A Pathogen's Swiss Army Knife

by Maren von Köck­ritz-Blick­wede

Staphy­lo­coc­cus au­reus is an amaz­ingly im­pres­sive bug that end­lessly fas­ci­nates and wor­ries mi­cro­bi­ol­o­gists. It has an ex­cep­tional abil­ity to ex­ploit host im­mune func­tions, thereby caus­ing a wide range of life-threat­en­ing in­fec­tions. For more than 40 years, new dis­cov­er­ies about its vir­u­lence po­ten­tial have been made at a steadily in­creas­ing pace.

Mech­a­nisms by which staph sub­verts in­nate im­mune de­fenses. Source

Re­cently, the ti­tle of a new pa­per in the Jour­nal of Bac­teriology caught my at­ten­tion: "Pro­tein A‑mediated mul­ti­cel­lu­lar be­hav­ior in Staphy­lo­coc­cus au­reus." This pa­per demon­strates the mul­ti­fac­eted roles of but one staphy­lo­coc­cal vir­u­lence fac­tor, namely Pro­tein A. This vir­u­lence fac­tor was the first sur­face pro­tein of S. au­reus to be iden­ti­fied in 1966. It is reg­u­lated mainly by a two-com­po­nent global reg­u­la­tory sys­tem called agr (for "ac­ces­sory gene reg­u­la­tory sys­tem"). Pro­tein A is pri­mar­ily known for its abil­ity to bind im­munoglob­u­lins. But where does it bind? Im­munoglob­u­lin mol­e­cules con­sist of two ends, Fab, which binds to anti­gens, and Fc, which sticks to op­sonins (the pro­teins that fa­cil­i­tate phago­cy­to­sis). When Pro­tein A on the staph sur­face binds to the Fc end, it makes it in­ac­ces­si­ble to the op­sonins, thus im­pair­ing phago­cy­to­sis of the bac­te­ria. Thus, Pro­tein A thwarts the phago­cytic sys­tem by keep­ing the staph from be­ing en­gulfed and sub­se­quently killed by the im­mune cells. Like many other bac­te­r­ial vir­u­lence fac­tors, Pro­tein A is a splen­did mech­a­nism to com­bat the im­mune re­sponse. Sev­eral stud­ies have demon­strated that pro­tein A is im­por­tant in staphy­lo­coc­cal vir­u­lence. For ex­am­ple, Pro­tein A‑defective mu­tants ex­hibit re­duced vir­u­lence in mouse mod­els of arthri­tis, sep­ticemia, and skin ab­scesses.

Pro­tein A as a multi-func­tional vir­u­lence fac­tor. Court­esy of Maren von Köck­ritz-Blick­­wede

Later on, Pro­tein A was found to have other prop­er­ties that mod­ify bi­o­log­i­cal re­sponses. For ex­am­ple, it binds to hu­man von Wille­brand fac­tor (vWF), an im­por­tant glyco­protein that me­di­ates platelet ad­he­sion at the site of en­dothelial dam­age. In this way, Pro­tein A fa­cil­i­tates the ad­herence of S. au­reus to vWF-coated sur­faces such as en­dovascular catheters. Pro­tein A can also stim­u­late inflam­mation in the lung (and there­fore tis­sue dam­age) by bind­ing to a re­cep­tor for tu­mor necro­sis fac­tor 1 (TNFR‑1) that is widely dis­trib­uted on the air­way ep­ithe­lium. This in­ter­ac­tion has been shown to play a cen­tral role in the patho­gen­e­sis of staphy­lo­coc­cal pneu­mo­nia.

Ad­di­tion­ally, Pro­tein A was re­cently shown to crip­ple hu­moral (an­ti­body-me­di­ated) im­mu­nity. It can bind to the re­gion on the sur­face of B lym­pho­cytes called V_H3 that is ad­ja­cent to the anti­gen-bind­ing do­main of ex­posed IgM mol­e­cules. Cells bear­ing the Pro­tein A‑V_H3 IgM com­plex are now stim­u­lated to pro­lif­er­ate and un­dergo apop­to­sis, which leads to a sig­nif­i­cant re­duc­tion of the reper­toire of po­ten­tial an­ti­body-se­cret­ing B cells in the spleen and bone mar­row. This mat­ters, be­cause in­di­vid­u­als who have suf­fered from staph in­fec­tions are usu­ally not pro­tected from re­oc­cur­rence since they can­not mount a strong an­ti­body re­sponse.

Elec­tron mi­cro­graph of S. au­reus aggre­gates cour­tesy of Man­fred Ro­hde, Hemholtz-Cen­ter for In­fec­tion Re­search, Braun­schweig, Ger­many

And now, Merino et al. have found a novel func­tion of this pro­tein: it pro­motes bac­te­r­ial ag­gre­ga­tion and the for­ma­tion of biofilms. The au­thors demon­strate that over­ex­pres­sion of Pro­tein A in an agr-neg­a­tive vari­ant of S. au­reus leads to cell ag­gre­ga­tion and biofilm for­ma­tion. In­ter­est­ingly, ad­di­tion of sol­u­ble Pro­tein A to the growth medium also in­duces ag­gre­ga­tion and biofilm develop­ment, sug­gest­ing that this pro­tein need not be co­va­lently linked to the cell wall to pro­mote mul­ti­cel­lu­lar be­hav­ior. These au­thors used a mouse sub­cu­ta­neous for­eign de­vice in­fec­tion model to show that Pro­tein A sig­nif­i­cantly con­tributed to the de­vel­op­ment of biofilm-re­lated in­fections in vivo. The de­tailed mech­a­nisms in­volved re­main to be de­ter­mined. But who knows? Fur­ther inves­tigation may re­veal yet more un­sus­pected im­munomod­u­la­tory roles for this par­tic­u­lar vir­u­lence fac­tor.

All of these stud­ies pro­vide ev­i­dence for the con­tri­bu­tion of pro­tein A to the suc­cess of S. au­reus as a hu­man pathogen. This is an ex­cep­tional vir­u­lence fac­tor, a sin­gle pro­tein that can tar­get mul­ti­ple im­muno­log­i­cally im­por­tant processes. It is prob­a­bly not a co­in­ci­dence that it is among the most highly con­served staph vir­u­lence fac­tors, or that its level of ex­pres­sion is sig­nif­i­cantly in­creased in staph iso­lated from in­va­sive hu­man in­fec­tions. Maybe we should pay even more at­ten­tion to it. That which makes for suc­cess might also make for vul­ner­a­bil­ity – a po­ten­tial tar­get for new strate­gies of dis­ease pre­ven­tion or treat­ment.

Maren von Köck­ritz-Blick­wede is a post-doc­toral awardee of the Deutsche Gesellschaft der Natur­forscher Leopold­ina (Halle, Ger­many), work­ing in Vic­tor Nizet's lab at the UCSD School of Med­i­cine. Her on­go­ing fas­ci­na­tion with S. au­reus be­gan with her PhD the­sis in Neustadt/Mariensee, Ger­many, on an­tibi­otic-de­pen­dent mod­u­la­tion of staphy­lo­coc­cal vir­u­lence prop­er­ties.