Abstract
Staphylococcus aureus is a commensal colonizer of both humans and animals, but also an opportunistic pathogen responsible for a multitude of diseases. In recent years, colonization of pigs by methicillin resistant S. aureus has become a problem with increasing numbers of humans being infected by livestock strains. In S. aureus colonization and virulence factor expression is controlled by the agr quorum sensing system, which responds to and is activated by self-generated, autoinducing peptides (AIPs). AIPs are also produced by coagulase negative staphylococci (CoNS) commonly found as commensals in both humans and animals, and interestingly, some of these inhibit S. aureus agr activity. Here, we have addressed if cross-communication occurs between S. aureus and CoNS strains isolated from pig nares, and if so, how properties such as host factor binding and biofilm formation are affected. From 25 pig nasal swabs we obtained 54 staphylococcal CoNS isolates belonging to 8 different species. Of these, none were able to induce S. aureus agr as monitored by reporter gene fusions to agr regulated genes but a number of agr-inhibiting species were identified including Staphylococcus hyicus, Staphylococcus simulans, Staphylococcus arlettae, Staphylococcus lentus, and Staphylococcus chromogenes. After establishing that the inhibitory activity was mediated via AgrC, the receptor of AIPs, we synthesized selective AIPs to explore their effect on adhesion of S. aureus to fibronectin, a host factor involved in S. aureus colonization. Here, we found that the CoNS AIPs did not affect adhesion of S. aureus except for strain 8325-4. When individual CoNS strains were co-cultured together with S. aureus we observed variable degrees of biofilm formation which did not correlate with agr interactions. Our results show that multiple CoNS species can be isolated from pig nares and that the majority of these produce AIPs that inhibit S. aureus agr. Further they show that the consequences of the interactions between CoNS and S. aureus are complex and highly strain dependent.
Highlights
Staphylococcus aureus is a common colonizer and opportunistic pathogen of both animals and humans
Production of both adhesins and toxins are controlled by the accessory gene regulator quorum sensing system with the former being produced at low bacterial cell densities and the latter at high cell densities (Yarwood and Schlievert, 2003). agr is composed of a two component system which senses a selfgenerated autoinducing peptide (AIP) that, by binding to the sensor histidine kinase AgrC, leads to phosphorylation of the AgrA response-regulator and expression of the main agr effector molecule, RNAIII
S. aureus A was classified as CC8 and S. aureus B as CC45. Strains belonging to both CC8 and CC45 have previously been found associated with live stock (Tang et al, 2017a). When these strains were separately treated with synthesized AIPs of S. hyicus, S. simulans, and S. chromogenes, that have been detected in a previous study (Gless et al, 2019), we observed a significant increase in S. aureus 8325-4 binding to fibronectin in the presence of the coagulase negative staphylococci (CoNS) AIPs, in comparison to the vehicle (DMSO)-treated control (Figure 6)
Summary
Staphylococcus aureus is a common colonizer and opportunistic pathogen of both animals and humans. In addition to colonization factors, S. aureus expresses a multitude of toxins and other factors necessary for virulence and biofilm formation (Archer et al, 2011; Kobayashi et al, 2015) Production of both adhesins and toxins are controlled by the accessory gene regulator (agr) quorum sensing system with the former being produced at low bacterial cell densities and the latter at high cell densities (Yarwood and Schlievert, 2003). An RNAIIIindependent agr gene regulation pathway exists, involving AgrA-mediated expression of a family of toxins called the phenol soluble modulins (PSMs) (Periasamy et al, 2012) These PSMs are important players in biofilm formation and dispersal linking agr and biofilm formation (Boles and Horswill, 2008; Periasamy et al, 2012). This group specificity has lead to an interest in studying the inhibitory activity of non-cognate AIPs as antivirulence sources targeting agr (Canovas et al, 2016; Tal-Gan et al, 2016)
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