Editing Staphylococcus aureus (section)

== Virulence factors ==
{{Main|Virulence factor}}

=== Enzymes ===
''Staphylococcus aureus'' produces various enzymes such as [[coagulase]] (bound and free coagulases) which facilitates the conversion of fibrinogen to fibrin to cause clots which is important in skin infections.<ref>{{cite journal | vauthors = Cheung GY, Bae JS, Otto M | title = Pathogenicity and virulence of ''Staphylococcus aureus'' | journal = Virulence | volume = 12 | issue = 1 | pages = 547–569 | date = December 2021 | pmid = 33522395 | pmc = 7872022 | doi = 10.1080/21505594.2021.1878688 }}</ref> [[Hyaluronidase]] (also known as spreading factor) breaks down [[hyaluronan|hyaluronic acid]] and helps in spreading it. [[Deoxyribonuclease]], which breaks down the DNA, protects ''S. aureus'' from [[Neutrophil extracellular traps|neutrophil extracellular trap]]-mediated killing.<ref>{{cite journal | vauthors = Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Köckritz-Blickwede M | title = Nuclease expression by ''Staphylococcus aureus'' facilitates escape from neutrophil extracellular traps | language = english | journal = Journal of Innate Immunity | volume = 2 | issue = 6 | pages = 576–586 | date = 2010 | pmid = 20829609 | pmc = 2982853 | doi = 10.1159/000319909 }}</ref><ref>{{cite journal | vauthors = Monteith AJ, Miller JM, Maxwell CN, Chazin WJ, Skaar EP | title = Neutrophil extracellular traps enhance macrophage killing of bacterial pathogens | language = EN | journal = Science Advances | volume = 7 | issue = 37 | pages = eabj2101 | date = September 2021 | pmid = 34516771 | pmc = 8442908 | doi = 10.1126/sciadv.abj2101 | bibcode = 2021SciA....7.2101M | doi-access = free }}</ref> ''S. aureus'' also produces [[lipase]] to digest lipids, [[staphylokinase]] to dissolve fibrin and aid in spread, and [[beta-lactamase]] for drug resistance.<ref>Medical Laboratory Manual For Tropical Countries vol two</ref>

=== Toxins ===

Depending on the strain, ''S. aureus'' is capable of secreting several [[exotoxin]]s, which can be categorized into three groups.  Many of these toxins are associated with specific diseases.<ref>{{cite journal | vauthors = Dinges MM, Orwin PM, Schlievert PM | title = Exotoxins of ''Staphylococcus aureus'' | journal = Clinical Microbiology Reviews | volume = 13 | issue = 1 | pages = 16–34, table of contents | date = January 2000 | pmid = 10627489 | pmc = 88931 | doi = 10.1128/cmr.13.1.16 }}</ref>

;Superantigens
:[[Antigen]]s known as [[superantigen]]s can induce [[toxic shock syndrome]] (TSS). This group comprises 25 staphylococcal [[enterotoxins]] (SEs) which have been identified to date and named alphabetically (SEA–SEZ),<ref>{{cite journal | vauthors = Etter D, Schelin J, Schuppler M, Johler S | title = Staphylococcal Enterotoxin C-An Update on SEC Variants, Their Structure and Properties, and Their Role in Foodborne Intoxications | journal = Toxins | volume = 12 | issue = 9 | pages = 584 | date = September 2020 | pmid = 32927913 | pmc = 7551944 | doi = 10.3390/toxins12090584 | doi-access = free }}</ref> including [[enterotoxin type B]] as well as the toxic shock syndrome toxin [[TSST-1]] which causes TSS associated with [[tampon]] use.  Toxic shock syndrome is characterized by [[fever]], [[erythema|erythematous rash]], [[Hypotension|low blood pressure]], [[Shock (circulatory)|shock]], [[Multiple organ dysfunction syndrome|multiple organ failure]], and [[desquamation|skin peeling]].  Lack of antibody to TSST-1 plays a part in the pathogenesis of TSS. Other strains of ''S. aureus'' can produce an [[enterotoxin]] that is the causative agent of a type of [[Gastroenteritis#Bacterial|gastroenteritis]]. This form of gastroenteritis is self-limiting, characterized by vomiting and diarrhea 1–6 hours after ingestion of the toxin, with recovery in 8 to 24 hours. Symptoms include nausea, vomiting, diarrhea, and major abdominal pain.<ref>{{cite journal | vauthors = Jarraud S, Peyrat MA, Lim A, Tristan A, Bes M, Mougel C, Etienne J, Vandenesch F, Bonneville M, Lina G | title = egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in ''Staphylococcus aureus'' | journal = Journal of Immunology | volume = 166 | issue = 1 | pages = 669–677 | date = January 2001 | pmid = 11123352 | doi = 10.4049/jimmunol.166.1.669 | doi-access = free }}</ref><ref name=becker/>

{{anchor|Exfoliative toxins}}
;Exfoliative toxins
{{See also|Exfoliatin}}
: [[Exfoliatin|Exfoliative toxins]] are exotoxins implicated in the disease [[staphylococcal scalded skin syndrome]] (SSSS), which occurs most commonly in infants and young children. It also may occur as epidemics in hospital nurseries. The [[protease]] activity of the exfoliative toxins causes peeling of the skin observed with SSSS.<ref name=becker>{{cite journal | vauthors = Becker K, Friedrich AW, Lubritz G, Weilert M, Peters G, Von Eiff C | title = Prevalence of genes encoding pyrogenic toxin superantigens and exfoliative toxins among strains of ''Staphylococcus aureus'' isolated from blood and nasal specimens | journal = Journal of Clinical Microbiology | volume = 41 | issue = 4 | pages = 1434–9 | date = April 2003 | pmid = 12682126 | pmc = 153929 | doi = 10.1128/jcm.41.4.1434-1439.2003 }}</ref>

;Other toxins
: Staphylococcal toxins that act on cell membranes include [[Staphylococcus aureus alpha toxin|alpha toxin]], [[Staphylococcus aureus beta toxin|beta toxin]], [[Staphylococcus aureus delta toxin|delta toxin]], and several bicomponent toxins. Strains of ''S. aureus'' can host [[phage]]s, such as the [[prophage]] Φ-PVL that produces [[Panton-Valentine leukocidin]] (PVL), to increase [[virulence]]. The bicomponent toxin PVL is associated with severe necrotizing pneumonia in children.<ref>{{cite journal | vauthors = Lina G, Piémont Y, Godail-Gamot F, Bes M, Peter MO, Gauduchon V, Vandenesch F, Etienne J | title = Involvement of Panton-Valentine leukocidin-producing ''Staphylococcus aureus'' in primary skin infections and pneumonia | journal = Clinical Infectious Diseases | volume = 29 | issue = 5 | pages = 1128–32 | date = November 1999 | pmid = 10524952 | doi = 10.1086/313461 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gillet Y, Issartel B, Vanhems P, Fournet JC, Lina G, Bes M, Vandenesch F, Piémont Y, Brousse N, Floret D, Etienne J | title = Association between ''Staphylococcus aureus'' strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients | journal = Lancet | volume = 359 | issue = 9308 | pages = 753–9 | date = March 2002 | pmid = 11888586 | doi = 10.1016/S0140-6736(02)07877-7 | s2cid = 20400336 }} As [http://reannecy.org/documents/Reanimation_Bibliographie/INFECTIOLOGIE/INFECTION%20PAR%20GERMES/BACTERIES/STAPH/2002%20PNP%20necrosante%20et%20panton%20valentine%20lancet.pdf PDF] {{webarchive|url=https://web.archive.org/web/20140714163825/http://reannecy.org/documents/Reanimation_Bibliographie/INFECTIOLOGIE/INFECTION%20PAR%20GERMES/BACTERIES/STAPH/2002%20PNP%20necrosante%20et%20panton%20valentine%20lancet.pdf |date=14 July 2014 }}</ref> The genes encoding the components of PVL are encoded on a [[bacteriophage]] found in community-associated MRSA strains.{{citation needed|date=February 2017}}

=== Type VII secretion system ===
{{See also|Type VII secretion system|l1=Type VII secretion system (T7SS)}}
A secretion system is a highly specialised multi-protein unit that is embedded in the cell envelope with the function of translocating effector proteins from inside of the cell to the extracellular space or into a target host cytosol. The exact structure and function of T7SS is yet to be fully elucidated. Currently, four proteins are known components of ''S. aureus'' type VII secretion system; EssC is a large integral membrane [[ATPase]] – which most likely powers the secretion systems and has been hypothesised forming part of the translocation channel. The other proteins are EsaA, EssB, EssA, that are membrane proteins that function alongside EssC to mediate protein secretion. The exact mechanism of how substrates reach the cell surface is unknown, as is the interaction of the three membrane proteins with each other and EssC.<ref name=":3">{{cite journal | vauthors = Bowman L, Palmer T | title = The Type VII Secretion System of ''Staphylococcus'' | journal = Annual Review of Microbiology | volume = 75 | issue = 1 | pages = 471–494 | date = October 2021 | pmid = 34343022 | doi = 10.1146/annurev-micro-012721-123600 | s2cid = 236915377 }}</ref>

'''T7 dependent effector proteins'''

EsaD is DNA [[endonuclease]] toxin secreted by ''S. aureus'', has been shown to inhibit growth of competitor ''S. aureus'' strain ''in vitro''.<ref name=":4">{{cite journal | vauthors = Cao Z, Casabona MG, Kneuper H, Chalmers JD, Palmer T | title = The type VII secretion system of ''Staphylococcus aureus'' secretes a nuclease toxin that targets competitor bacteria | journal = Nature Microbiology | volume = 2 | issue = 1 | pages = 16183 | date = October 2016 | pmid = 27723728 | pmc = 5325307 | doi = 10.1038/nmicrobiol.2016.183 }}</ref> EsaD is cosecreted with [[Chaperone (protein)|chaperone]] EsaE, which stabilises EsaD structure and brings EsaD to EssC for secretion.<ref name=":4" /><ref name=":3" /> Strains that produce EsaD also co-produce EsaG, a cytoplasmic anti-toxin that protects the producer strain from EsaD's toxicity.<ref name=":4" />

TspA is another toxin that mediates intraspecies competition. It is a bacteriostatic toxin that has a membrane depolarising activity facilitated by its [[C-terminal domain]]. Tsai is a transmembrane protein that confers immunity to the producer strain of TspA, as well as the attacked strains. There is genetic variability of the C-terminal domain of TspA therefore, it seems like the strains may produce different TspA variants to increase competitiveness.<ref name=":5">{{cite journal | vauthors = Ulhuq FR, Gomes MC, Duggan GM, Guo M, Mendonca C, Buchanan G, Chalmers JD, Cao Z, Kneuper H, Murdoch S, Thomson S, Strahl H, Trost M, Mostowy S, Palmer T | title = A membrane-depolarizing toxin substrate of the ''Staphylococcus aureus'' type VII secretion system mediates intraspecies competition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 34 | pages = 20836–47 | date = August 2020 | pmid = 32769205 | pmc = 7456083 | doi = 10.1073/pnas.2006110117 | bibcode = 2020PNAS..11720836U | doi-access = free }}</ref>

Toxins that play a role in intraspecies competition confers an advantage by promoting successful colonisation in polymicrobial communities such as the nasopharynx and lung by outcompeting lesser strains.<ref name=":5" />

There are also T7 effector proteins that play role a in pathogenesis, for example mutational studies of ''S. aureus'' have suggested that EsxB and EsxC contribute to persistent infection in a murine abscess model.<ref>{{cite journal | vauthors = Burts ML, Williams WA, DeBord K, Missiakas DM | title = EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis of ''Staphylococcus aureus'' infections | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 4 | pages = 1169–74 | date = January 2005 | pmid = 15657139 | pmc = 545836 | doi = 10.1073/pnas.0405620102 | bibcode = 2005PNAS..102.1169B | doi-access = free }}</ref>

EsxX has been implicated in [[neutrophil]] lysis, therefore suggested as contributing to the evasion of host immune system. Deletion of ''essX'' in ''S. aureus'' resulted in significantly reduced resistance to neutrophils and reduced virulence in murine skin and blood infection models.<ref>{{cite journal | vauthors = Dai Y, Wang Y, Liu Q, Gao Q, Lu H, Meng H, Qin J, Hu M, Li M | title = A Novel ESAT-6 Secretion System-Secreted Protein EsxX of Community-Associated ''Staphylococcus aureus'' Lineage ST398 Contributes to Immune Evasion and Virulence | journal = Frontiers in Microbiology | volume = 8 | pages = 819 | date = 2017-05-05 | pmid = 28529509 | pmc = 5418362 | doi = 10.3389/fmicb.2017.00819 | doi-access = free }}</ref>

Altogether, T7SS and known secreted effector proteins are a strategy of pathogenesis by improving fitness against competitor ''S. aureus'' species as well as increased virulence via evading the innate immune system and optimising persistent infections.{{citation needed|date=August 2022}}

=== Small RNA ===
The list of [[small RNA]]s involved in the control of bacterial virulence in ''S. aureus'' is growing. This can be facilitated by factors such as increased biofilm formation in the presence of increased levels of such small RNAs.<ref name=Kim14>{{cite journal | vauthors = Kim S, Reyes D, Beaume M, Francois P, Cheung A | title = Contribution of teg49 small RNA in the 5' upstream transcriptional region of sarA to virulence in ''Staphylococcus aureus'' | journal = Infection and Immunity | volume = 82 | issue = 10 | pages = 4369–79 | date = October 2014 | pmid = 25092913 | pmc = 4187880 | doi = 10.1128/iai.02002-14 }}</ref> For example, [[RNAIII]],<ref>{{cite journal | vauthors = Chevalier C, Boisset S, Romilly C, Masquida B, Fechter P, Geissmann T, Vandenesch F, Romby P | title = ''Staphylococcus aureus'' RNAIII binds to two distant regions of coa mRNA to arrest translation and promote mRNA degradation | journal = PLOS Pathogens | volume = 6 | issue = 3 | pages = e1000809 | date = March 2010 | pmid = 20300607 | pmc = 2837412 | doi = 10.1371/journal.ppat.1000809 | doi-access = free }}</ref> [[SprD]],<ref>{{cite journal | vauthors = Chabelskaya S, Gaillot O, Felden B | title = A ''Staphylococcus aureus'' small RNA is required for bacterial virulence and regulates the expression of an immune-evasion molecule | journal = PLOS Pathogens | volume = 6 | issue = 6 | pages = e1000927 | date = June 2010 | pmid = 20532214 | pmc = 2880579 | doi = 10.1371/journal.ppat.1000927 | doi-access = free }}</ref> SprC,<ref>{{cite journal | vauthors = Le Pabic H, Germain-Amiot N, Bordeau V, Felden B | title = A bacterial regulatory RNA attenuates virulence, spread and human host cell phagocytosis | journal = Nucleic Acids Research | volume = 43 | issue = 19 | pages = 9232–48 | date = October 2015 | pmid = 26240382 | pmc = 4627067 | doi = 10.1093/nar/gkv783 }}</ref><ref>{{cite journal | vauthors = Mauro T, Rouillon A, Felden B | title = Insights into the regulation of small RNA expression: SarA represses the expression of two sRNAs in ''Staphylococcus aureus'' | journal = Nucleic Acids Research | volume = 44 | issue = 21 | pages = 10186–200 | date = December 2016 | pmid = 27596601 | pmc = 5137438 | doi = 10.1093/nar/gkw777 }}</ref> [[Rsa RNA|RsaE]],<ref>{{cite journal | vauthors = Bohn C, Rigoulay C, Chabelskaya S, Sharma CM, Marchais A, Skorski P, Borezée-Durant E, Barbet R, Jacquet E, Jacq A, Gautheret D, Felden B, Vogel J, Bouloc P | title = Experimental discovery of small RNAs in ''Staphylococcus aureus'' reveals a riboregulator of central metabolism | journal = Nucleic Acids Research | volume = 38 | issue = 19 | pages = 6620–36 | date = October 2010 | pmid = 20511587 | pmc = 2965222 | doi = 10.1093/nar/gkq462 }}</ref> SprA1,<ref>{{cite journal | vauthors = Sayed N, Jousselin A, Felden B | title = A cis-antisense RNA acts in trans in ''Staphylococcus aureus'' to control translation of a human cytolytic peptide | journal = Nature Structural & Molecular Biology | volume = 19 | issue = 1 | pages = 105–112 | date = December 2011 | pmid = 22198463 | doi = 10.1038/nsmb.2193 | s2cid = 8217681 | url = https://www.hal.inserm.fr/inserm-00696345/file/NSMBfinal.pdf }}</ref> SSR42,<ref>{{cite journal | vauthors = Morrison JM, Miller EW, Benson MA, Alonzo F, Yoong P, Torres VJ, Hinrichs SH, Dunman PM | title = Characterization of SSR42, a novel virulence factor regulatory RNA that contributes to the pathogenesis of a ''Staphylococcus aureus'' USA300 representative | journal = Journal of Bacteriology | volume = 194 | issue = 11 | pages = 2924–38 | date = June 2012 | pmid = 22493015 | pmc = 3370614 | doi = 10.1128/JB.06708-11 }}</ref> ArtR,<ref>{{cite journal | vauthors = Xue T, Zhang X, Sun H, Sun B | title = ArtR, a novel sRNA of ''Staphylococcus aureus'', regulates α-toxin expression by targeting the 5' UTR of sarT mRNA | journal = Medical Microbiology and Immunology | volume = 203 | issue = 1 | pages = 1–12 | date = February 2014 | pmid = 23955428 | doi = 10.1007/s00430-013-0307-0 | s2cid = 18371872 }}</ref> [[SprX small RNA|SprX]], [[Teg49 small RNA|Teg49]], <ref name=Kim14/> and IsrR.<ref>{{cite journal | vauthors = Coronel-Tellez RH, Pospiech M, Barrault M, Liu W, Bordeau V, Vasnier C, Felden B, Sargueil B, Bouloc P | title = sRNA-controlled iron sparing response in Staphylococci | journal = Nucleic Acids Research | volume = 50 | issue = 15 | pages = 8529–8546 | date = August 2022 | pmid = 35904807| pmc =  9410917 | doi = 10.1093/nar/gkac648 }}</ref> 

===DNA repair===

Host [[neutrophil]]s cause [[DNA damage (naturally occurring)|DNA double-strand breaks]] in  ''S. aureus'' through the production of [[reactive oxygen species]].<ref name="Ha2020">{{cite journal |vauthors=Ha KP, Clarke RS, Kim GL, Brittan JL, Rowley JE, Mavridou DA, Parker D, Clarke TB, Nobbs AH, Edwards AM |title=Staphylococcal DNA Repair Is Required for Infection |journal=mBio |volume=11 |issue=6 |pages=e02288-20 |date=November 2020 |pmid=33203752 |pmc=7683395 |doi=10.1128/mBio.02288-20 }}</ref>  For infection of a host to be successful, ''S. aureus'' must survive such damages caused by the hosts' defenses.  The two protein complex RexAB encoded by ''S. aureus'' is employed in the [[homologous recombination|recombinational repair]] of DNA double-strand breaks.<ref name = Ha2020/>

=== Strategies for post-transcriptional regulation by 3'untranslated region ===
Many [[Messenger RNA|mRNAs]] in ''S. aureus'' carry [[three prime untranslated region]]s (3'UTR) longer than 100 [[nucleotide]]s, which may potentially have a regulatory function.<ref name="Mozos">{{cite journal | vauthors = Ruiz de los Mozos I, Vergara-Irigaray M, Segura V, Villanueva M, Bitarte N, Saramago M, Domingues S, Arraiano CM, Fechter P, Romby P, Valle J, Solano C, Lasa I, Toledo-Arana A | title = Base pairing interaction between 5'- and 3'-UTRs controls icaR mRNA translation in ''Staphylococcus aureus'' | journal = PLOS Genetics | volume = 9 | issue = 12 | pages = e1004001 | date = 2013 | pmid = 24367275 | pmc = 3868564 | doi = 10.1371/journal.pgen.1004001 | doi-access = free }}</ref>

Further investigation of i''caR'' mRNA (mRNA coding for the repressor of the main expolysaccharidic compound of the bacteria biofilm matrix) demonstrated that the 3'UTR binding to the [[Five prime untranslated region|5' UTR]] can interfere with the translation initiation complex and generate a double stranded substrate for [[Ribonuclease III|RNase III]]. The interaction is between the UCCCCUG motif in the 3'UTR and the [[Shine-Dalgarno sequence|Shine-Dalagarno]] region at the 5'UTR. Deletion of the motif resulted in IcaR repressor accumulation and inhibition of biofilm development.<ref name= Mozos/> The biofilm formation is the main cause of ''Staphylococcus'' implant infections.<ref>{{cite journal | vauthors = Arciola CR, Campoccia D, Speziale P, Montanaro L, Costerton JW | title = Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials | journal = Biomaterials | volume = 33 | issue = 26 | pages = 5967–82 | date = September 2012 | pmid = 22695065 | doi = 10.1016/j.biomaterials.2012.05.031 }}</ref>

=== Biofilm ===
[[Biofilm]]s are groups of microorganisms, such as bacteria, that attach to each other and grow on wet surfaces.<ref name="Vidyasagar, A. 2016">Vidyasagar, A. (2016). What Are Biofilms? ''Live Science.''</ref> The ''S. aureus'' biofilm is embedded in a [[glycocalyx]] slime layer and can consist of [[teichoic acid]]s, host proteins, [[extracellular DNA]] (eDNA) and sometimes polysaccharide intercellular antigen (PIA).  S. aureus biofilms are important in disease pathogenesis, as they can contribute to antibiotic resistance and immune system evasion.<ref name="Archer_2011" /> ''S. aureus'' biofilm has high resistance to antibiotic treatments and host immune response.<ref name="Vidyasagar, A. 2016"/> One hypothesis for explaining this is that the biofilm matrix protects the embedded cells by acting as a barrier to prevent antibiotic penetration. However, the biofilm matrix is composed with many water channels, so this hypothesis is becoming increasingly less likely, but a biofilm matrix possibly contains antibiotic‐degrading enzymes such as β-lactamases, which can prevent antibiotic penetration.<ref>{{cite journal | vauthors = de la Fuente-Núñez C, Reffuveille F, Fernández L, Hancock RE | title = Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies | journal = Current Opinion in Microbiology | volume = 16 | issue = 5 | pages = 580–9 | date = October 2013 | pmid = 23880136 | doi = 10.1016/j.mib.2013.06.013 }}</ref> Another hypothesis is that the conditions in the biofilm matrix favor the formation of [[persister cell]]s, which are highly antibiotic-resistant, dormant bacterial cells.<ref name="Archer_2011" /> ''S. aureus'' biofilms also have high resistance to host immune response. Though the exact mechanism of resistance is unknown, ''S. aureus'' biofilms have increased growth under the presence of [[cytokine]]s produced by the host immune response.<ref>{{cite journal | vauthors = McLaughlin RA, Hoogewerf AJ | title = Interleukin-1beta-induced growth enhancement of ''Staphylococcus aureus'' occurs in biofilm but not planktonic cultures | journal = Microbial Pathogenesis | volume = 41 | issue = 2–3 | pages = 67–79 | date = August 2006 | pmid = 16769197 | doi = 10.1016/j.micpath.2006.04.005 }}</ref> Host antibodies are less effective for ''S. aureus'' biofilm due to the heterogeneous [[antigen]] distribution, where an antigen may be present in some areas of the biofilm, but completely absent from other areas.<ref name="Archer_2011" />

Studies in biofilm development have shown to be related to changes in gene expression. There are specific genes that were found to be crucial in the different biofilm growth stages. Two of these genes include rocD and gudB, which encode for the enzyme's [[ornithine-oxo-acid transaminase]] and [[glutamate dehydrogenase]], which are important for amino acid metabolism. Studies have shown biofilm development rely on amino acids [[glutamine]] and [[glutamate]] for proper metabolic functions.<ref>{{cite journal | vauthors = Nassar R, Hachim M, Nassar M, Kaklamanos EG, Jamal M, Williams D, Senok A | title = Microbial Metabolic Genes Crucial for ''S. aureus'' Biofilms: An Insight From Re-analysis of Publicly Available Microarray Datasets | language = English | journal = Frontiers in Microbiology | volume = 11 | pages = 607002 | date = 2021 | pmid = 33584569 | pmc = 7876462 | doi = 10.3389/fmicb.2020.607002 | doi-access = free }}</ref>

=== Other immunoevasive strategies ===

;Protein A

[[Protein A]] is anchored to staphylococcal [[peptidoglycan]] pentaglycine bridges (chains of five [[glycine]] residues) by the [[Peptidyl transferase|transpeptidase]] [[sortase]] A.<ref>{{cite journal | vauthors = Schneewind O, Fowler A, Faull KF | title = Structure of the cell wall anchor of surface proteins in ''Staphylococcus aureus'' | journal = Science | volume = 268 | issue = 5207 | pages = 103–6 | date = April 1995 | pmid = 7701329 | doi = 10.1126/science.7701329 | bibcode = 1995Sci...268..103S }}</ref> Protein A, an [[Immunoglobulin G|IgG]]-binding protein, binds to the [[Fc region]] of an [[antibody]].  In fact, studies involving mutation of genes coding for protein A resulted in a lowered virulence of ''S. aureus'' as measured by survival in blood, which has led to speculation that protein A-contributed virulence requires binding of antibody Fc regions.<ref>{{cite journal | vauthors = Patel AH, Nowlan P, Weavers ED, Foster T | title = Virulence of protein A-deficient and alpha-toxin-deficient mutants of ''Staphylococcus aureus'' isolated by allele replacement | journal = Infection and Immunity | volume = 55 | issue = 12 | pages = 3103–10 | date = December 1987 | pmid = 3679545 | pmc = 260034 | doi = 10.1128/IAI.55.12.3103-3110.1987 }}</ref>

Protein A in various recombinant forms has been used for decades to bind and purify a wide range of antibodies by [[immunoaffinity chromatography]].  Transpeptidases, such as the sortases responsible for anchoring factors like protein A to the staphylococcal peptidoglycan, are being studied in hopes of developing new antibiotics to target MRSA infections.<ref>{{cite journal | vauthors = Zhu J, Lu C, Standland M, Lai E, Moreno GN, Umeda A, Jia X, Zhang Z | title = Single mutation on the surface of ''Staphylococcus aureus'' Sortase A can disrupt its dimerization | journal = Biochemistry | volume = 47 | issue = 6 | pages = 1667–74 | date = February 2008 | pmid = 18193895 | doi = 10.1021/bi7014597 }}</ref>

[[File:Staphylococcus aureus on TSA.jpg|thumb|''S. aureus'' on [[trypticase soy agar]]:  The strain is producing a yellow pigment [[staphyloxanthin]]. ]]

;Staphylococcal pigments

Some strains of ''S. aureus'' are capable of producing [[staphyloxanthin]] – a golden-coloured [[carotenoid]] [[pigment]].  This pigment acts as a [[virulence factor]], primarily by being a bacterial [[antioxidant]] which helps the microbe evade the [[reactive oxygen species]] which the host immune system uses to kill pathogens.<ref name="staphylotoxin">{{cite journal | vauthors = Clauditz A, Resch A, Wieland KP, Peschel A, Götz F | title = Staphyloxanthin plays a role in the fitness of ''Staphylococcus aureus'' and its ability to cope with oxidative stress | journal = Infection and Immunity | volume = 74 | issue = 8 | pages = 4950–3 | date = August 2006 | pmid = 16861688 | pmc = 1539600 | doi = 10.1128/IAI.00204-06 }}</ref><ref name="JExpMed2005-Liu">{{cite journal | vauthors = Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM, Bastian JF, Fierer J, Nizet V | title = ''Staphylococcus aureus'' golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity | journal = The Journal of Experimental Medicine | volume = 202 | issue = 2 | pages = 209–215 | date = July 2005 | pmid = 16009720 | pmc = 2213009 | doi = 10.1084/jem.20050846 }}</ref>

[[Mutant|Mutant strains]] of ''S. aureus'' modified to lack staphyloxanthin are less likely to survive incubation with an oxidizing chemical, such as [[hydrogen peroxide]], than pigmented strains. Mutant colonies are quickly killed when exposed to human [[Neutrophil granulocyte|neutrophils]], while many of the pigmented colonies survive.<ref name="staphylotoxin" /> In mice, the pigmented strains cause lingering [[abscess]]es when inoculated into wounds, whereas wounds infected with the unpigmented strains quickly heal.{{citation needed|date=December 2022}}

These tests suggest the ''Staphylococcus'' strains use staphyloxanthin as a defence against the normal human immune system.  Drugs designed to inhibit the production of staphyloxanthin may weaken the bacterium and renew its susceptibility to antibiotics.<ref name="JExpMed2005-Liu"/> In fact, because of similarities in the pathways for biosynthesis of staphyloxanthin and human [[cholesterol]], a drug developed in the context of cholesterol-lowering therapy was shown to block ''S. aureus'' pigmentation and disease progression in a [[mouse model|mouse infection model]].<ref name="Science2008-Liu">{{cite journal | vauthors = Liu CI, Liu GY, Song Y, Yin F, Hensler ME, Jeng WY, Nizet V, Wang AH, Oldfield E | title = A cholesterol biosynthesis inhibitor blocks ''Staphylococcus aureus'' virulence | journal = Science | volume = 319 | issue = 5868 | pages = 1391–4 | date = March 2008 | pmid = 18276850 | pmc = 2747771 | doi = 10.1126/science.1153018 | bibcode = 2008Sci...319.1391L }}</ref>

;Resistance to Hypothiocyanous Acid (HOSCN)

''Staphylococcus aureus'' has developed an adaptive mechanism to tolerate [[hypothiocyanous acid]] (HOSCN), a potent oxidant produced by the human immune system.<ref name="Barrett2012">{{cite journal |last1=Barrett |first1=T. J. |last2=Hawkins |first2=C. L. |year=2012 |title=Hypothiocyanous Acid: Benign or Deadly? |journal=Chemical Research in Toxicology |volume=25 |issue=2 |pages=263–273 |doi=10.1021/tx200219s|pmid=22053976 }}</ref><ref name="Loi2023">{{cite journal |last1=Loi |first1=V. Van |last2=Busche |first2=T. |last3=Schnaufer |first3=F. |last4=Kalinowski |first4=J. |last5=Antelmann |first5=H. |year=2023 |title=The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in ''Staphylococcus aureus'' |journal=Microbiology Spectrum |volume=11 |issue=6 |pages=e03252-23 |doi=10.1128/spectrum.03252-23|pmid=37930020 |pmc=10715087 }}</ref> Compared to other methicillin-resistant ''S. aureus'' ([[MRSA]]) strains and bacterial pathogens such as ''[[Pseudomonas aeruginosa]]'', ''Escherichia coli'', and ''[[Streptococcus pneumoniae]]'', ''S. aureus'' exhibits greater resistance to HOSCN.<ref name="Shearer2023">{{cite journal |last1=Shearer |first1=H. L. |last2=Loi |first2=V. V. |last3=Weiland |first3=P. |last4=Bange |first4=G. |last5=Altegoer |first5=F. |last6=Hampton |first6=M. B. |last7=Antelmann |first7=H. |last8=Dickerhof |first8=N. |year=2023 |title=MerA functions as a hypothiocyanous acid reductase and defense mechanism in ''Staphylococcus aureus'' |journal=Molecular Microbiology |volume=119 |issue=4 |pages=456–470 |doi=10.1111/MMI.15035|doi-access=free |pmid=36779383 }}</ref>  

This resistance is linked to the ''merA'' gene, which encodes a flavoprotein disulfide reductase (FDR) enzyme.<ref name="Shearer2023"/> ''S. aureus'' MerA shares similarities with HOSCN reductases from other bacteria, including ''S. pneumoniae'' (50% [[sequence identity]], 66% positives) and RclA in ''[[E. coli]]'' (50% sequence identity, 65% positives).<ref name="Shearer2023"/> These enzymes play a crucial role in [[oxidative stress]] defense by using [[NADPH]] as a [[Cofactor (biochemistry)|cofactor]] to reduce [[disulfide bonds]], thereby mitigating the [[oxidative damage]] caused by HOSCN.<ref name="Shearer2022">{{cite journal |last1=Shearer |first1=H. L. |last2=Pace |first2=P. E. |last3=Paton |first3=J. C. |last4=Hampton |first4=M. B. |last5=Dickerhof |first5=N. |year=2022 |title=A newly identified flavoprotein disulfide reductase Har protects ''Streptococcus pneumoniae'' against hypothiocyanous acid |journal=Journal of Biological Chemistry |volume=298 |issue=9 |pages=102359 |doi=10.1016/J.JBC.2022.102359|doi-access=free |pmid=35952759 |pmc=9483559 }}</ref> This mechanism enhances ''S. aureus'' survival within the host by counteracting the immune system’s oxidative attack.<ref name="Loi2023"/><ref name="Shearer2023"/>  

Functional characterization of MerA has revealed that the amino acid residue Cys43 (C43) is essential for its enzymatic activity against HOSCN.<ref name="Shearer2022"/> Additionally, the expression of ''merA'' in ''S. aureus'' is regulated by the ''hypR'' gene, a transcriptional suppressor that modulates the bacterial response to oxidative stress.<ref name="Shearer2023"/>