Abstract
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 SggT7SST05). We showed that core genes within the SggT7SST05 locus are expressed in vitro and in the colon of mice. Western blot analysis showed that SggEsxA, a protein predicted to be a T7SS secretion substrate, is detected in the bacterial culture supernatant, indicating that this SggT7SST05 is functional. Deletion of SggT7SST05 (TX20005Δesx) 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 SggT7SST05-secreted factors are responsible for the pro-proliferative activity of Sgg, whereas Sgg adherence to host cells requires both SggT7SST05-secreted and bacterial surface-associated factors. In a murine gut colonization model, TX20005Δesx 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 TX20005Δesx did not. Examination of the Sgg load in the colon in the CRC model suggests that SggT7SST05-mediated activities are directly involved in the promotion of colon tumors. Taken together, these results reveal SggT7SST05 as a previously unrecognized pathogenicity determinant for Sgg colonization of the colon and promotion of colon tumors.
Highlights
Colorectal cancer (CRC) is the third most common cancer among men and women, and a leading cause of cancer-related deaths worldwide [1]
We further demonstrate that SggT7SST05-mediated activities are important for Sgg to colonize the colon and to promote the development of colon tumors
These findings reveal SggT7SST05 as a novel pathogenicity determinant of Sgg and provide a critical breakthrough in our efforts to understand how Sgg influences the development of CRC
Summary
Colorectal cancer (CRC) is the third most common cancer among men and women, and a leading cause of cancer-related deaths worldwide [1]. Certain bacterial species are able to promote the development of colon tumors in pre-clinical models of CRC [2,3,5,6,12,13,14]. This has raised the possibility that by targeting specific CRC-promoting microbes, we can improve the way CRC is diagnosed, treated and managed. To achieve this goal, understanding the molecular mechanism underlying the cancer-promoting capability of specific microbes is critical
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