Crossed Wires: Interspecies Interference Blocks Pathogen Colonization
Authors: Christopher A. Lopez, Eric P. Skaar
Journal: Cell Host & Microbe (2017)

Commensal bacteria protect against invading pathogens using many strategies. In this issue of Cell Host & Microbe, Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar find that a commensal blocks Staphylococcus aureus colonization by producing a signal to shut down virulence. Commensal bacteria protect against invading pathogens using many strategies. In this issue of Cell Host & Microbe, Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar find that a commensal blocks Staphylococcus aureus colonization by producing a signal to shut down virulence. The Gram-positive bacterium Staphylococcus aureus is an important cause of healthcare-associated infections due in part to its ability to survive in multiple environments. In humans, S. aureus asymptomatically colonizes the nares of up to 50% of individuals permanently or intermittently, living essentially as a commensal (Frank et al., 2010Frank D.N. Feazel L.M. Bessesen M.T. Price C.S. Janoff E.N. Pace N.R. PLoS One. 2010; 5: e10598Crossref PubMed Scopus (290) Google Scholar). However, S. aureus colonization represents a significant risk factor for subsequent S. aureus infections. Antibiotic treatments to limit S. aureus colonization are decreasingly effective due to an increased prevalence of multi-drug-resistant strains. The bacterial communities living in close association with mammalian hosts, referred to as the microbiota, provide a degree of protection against pathogenic microbes. On the skin, members of the dominant phylum Actinobacteria can limit S. aureus colonization, and in the clinic, S. aureus burdens are negatively associated with Propionibacterium and Corynebacterium (Frank et al., 2010Frank D.N. Feazel L.M. Bessesen M.T. Price C.S. Janoff E.N. Pace N.R. PLoS One. 2010; 5: e10598Crossref PubMed Scopus (290) Google Scholar). Based on this microbiota-mediated colonization resistance, there is great interest in exploiting competing commensal bacteria to lower S. aureus burdens on the skin. Although several studies have reported competing interactions between S. aureus and the microbiota as they battle for limited resources, the details of these interactions and their causal relationships have not been firmly established. Aside from intra-phyla competition, S. aureus must also contend with other Staphylococcus species. For instance, S. epidermidis, another common skin inhabitant, antagonizes S. aureus colonization and virulence (Laborel-Préneron et al., 2015Laborel-Préneron E. Bianchi P. Boralevi F. Lehours P. Fraysse F. Morice-Picard F. Sugai M. Sato’o Y. Badiou C. Lina G. et al.PLoS One. 2015; 10: e0141067PubMed Google Scholar, Sugimoto et al., 2013Sugimoto S. Iwamoto T. Takada K. Okuda K. Tajima A. Iwase T. Mizunoe Y. J. Bacteriol. 2013; 195: 1645-1655Crossref PubMed Scopus (146) Google Scholar, Vandecandelaere et al., 2014Vandecandelaere I. Depuydt P. Nelis H.J. Coenye T. Pathog. Dis. 2014; 70: 321-331Crossref PubMed Scopus (42) Google Scholar). Interestingly, one mechanism attributed to S. epidermidis-induced inhibition of S. aureus colonization is via interference with quorum sensing signaling. In Gram-positive bacteria, quorum sensing involves the production and secretion of short autoinducing peptides (AIPs), with AIP density serving as a marker of bacterial population density. S. aureus senses AIP concentration through the sensor histidine kinase AgrC, which controls the downstream activation of a DNA-binding response regulator AgrA (Le and Otto, 2015Le K.Y. Otto M. Front. Microbiol. 2015; 6: 1174Crossref PubMed Scopus (244) Google Scholar). Once activated, AgrA increases transcription of the agrBDCA operon, which encodes the two-component system AgrCA and AIP production and export through AgrBD (Le and Otto, 2015Le K.Y. Otto M. Front. Microbiol. 2015; 6: 1174Crossref PubMed Scopus (244) Google Scholar) (Figure 1). Additionally, AgrA increases transcription of RNAIII, a global regulator that controls expression of multiple S. aureus virulence factors (Le and Otto, 2015Le K.Y. Otto M. Front. Microbiol. 2015; 6: 1174Crossref PubMed Scopus (244) Google Scholar) (Figure 1). Therefore, S. epidermidis has the potential to downregulate S. aureus virulence through quorum sensing interference and to impede the pathogen’s ability to survive in the nares. How quorum sensing interference directs the relationships between S. aureus and other closely related members of the skin microbiota besides S. epidermidis has received less attention. To probe the S. aureus quorum sensing response to other Staphylococcus species, Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar grew S. aureus harboring fluorescent transcription reporters for each of four agr types in the presence of spent media from an array of coagulase negative Staphylococcus clinical isolates. While many of the isolates exhibited some inhibitory activity against the S. aureus reporter strains, S. caprae significantly inhibited all four agr types. S. caprae is commonly found on dairy goats, with recent studies also identifying the bacterium on human skin (d’Ersu et al., 2016d’Ersu J. Aubin G.G. Mercier P. Nicollet P. Bémer P. Corvec S. J. Clin. Microbiol. 2016; 54: 106-113Crossref PubMed Scopus (17) Google Scholar). Little is known regarding how S. caprae interacts with S. aureus other than both being associated with a similar skin niche. Here, Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar found that S. caprae-spent media reduced agr transcription but did not inhibit S. aureus growth. Further experiments to determine the identity of the unknown secreted factor revealed that S. caprae secreted an AIP encoded by the S. caprae agrBD genes that inhibited S. aureus agr and RNAIII transcription upstream of the response regulator AgrA, suggesting that interference likely occurred through interaction with the sensor AgrC. The group next synthesized the S. caprae AIP and described its structure as an 8-aa-long peptide with a five-membered thiolactone ring indicative of an AIP. This synthesized AIP reduced S. aureus agr expression in a similar pattern as S. caprae-spent supernatant, showing that S. caprae AIP release could interfere with S. aureus quorum sensing to govern pathogen colonization or virulence. Though S. caprae AIP mediated quorum sensing interference in culture, it is important to understand the downstream impact on pathogen virulence in a complex and relevant system. To this end, Paharik and colleagues (Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) used a mouse model of methicillin-resistant S. aureus (MRSA) intradermal infection. Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar found that synthesized S. caprae AIP administered at the time of MRSA inoculation was effective at reducing bacterial burdens and limiting tissue damage. The reduced MRSA burdens were not a function of growth inhibition, as the AIP was earlier shown to have no effect on S. aureus growth rate, but instead is likely a result of a decreased capacity of S. aureus to resist host defenses. The S. aureus agr system is responsible for controlling multiple virulence traits, including expression of genes responsible for thwarting the immune response (Le and Otto, 2015Le K.Y. Otto M. Front. Microbiol. 2015; 6: 1174Crossref PubMed Scopus (244) Google Scholar). Therefore, downregulation of these virulence genes through AIP-mediated inhibition of S. aureus quorum sensing leaves the pathogen more susceptible to destruction following a primary immune response. The protection afforded by the S. caprae AIP was also evident in established MRSA infections, where AIP administration promoted wound healing that corresponded with reduced S. aureus burdens. Paharik and colleagues (Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) hypothesized that S. caprae competes with S. aureus in the skin environment using quorum sensing interference to provide a fitness advantage. Indeed, cutaneous co-inoculation with S. caprae and S. aureus resulted in smaller lesion sizes and reduced S. aureus burdens comparable to the results when the synthesized AIP was administered along with S. aureus. The decreased tissue damage correlated with a downregulation of the S. aureus agr expression only when S. caprae was present in the wound, thus linking S. caprae quorum sensing interference with S. aureus virulence inhibition. Quorum sensing interference is a promising avenue in the treatment of infections caused by pathogens that are increasingly resistant to the existing antibiotic arsenal. Quorum sensing plays a fundamental role in regulating virulence in diverse bacterial pathogens (Ali et al., 2017Ali L. Goraya M.U. Arafat Y. Ajmal M. Chen J.L. Yu D. Int. J. Mol. Sci. 2017; 18: 18Crossref Scopus (69) Google Scholar, Rutherford and Bassler, 2012Rutherford S.T. Bassler B.L. Cold Spring Harb. Perspect. Med. 2012; 2: 2Crossref Scopus (1141) Google Scholar). Yet, since quorum sensing interference does not directly inhibit bacterial growth, some have suggested that therapeutics that target quorum sensing will not provide a selective pressure and hence delay the evolution of resistance. This hypothesis, however, has been recently challenged, as studies on Pseudomonas aeruginosa are providing evidence that, in certain environments, quorum sensing interference can result in alterations in metabolism that affect growth, thus adding selective pressure while also increasing virulence (García-Contreras, 2016García-Contreras R. Front. Microbiol. 2016; 7: 1454Crossref PubMed Scopus (54) Google Scholar). These studies serve to highlight the need to build on our understanding of how quorum sensing is regulated and the consequences of manipulating that system with potential therapeutics. The new study by Paharik et al., 2017Paharik A.E. Parlet C.P. Chung N. Todd D.A. Rodriguez E.I. Van Dyke M.J. Cech N.B. Horswill A.R. Cell Host Microbe. 2017; 22 (this issue): 746-756Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar adds valuable insight into how the commensal bacterium S. caprae can reduce S. aureus virulence and promote enhanced tissue recovery following infection. Additionally, this work underscores the role of quorum sensing in directing microbe-microbe interactions on the skin that could lead to strategies aimed at reducing S. aureus colonization to decrease the risk of downstream infections. Coagulase-Negative Staphylococcal Strain Prevents Staphylococcus aureus Colonization and Skin Infection by Blocking Quorum SensingPaharik et al.Cell Host & MicrobeNovember 30, 2017In BriefPaharik, Parlet, et al. demonstrate that the human commensal Staphylococcus caprae competes with Staphylococcus aureus by inhibiting quorum sensing. Through signal interference, S. caprae reduces methicillin-resistant S. aureus burden in both skin colonization and infection, highlighting the benefits of healthy skin flora and suggesting a new avenue for probiotic therapy. Full-Text PDF Open Archive