Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus.
In recent years, there has been a dramatic increase in the incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. MW2 (pulsed-field type USA400), the prototype CA-MRSA strain, is highly virulent and has enhanced ability to evade killing by neutrophils. Although progress has been made, the molecular basis for enhanced virulence of CA-MRSA remains incompletely defined. To that end, we studied resistance of MW2 to key microbicides of human neutrophils. Hydrogen peroxide (H2O2), hypochlorous acid, and azurophilic granule proteins had significant bacteriostatic but limited staphylocidal activity toward MW2 under the conditions tested. An MW2-specific microarray revealed common changes in S. aureus gene expression following exposure to each microbicide, such as up-regulation of transcripts involved in gene regulation (e.g., saeRS and kdpDE) and stress response. Azurophilic granule proteins elicited the greatest number of changes in MW2 transcripts, including up-regulation of mRNAs encoding multiple toxins and hemolysins (e.g., hlgA, hlgB, hlgC, hla, lukS-PV, lukF-PV, sec4, and set17-26). Notably, H2O2 triggered up-regulation of transcripts related to heme/iron uptake (e.g., isdA, isdB, and isdCDEFsrtBisdG), and an isogenic isdAB-negative strain of MW2 had increased susceptibility to H2O2 (p<0.001) and human neutrophils (p<0.05) compared with the wild-type parental strain. These findings reveal a S. aureus survival response wherein Iron-regulated surface determinant (Isd) proteins are important for resistance to innate host defense. Collectively, the data provide an enhanced view of the mechanisms used by S. aureus to circumvent destruction by the innate immune system.
Palazzolo-Ballance
Amy M
AM
Laboratory of Human Bacterial Pathogenesis, Research Technologies Section, Genomics Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Reniere
Michelle L
ML
Braughton
Kevin R
KR
Sturdevant
Daniel E
DE
Otto
Michael
M
Kreiswirth
Barry N
BN
Skaar
Eric P
EP
DeLeo
Frank R
FR
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000235:genetics; D001427:Bacterial Toxins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D017714:Community-Acquired Infections / Q000276:immunology* / Q000382:microbiology*; D015870:Gene Expression / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial; D006460:Hemolysin Proteins / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000494:pharmacology; D007113:Immunity, Innate; D007501:Iron; D016106:Methicillin Resistance; D009504:Neutrophils / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D027682:Cation Transport Proteins; D006460:Hemolysin Proteins; C512791:IsdA protein, Staphylococcus aureus; C510010:IsdB protein, Staphylococcus aureus; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D007501:Iron