AUTHOR=Krueger Annika , Zaugg Julian , Chisholm Sarah , Linedale Richard , Lachner Nancy , Teoh Siok Min , Tuong Zewen K. , Lukowski Samuel W. , Morrison Mark , Soyer H. Peter , Hugenholtz Philip , Hill Michelle M. , Frazer Ian H. 

TITLE=Secreted Toxins From Staphylococcus aureus Strains Isolated From Keratinocyte Skin Cancers Mediate Pro-tumorigenic Inflammatory Responses in the Skin

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.789042

DOI=10.3389/fmicb.2021.789042

ISSN=1664-302X

ABSTRACT=<p>Squamous cell carcinoma (SCC) is a common type of skin cancer that typically arises from premalignant precursor lesions named actinic keratoses (AK). Chronic inflammation is a well-known promoter of skin cancer progression. AK and SCC have been associated with an overabundance of the bacterium <italic>Staphylococcus aureus</italic> (<italic>S. aureus</italic>). Certain secreted products from <italic>S. aureus</italic> are known to promote cutaneous pro-inflammatory responses; however, not all <italic>S. aureus</italic> strains produce these. As inflammation plays a key role in SCC development, we investigated the pro-inflammatory potential and toxin secretion profiles of skin-cancer associated <italic>S. aureus</italic>. Sterile culture supernatants (“secretomes”) of <italic>S. aureus</italic> clinical strains isolated from AK and SCC were applied to human keratinocytes <italic>in vitro.</italic> Some <italic>S. aureus</italic> secretomes induced keratinocytes to overexpress inflammatory mediators that have been linked to skin carcinogenesis, including IL-6, IL-8, and TNFα. A large phenotypic variation between the tested clinical strains was observed. Strains that are highly pro-inflammatory <italic>in vitro</italic> also caused more pronounced skin inflammation in mice. Proteomic characterization of <italic>S. aureus</italic> secretomes using mass spectrometry established that specific <italic>S. aureus</italic> enzymes and cytolytic toxins, including hemolysins, phenol-soluble modulins, and serine proteases, as well as currently uncharacterized proteins, correlate with the pro-inflammatory <italic>S. aureus</italic> phenotype. This study is the first to describe the toxin secretion profiles of AK and SCC-associated <italic>S. aureus</italic>, and their potential to induce a pro-inflammatory environment in the skin. Further studies are needed to establish whether these <italic>S. aureus</italic> products promote SCC development by mediating chronic inflammation.</p>