Using Quantitative Spectrometry to Understand the Influence of Genetics and Nutritional Perturbations On the Virulence Potential of Staphylococcus aureus

Staphylococcus aureus (Sa) is the leading cause of a variety of bacterial infections ranging from superficial skin infections to invasive and life threatening diseases such as septic bacteremia, necrotizing pneumonia, and endocarditis. The success of Sa as a human pathogen is contributed to its ability to adapt to different environments by changing expression, production, or secretion of virulence factors. Although Sa immune evasion is well-studied, the regulation of virulence factors under different nutrient and growth conditions is still not well understood. Here, we used label-free quantitative mass spectrometry to quantify and compare the Sa exoproteins (i.e. exoproteomes) of master regulator mutants or established reference strains. Different environmental conditions were addressed by growing the bacteria in rich or minimal media at different phases of growth. We observed clear differences in the composition of the exoproteomes depending on the genetic background or growth conditions. The relative abundance of cytotoxins determined in our study correlated well with differences in cytotoxicity measured by lysis of human neutrophils. Our findings demonstrate that label-free quantitative mass spectrometry is a versatile tool for predicting the virulence of bacterial strains and highlights the importance of the experimental design for in vitro studies. Furthermore, the results indicate that label-free proteomics can be used to cluster isolates into groups with similar virulence properties, highlighting the power of label-free quantitative mass spectrometry to distinguish Sa strains. Staphylococcus aureus (Sa) is the leading cause of a variety of bacterial infections ranging from superficial skin infections to invasive and life threatening diseases such as septic bacteremia, necrotizing pneumonia, and endocarditis. The success of Sa as a human pathogen is contributed to its ability to adapt to different environments by changing expression, production, or secretion of virulence factors. Although Sa immune evasion is well-studied, the regulation of virulence factors under different nutrient and growth conditions is still not well understood. Here, we used label-free quantitative mass spectrometry to quantify and compare the Sa exoproteins (i.e. exoproteomes) of master regulator mutants or established reference strains. Different environmental conditions were addressed by growing the bacteria in rich or minimal media at different phases of growth. We observed clear differences in the composition of the exoproteomes depending on the genetic background or growth conditions. The relative abundance of cytotoxins determined in our study correlated well with differences in cytotoxicity measured by lysis of human neutrophils. Our findings demonstrate that label-free quantitative mass spectrometry is a versatile tool for predicting the virulence of bacterial strains and highlights the importance of the experimental design for in vitro studies. Furthermore, the results indicate that label-free proteomics can be used to cluster isolates into groups with similar virulence properties, highlighting the power of label-free quantitative mass spectrometry to distinguish Sa strains. Staphylococcus aureus (Sa) 1The abbreviations used are: Sa, Staphylococcus aureus; agr, accessory gene regulator; Asn, asparagines; CA, community associated; CC, clonal complex; Cys, cysteine; FDR, false discovery rate; Gln, glutamine; HA, hospital associated; hPMNs, human polymorphonuclear leukocytes or neutrophils; LFQ, label-free quantitation as calculated by MaxQuant; Met, methionine; MLST, multilocus sequence typing; MRSA, Methicillin-resistant Staphylococcus aureus; MSSA, Methicillin-sensitive Staphylococcus aureus; NETs, neutrophil extracellular nets; PSM, peptide spectral match; pvl, Panton–Valentine leukocidin gene; Rot, repressor of toxins; RPMI, Roswell Park Memorial Institute medium-Cassamino acid; Sae, Sa exoprotein expression; SCCmec, staphylococcal cassette chromosome mec; ST, strain type; TSB, Tryptic Soy Broth; WT, wild type; TCS, Two-component system.1The abbreviations used are: Sa, Staphylococcus aureus; agr, accessory gene regulator; Asn, asparagines; CA, community associated; CC, clonal complex; Cys, cysteine; FDR, false discovery rate; Gln, glutamine; HA, hospital associated; hPMNs, human polymorphonuclear leukocytes or neutrophils; LFQ, label-free quantitation as calculated by MaxQuant; Met, methionine; MLST, multilocus sequence typing; MRSA, Methicillin-resistant Staphylococcus aureus; MSSA, Methicillin-sensitive Staphylococcus aureus; NETs, neutrophil extracellular nets; PSM, peptide spectral match; pvl, Panton–Valentine leukocidin gene; Rot, repressor of toxins; RPMI, Roswell Park Memorial Institute medium-Cassamino acid; Sae, Sa exoprotein expression; SCCmec, staphylococcal cassette chromosome mec; ST, strain type; TSB, Tryptic Soy Broth; WT, wild type; TCS, Two-component system. asymptomatic colonization of the nares, skin or gastrointestinal tract is detected in ∼30% of humans (1.Diekema D.J. Pfaller M.A. Schmitz F.J. Smayevsky J. Bell J. Jones R.N. Beach M. Group S.P. Survey of infections because of Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999.Clin. Infect. Dis. 2001; 32: S114-S132Crossref PubMed Scopus (1109) Google Scholar, 2.Kluytmans J. van Belkum A. Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks.Clin. Microbiol. Rev. 1997; 10: 505-520Crossref PubMed Google Scholar). At the same time, Sa is also responsible for a variety of diseases ranging from skin and soft tissue infections to invasive diseases such as bacteremia, necrotizing pneumonia, and infective endocarditis (3.David M.Z. Daum R.S. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.Clin. Microbiol. Rev. 2010; 23: 616-687Crossref PubMed Scopus (1398) Google Scholar, 4.Tong S.Y. Davis J.S. Eichenberger E. Holland T.L. Fowler Jr., V.G. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.Clin. Microbiol. Rev. 2015; 28: 603-661Crossref PubMed Scopus (2377) Google Scholar). How Sa switches its lifestyle from a commensal bacterium to a dangerous human pathogen is not well understood. Of particular concern is the emergence of difficult to treat, community-associated methicillin-resistant Sa (CA-MRSA) that began in the 1990s. The rise of CA-MRSA indicates that MRSA strains evolved from a traditionally nosocomial pathogen to a pathogen that causes disease in healthy individuals with no healthcare associated risk factors (3.David M.Z. Daum R.S. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.Clin. Microbiol. Rev. 2010; 23: 616-687Crossref PubMed Scopus (1398) Google Scholar, 5.Thurlow L.R. Joshi G.S. Richardson A.R. Virulence strategies of the dominant USA300 lineage of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).FEMS Immunol. Med. Microbiol. 2012; 65: 5-22Crossref PubMed Scopus (103) Google Scholar). The most successful CA-MRSA in the United States of America is the USA300 lineage (3.David M.Z. Daum R.S. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic.Clin. Microbiol. Rev. 2010; 23: 616-687Crossref PubMed Scopus (1398) Google Scholar, 4.Tong S.Y. Davis J.S. Eichenberger E. Holland T.L. Fowler Jr., V.G. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.Clin. Microbiol. Rev. 2015; 28: 603-661Crossref PubMed Scopus (2377) Google Scholar). The success of CA-MRSA as a formidable human pathogen is largely because of an array of virulence factors that are adept at disarming the human immune system (6.Thammavongsa V. Kim H.K. Missiakas D. Schneewind O. Staphylococcal manipulation of host immune responses.Nat. Rev. Microbiol. 2015; 13: PubMed Scopus Google Scholar). such as staphylococcal and staphylococcal of to human and by immune E. van of human with a staphylococcal of a of evasion by Staphylococcus PubMed Scopus Google Scholar, A. J. from with human Immunol. Google Scholar, J. in from Staphylococcus of the and J. PubMed Scopus Google Scholar). such as staphylococcal and M. A. J.S. van van van evasion by a staphylococcal that on Immunol. PubMed Scopus Google Scholar, M. van J. van van van of and immune evasion by Staphylococcus Microbiol. 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We the exoprotein of Sa USA300 master regulator and to in minimal or rich wild USA300 to or and different reference Sa strains to different clonal our study a rich the of the CA-MRSA in the United States, and Sa Sa strains were at on Tryptic Soy in Tryptic Soy or Roswell Park Memorial Institute media with were in growth media in at a or in growth media in with at to The and of the M.A. and to of the staphylococcal 2012; PubMed Scopus Google Scholar, M.A. J.S. A.R. is a regulator of Staphylococcus aureus Microbiol. 2015; PubMed Scopus Google M.A. and to of the staphylococcal 2012; PubMed Scopus Google and a sequence virulence gene to USA300 Infect. Dis. 2010; PubMed Scopus Google growth Sa strain at in or from in in a with at at were at the of the and at the a were from from the were from and human polymorphonuclear were as A. to Staphylococcus aureus PubMed Scopus Google Scholar). were in with were as M.A. H. A. of by a MRSA of a Microbiol. PubMed Scopus Google Scholar, A. 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Microbiol. 2015; 13: PubMed Scopus Google Scholar). we used a to the Sa and in exoproteomes with the of the conditions the Sa can be a that of are or M. the of PubMed Scopus Google Scholar). Here, we to the study of such by exoproteins on virulence and and by on of to in the secretion of virulence factors. we our label-free mass spectrometry by of and in and minimal we exoproteomes of to growth phases in rich and minimal the virulence factors at and conditions of Sa growth and a of and growth we to a of reference strains to the is of our study we used mutants of master that are well in the M.A. H. A. of by a MRSA of a Microbiol. PubMed Scopus Google Scholar, E. M. A. Staphylococcus aureus the of virulence factors and the regulator by an PubMed Scopus Google Scholar, E. D. A. of in Staphylococcus aureus by the J. PubMed Scopus Google Scholar, J. of staphylococcal virulence factors is by a J. PubMed Scopus Google Scholar, A. 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Of the in minimal with the same in rich and in the and similar to the our to groups of that not the of and be of studies. to Sa virulence used E. D. D. of Staphylococcus aureus by the 2001; PubMed Scopus Google Scholar, A.R. The Staphylococcus aureus regulator and virulence by PubMed Scopus Google Scholar, D. J.S. of in Staphylococcus aureus 2015; 10: PubMed Scopus Google Scholar, A. of Staphylococcus aureus and PubMed Scopus Google Scholar, J. gene in Staphylococcus aureus with PubMed Scopus Google to study in the Sa or at the results not of the is a of virulence and Sa R.S. M. virulence in nosocomial to methicillin-resistant Staphylococcus Infect. Dis. 2015; PubMed Scopus Google Scholar). We and to study Sa virulence D. J. A. Kim J. Staphylococcus aureus leukocidin and by PubMed Scopus Google Scholar, Kim H.K. G.S. Kim Kim The gene from Staphylococcus aureus: and to and of gene Microbiol. PubMed Scopus Google Scholar, A. van M. D. The Staphylococcus aureus J. Med. Microbiol. 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We the power of label-free quantitative proteomics for the of the virulence of Sa strains. the pathogen to the host immune of the in predicting the virulence of emerging is to and the different bacterial strains a quantitative mass spectrometry are with similar background of the and most of the not the of Sa strains a of gene gene or differences The most in proteomics of the into are mass spectrometry and the sequence in to a or is in to a Here, the peptide a strains in to and the of the mass is that of different Sa strains is and the sequence of a is not observed by mass the sequence of a can is to the peptide and for a to different strains. the are to strains and sequence The of Staphylococcus Rev. PubMed Scopus Google Scholar, The of Staphylococcus aureus on the lysis and Microbiol. PubMed Scopus Google as by of H. A. M. M. A. J. E. E. of and of Staphylococcus aureus with a human 2015; PubMed Scopus Google Scholar). be to the gene of the we groups of strains as by on for of as PubMed Scopus Google Scholar). compare the of the the reference strains of we strain to as a and to for for of its gene to compare the strains with different to as a groups and of that strains. to that quantitation of is on mass spectrometry (i.e. quantitation to in the sequence of for a gene and no (i.e. the be in and be to the we our of mass spectrometry with the of and be an tool to the H. V. D. J. Jones M. M. J. H. D. O. of isolates of for the PubMed Scopus Google Scholar). We that with and the to an tool for predicting the virulence of in the of emerging strains. mass spectrometry and results to the the with the and with with

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