While bacteriophages are recognized as an effective alternative to treat infections caused by drug resistant pathogens, some bacteriophages in particular the temperate bacteriophage may also influence the virulence of the host bacteria in distinct ways. In this study, we isolated a bacteriophage vB_Saus_PHB21 from an epidermal sample of Siberian tiger (Panthera tigris altaica) using an MRSA strain SA14 as the indicator. Our following laboratory tests and whole genome sequencing analyses revealed that vB_Saus_PHB21 was a temperate bacteriophage belonging to the Siphoviridae family, and this bacteriophage did not contain any virulence genes. However, the integration of PHB21 genome into the host MRSA increased the bacterial capacities of cell adhesion, anti-phagocytosis, and biofilm formation. Challenge of the lysogenic strain (SA14⁺) caused severe mortalities in both Galleria mellonella and mouse models. Mice challenged with SA14⁺ showed more serious organ lesions and produced higher inflammatory cytokines (IL-8, IFN-γ and TNF-α) compared to those challenged with SA14. In mechanism, we found the integration of PHB21 genome caused the upregulated expression of many genes encoding products involved in bacterial biofilm formation, adherence to host cells, anti-phagocytosis, and virulence. This study may provide novel knowledge of “bacteria-phage-interactions” in MRSA.

KEYWORDS:

• Bacteriophage
• methicillin-resistant Staphylococcus aureus
• biofilm formation
• virulence
• lysogens

Acknowledgments

We thank staffs at Qingdao Zoo, China, for sample collection. Zhong Peng acknowledges the financial support from China Postdoctoral Science Foundation (grant numbers: 2020T130232 and 2018M640719).

Data availability

All sequence data generated in this study are deposited into NCBI database under the Bioproject (accession number: PRJNA720778). GenBank accession numbers for the complete genome sequences of Staphylococcus aureus bacteriophage phage vB_Saus_PHB21 and Staphylococcus aureus lysogenic strain SA14⁺ are MW924497 and CP073012, respectively. Sequence Read Archive (SRA) accession number for the transcriptome sequence is SRR14193019.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported in part by the National Key R & D Program of China (grant number: 2017YFC1600100), the Hubei Provincial Key R & D program (grant number: 2021BBA085), and the Walmart Foundation (Project no. 61626817).