Open AccessA type VII secretion system of Streptococcus gallolyticus subsp. gallolyticus contributes to gut colonization and the development of colon tumors
Author(s) -
John Taylor,
Xinsheng Gao,
Juan Xu,
Michael Holder,
Joseph F. Petrosino,
Ritesh Kumar,
Wen Liu,
Magnus Höök,
Cameron A. MacKenzie,
Andrew Hillhouse,
Wesley Brashear,
Maria Patricia Nunez,
Yi Xu
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009182
Subject(s) - biology , secretion , microbiology and biotechnology , virulence , pathogenicity island , gene , genetics , biochemistry
Streptococcus gallolyticus subspecies gallolyticus ( Sgg ) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. However, the molecular determinants involved in Sgg pathogenicity in the gut are unknown. Bacterial type VII secretion systems (T7SS) mediate pathogen interactions with their host and are important for virulence in pathogenic mycobacteria and Staphylococcus aureus . Through genome analysis, we identified a locus in Sgg strain TX20005 that encodes a putative type VII secretion system (designated as Sgg T7SS T05 ). We showed that core genes within the Sgg T7SS T05 locus are expressed in vitro and in the colon of mice. Western blot analysis showed that Sgg EsxA, a protein predicted to be a T7SS secretion substrate, is detected in the bacterial culture supernatant, indicating that this Sgg T7SS T05 is functional. Deletion of Sgg T7SS T05 (TX20005Δ esx ) resulted in impaired bacterial adherence to HT29 cells and abolished the ability of Sgg to stimulate HT29 cell proliferation. Analysis of bacterial culture supernatants suggest that Sgg T7SS T05 -secreted factors are responsible for the pro-proliferative activity of Sgg , whereas Sgg adherence to host cells requires both Sgg T7SS T05 -secreted and bacterial surface-associated factors. In a murine gut colonization model, TX20005Δ esx showed significantly reduced colonization compared to the parent strain. Furthermore, in a mouse model of CRC, mice exposed to TX20005 had a significantly higher tumor burden compared to saline-treated mice, whereas those exposed to TX20005Δ esx did not. Examination of the Sgg load in the colon in the CRC model suggests that Sgg T7SS T05 -mediated activities are directly involved in the promotion of colon tumors. Taken together, these results reveal Sgg T7SS T05 as a previously unrecognized pathogenicity determinant for Sgg colonization of the colon and promotion of colon tumors.