quantifying-cytotoxicity-staphylococcus-aureus-against-human

Quantifying the Cytotoxicity of <em>Staphylococcus aureus</em> Against Human Polymorphonuclear Leukocytes

Staphylococcus aureus is capable of secreting a wide range of leukocidins that target and disrupt the membrane integrity of polymorphonuclear leukocytes ...

Montana State University

The heme-binding proteins Shp and HtsA are part of the heme acquisition machinery found in Streptococcus pyogenes. The hexacoordinate heme (Fe(II)-protoporphyrin IX) or hemochrome form of holoShp (hemoShp) is stable in air in Tris-HCl buffer, pH 8.0, binds to apoHtsA with a K(d) of 120 +/- 18 microm, and transfers its heme to apoHtsA with a rate constant of 28 +/- 6s(-1) at 25 degrees C, pH 8.0. The hemoHtsA product then autoxidizes to the hexacoordinate hemin (Fe(III)-protoporphyrin IX) or hemichrome form (hemiHtsA) with an apparent rate constant of 0.017 +/- 0.002 s(-1). HemiShp also rapidly transfers hemin to apoHtsA through a hemiShp.apoHtsA complex (K(d) = 48 +/- 7 microM) at a rate approximately 40,000 times greater than the rate of simple hemin dissociation from hemiShp into solvent (k(transfer) = 43 +/- 3s(-1) versus k(-hemin) = 0.0003 +/- 0.00006 s(-1)). The rate constants for hemin binding to and dissociation from HtsA (k'(hemin) approximately 80 microm(-1) s(-1), k(-hemin) = 0.0026 +/- 0.0002 s(-1)) are 50- and 10-fold greater than the corresponding rate constants for Shp (k(hemin) approximately 1.6 microM(-1) s(-1), k(-hemin) = 0.0003 s(-1)), which implies that HtsA has a more accessible active site. However, the affinity of apoHtsA for hemin (k(hemin) approximately 31,000 microm(-1)) is roughly 5-fold greater than that of apoShp (k(hemin) approximately 5,300 microM(-1)), accounting for the net transfer from Shp to HstA. These results support a direct, rapid, and affinity-driven mechanism of heme and hemin transfer from the cell surface receptor Shp to the ATP-binding cassette transporter system.

The mechanism of direct heme transfer from the streptococcal cell surface protein Shp to HtsA of the HtsABC transporter.

Hemo es una fuente de hierro recomendado: de bacterias pat&oacute;genas. Streptococcus equi subespecie equi es un pat&oacute;geno bacteriano que causa estrangula en caballos. Se desconoce si S. equi tiene un transportador de adquisici&oacute;n de hemo.

Identificaci&oacute;n y caracterizaci&oacute;n de la prote&iacute;nas heme SeShp y SeHtsA de Streptococcus equi subespecie equi.

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&#x9274;&#x5B9A;&#x4E0E;&#x8840;&#x7EA2;&#x7D20;&#x7ED3;&#x5408;&#x86CB;&#x767D; SeShp &#x548C; SeHtsA &#x7684;&#x94FE;&#x7403;&#x83CC;&#x94FE;&#x7403;&#x83CC;&#x4E9A;&#x79CD;&#x76F8;&#x7B49;&#x7684;&#x8868;&#x5F81;&#x3002;

Heme is a preferred iron source of bacterial pathogens. Streptococcus equi subspecies equi is a bacterial pathogen that causes strangles in horses. Whether S. equi has a heme acquisition transporter is unknown.

Identification and characterization of the heme-binding proteins SeShp and SeHtsA of Streptococcus equi subspecies equi.

L&#39;h&egrave;me est une source de fer privil&eacute;gi&eacute;e des bact&eacute;ries pathog&egrave;nes. Streptococcus equi sous-esp&egrave;ce equi est un bact&eacute;rie pathog&egrave;ne qui provoque la gourme chez le cheval. Si S. equi a un transporteur d&#39;acquisition h&egrave;me est inconnue.

Identification et caract&eacute;risation de la prot&eacute;ines liant l&#39;h&egrave;me SeShp et SeHtsA de Streptococcus equi sous-esp&egrave;ce equi.

H&auml;m ist eine bevorzugte Eisen-Quelle von bakteriellen Erregern. Streptococcus Equi Unterart Equi ist ein bakterieller Erreger, die W&uuml;rgegriffe verursacht bei Pferden. Ob S. Equi einen H&auml;m-Akquisition-Transporter hat ist unbekannt.

Identifizierung und Charakterisierung von der H&auml;m-bindene Proteine SeShp und SeHtsA von Streptococcus Equi Unterart Equi.

EME &egrave; una fonte di ferro preferito di agenti patogeni batterici. Streptococcus equi sottospecie equi &egrave; un patogeno batterico che provoca adenite in cavalli. Se S. equi &egrave; un trasportatore di acquisizione dell&#39;eme &egrave; sconosciuto.

Identificazione e caratterizzazione di proteine eme-associazione SeShp e SeHtsA di Streptococcus equi sottospecie equi.

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&#x540C;&#x5B9A;&#x304A;&#x3088;&#x3073;&#x30D8;&#x30E0;&#x7D50;&#x5408;&#x86CB;&#x767D;&#x8CEA; SeShp &#x3068;&#x9023;&#x9396;&#x7403;&#x83CC; SeHtsA equi &#x306E;&#x4E9C;&#x7A2E;&#x7B49;&#x3002;

Heme&#xC740; &#xC138;&#xADE0;&#xC131; &#xBCD1;&#xC6D0; &#xCCB4;&#xC758; &#xAE30;&#xBCF8; &#xCCA0; &#xC18C;&#xC2A4;. &#xC5F0;&#xC1C4; &#xC0C1; &#xAD6C; &#xADE0; &#xB3D9;&#xB4F1; &#xC885;&#xC5D0;&#xC11C; &#xB3D9;&#xB4F1; strangles&#xB97C; &#xC77C;&#xC73C;&#xD0A4;&#xB294; &#xC138;&#xADE0;&#xC131; &#xBCD1;&#xC6D0; &#xCCB4;&#xB294; &#xB9D0;&#xC5D0;. S. &#xB3D9;&#xB4F1; heme &#xC218;&#xC9D1; &#xC804;&#xC1A1; &#xB418;&#xC5C8;&#xB294;&#xC9C0; &#xC54C; &#xC218; &#xC788;&#xB2E4;.

&#xC2E0;&#xBD84;&#xC99D;&#xACFC; heme &#xBC14;&#xC778;&#xB529; &#xB2E8;&#xBC31;&#xC9C8; Seshp&#xC640; Sehtsa&#xC758; &#xC5F0;&#xC1C4; &#xC0C1; &#xAD6C; &#xADE0; &#xB3D9;&#xB4F1; &#xC885;&#xC5D0;&#xC11C; &#xB3D9;&#xB4F1;&#xC758; &#xD2B9;&#xC131; &#xBD84;&#xC11D;.

In recent years there has been an increase in the incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in healthy individuals, the cause of which is largely unknown. CA-MRSA primarily causes skin and soft-tissue infections but certain strains are also associated with unusually severe pathology. The purpose of this review is to provide a critical analysis of our current knowledge of virulence factors contributing to skin and soft-tissue infections caused by CA-MRSA.

Community-associated methicillin-resistant Staphylococcus aureus skin infections: advances toward identifying the key virulence factors.

Methicillin-resistant Staphylococcus aureus is problematic both in hospitals and in the community. Currently, we have limited understanding of mechanisms of innate immune evasion used by S. aureus. To that end, we created an isogenic deletion mutant in strain MW2 (USA400) of the saeR/S 2-component gene regulatory system and studied its role in mouse models of pathogenesis and during human neutrophil interaction. In this study, we demonstrate that saeR/S plays a distinct role in S. aureus pathogenesis and is vital for virulence of MW2 in a mouse model of sepsis. Moreover, deletion of saeR/S significantly impaired survival of MW2 in human blood and after neutrophil phagocytosis. Microarray analysis revealed that SaeR/S of MW2 influences expression of a wide variety of genes with diverse biological functions. These data provide new insight into how virulence is regulated in S. aureus and associates a specific staphylococcal gene-regulatory system with invasive staphylococcal disease.

The SaeR/S gene regulatory system is essential for innate immune evasion by Staphylococcus aureus.

This investigation examines the role of the SaeR/S 2-component system in USA300, a prominent circulating clone of community-associated methicillin-resistant Staphylococcus aureus. Using a saeR/S isogenic deletion mutant of USA300 (USA300DeltasaeR/S) in murine models of sepsis and soft-tissue infection revealed that this sensory system is critical to pathogenesis of USA300 during both superficial and invasive infection. Oligonucleotide microarray and real-time reverse-transcriptase polymerase chain reaction identified numerous extracellular virulence genes that are down-regulated in USA300DeltasaeR/S. Unexpectedly, an up-regulation of mecA and mecR1 corresponded to increased methicillin resistance in USA300DeltasaeR/S. 5'-RACE analysis defined transcript start sites for sbi, efb, mecA, lukS-PV, hlb, SAUSA300_1975, and hla, to underscore a conserved consensus sequence within promoter regions of genes under strong SaeR/S transcriptional regulation. Electrophoretic mobility shift assay experiments illustrated direct binding of SaeR(His) to promoter regions containing the conserved consensus sequence. Collectively, the findings of this investigation demonstrate that SaeR/S directly interacts with virulence gene promoters to significantly influence USA300 pathogenesis.

SaeR binds a consensus sequence within virulence gene promoters to advance USA300 pathogenesis.

The heme-binding proteins Shp and HtsA of Streptococcus pyogenes are part of the heme acquisition machinery in which Shp directly transfers its heme to HtsA. Mutagenesis and spectroscopic analyses were performed to identify the heme axial ligands in HtsA and to characterize axial mutants of HtsA. Replacements of the M79 and H229 residues, not the other methionine and histidine residues, with alanine convert UV-vis spectra of HtsA with a low-spin, hexacoordinate heme iron into spectra of high-spin heme complexes. Ferrous M79A and H229A HtsA mutants possess magnetic circular dichroism (MCD) spectra that are similar with those of proteins with pentacoordinate heme iron. Ferric M79A HtsA displays UV-vis, MCD, and resonance Raman (RR) spectra that are typical of a hexacoordinate heme iron with histidine and water ligands. In contrast, ferric H229A HtsA has UV-vis, MCD, and RR spectra that represent a pentacoordinate heme iron complex with a methionine axial ligand. Imidazole readily forms a low-spin hexacoordinate adduct with M79A HtsA with a K(d) of 40.9 muM but not with H229A HtsA, and cyanide binds to M79A and H229A with K(d) of 0.5 and 19.1 microM, respectively. The ferrous mutants rapidly bind CO and form simple CO complexes. These results establish the H229 and M79 residues as the axial ligands of the HtsA heme iron, indicate that the M79 side is more accessible to the solvent than the H229 side of the bound heme in HtsA, and provide unique spectral features for a protein with pentacoordinate, methionine-ligated heme iron. These findings will facilitate elucidation of the molecular mechanism and structural basis for rapid and direct heme transfer from Shp to HtsA.

Spectroscopic identification of heme axial ligands in HtsA that are involved in heme acquisition by Streptococcus pyogenes.

Staphylococcus aureus is an important pathogen that continues to be a significant global health threat because of the prevalence of methicillin-resistant S. aureus strains (MRSA). The pathogenesis of this organism is partly attributed to the production of a large repertoire of cytotoxins that target and kill innate immune cells, which provide the first line of defence against S. aureus infection. Here we demonstrate that leukocidin A/B (LukAB) is required and sufficient for the ability of S. aureus, including MRSA, to kill human neutrophils, macrophages and dendritic cells. LukAB targets the plasma membrane of host cells resulting in cellular swelling and subsequent cell death. We found that S. aureus lacking lukAB are severely impaired in their ability to kill phagocytes during bacteria-phagocyte interaction, which in turn renders the lukAB-negative staphylococci more susceptible to killing by neutrophils. Notably, we show that lukAB is expressed in vivo within abscesses in a murine infection model and that it contributes significantly to pathogenesis of MRSA in an animal host. Collectively, these results extend our understanding of how S. aureus avoids phagocyte-mediated clearance, and underscore LukAB as an important factor that contributes to staphylococcal pathogenesis.

Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis.

This investigation examines the influence of alpha-toxin (Hla) during USA300 infection of human leukocytes. Survival of an USA300 isogenic deletion mutant of hla (USA300Δhla) in human blood was comparable to the parental wild-type strain and polymorphonuclear leukocyte (PMN) plasma membrane permeability caused by USA300 did not require Hla. Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) following infection by USA300, USA300Δhla, and USA300Δhla transformed with a plasmid over-expressing Hla (USA300Δhla Comp) demonstrated this toxin plays a significant role inducing plasma membrane permeability of CD14(+), CD3(+), and CD19(+) PBMCs. Rapid plasma membrane permeability independent of Hla was observed for PMNs, CD14(+) and CD19(+) PBMCs following intoxication with USA300 supernatant while the majority of CD3(+) PBMC plasma membrane permeability induced by USA300 required Hla. Addition of recombinant Hla to USA300Δhla supernatant rescued CD3(+) and CD19(+) PBMC plasma membrane permeability generated by USA300 supernatant. An observed delay in plasma membrane permeability caused by Hla in conjunction with Annexin V binding and ApoBrdU Tunel assays examining PBMCs intoxicated with recombinant Hla or infected with USA300, USA300Δhla, USA300Δhla Comp, and USA300ΔsaeR/S suggest Hla induces programmed cell death of monocytes, B cells, and T cells that results in plasma membrane permeability. Together these findings underscore the importance of Hla during S. aureus infection of human tissue and specifically demonstrate Hla activity during USA300 infection triggers programmed cell death of human monocytes, T cells and B cells that leads to plasma membrane permeability.

Alpha-toxin induces programmed cell death of human T cells, B cells, and monocytes during USA300 infection.

Several prominent bacterial pathogens secrete nuclease (Nuc) enzymes that have an important role in combating the host immune response. Early studies of Staphylococcus aureus Nuc attributed its regulation to the agr quorum-sensing system. However, recent microarray data have indicated that nuc is under the control of the SaeRS two-component system, which is a major regulator of S. aureus virulence determinants. Here we report that the nuc gene is directly controlled by the SaeRS two-component system through reporter fusion, immunoblotting, Nuc activity measurements, promoter mapping, and binding studies, and additionally, we were unable identify a notable regulatory link to the agr system. The observed SaeRS-dependent regulation was conserved across a wide spectrum of representative S. aureus isolates. Moreover, with community-associated methicillin-resistant S. aureus (CA MRSA) in a mouse model of peritonitis, we observed in vivo expression of Nuc activity in an SaeRS-dependent manner and determined that Nuc is a virulence factor that is important for in vivo survival, confirming the enzyme's role as a contributor to invasive disease. Finally, natural polymorphisms were identified in the SaeRS proteins, one of which was linked to Nuc regulation in a CA MRSA USA300 endocarditis isolate. Altogether, our findings demonstrate that Nuc is an important S. aureus virulence factor and part of the SaeRS regulon.

Staphylococcus aureus nuclease is an SaeRS-dependent virulence factor.

The ability of Staphylococcus aureus to infect tissues is dependent on precise control of virulence through gene-regulatory systems. While the SaeR/S two-component system has been shown to be a major regulator of S. aureus virulence, the influence of the host environment on SaeR/S-regulated genes (saeR/S targets) remains incompletely defined. Using QuantiGene 2.0 transcriptional assays, we examined expression of genes with the SaeR binding site in USA300 exposed to human and mouse neutrophils and host-derived peptides and during subcutaneous skin infection. We found that only some of the saeR/S targets, as opposed to the entire SaeR/S virulon, were activated within 5 and 10 min of interacting with human neutrophils as well as α-defensin. Furthermore, mouse neutrophils promoted transcription of saeR/S targets despite lacking α-defensin, and the murine skin environment elicited a distinctive expression profile of saeR/S targets. These findings indicate that saeR/S-mediated transcription is unique to and dependent on specific host stimuli. By using isogenic USA300ΔsaeR/S and USA300Δagr knockout strains, we also determined that SaeR/S is the major regulator of virulence factors, while Agr, a quorum-sensing two-component system, has moderate influence on transcription of the saeR/S targets under the tested physiological conditions. 

The role of innate immunity in promoting SaeR/S-mediated virulence in Staphylococcus aureus.

This investigation examines the influence of α-toxin (Hla) expression by CA-MRSA on host immune cell integrity and cytokine expression during infection of human blood. Flow cytometry analysis of human blood infected by Staphylococcus aureus PFGE type USA300 or a USA300Δhla demonstrated that Hla expression significantly increased plasma membrane permeability of human CD14(+) monocytes. The increased susceptibility of human CD14(+) monocytes to Hla toxicity paralleled the high cell-surface expression on these cell types of ADAM10. USA300 rapidly associated with PMNs and monocytes but not T cells following inoculation of human blood. Transcription analysis indicated a strong up-regulation of proinflammatory cytokine transcription following infection of human blood by USA300 and USA300Δhla. CBAs and ELISAs determined that IL-6, IL-10, TNF-α, IFN-γ, IL-1β, IL-8, and IL-4 are significantly up-regulated during the initial phases of human blood infection by USA300 relative to mock-infected blood but failed to distinguish any significant differences in secreted cytokine protein concentrations during infection by USA300Δhla relative to USA300. Collectively, these findings demonstrate that expression of Hla by USA300 has a significant impact on human CD14(+) monocyte plasma membrane integrity but is not exclusively responsible for the proinflammatory cytokine profile induced by USA300 during the initial stages of human blood infection. 

The impact of α-toxin on host cell plasma membrane permeability and cytokine expression during human blood infection by CA-MRSA USA300.

In addition to the well characterized function of chemokines in mediating the homing and accumulation of leukocytes to tissues, some chemokines also exhibit potent antimicrobial activity. Little is known of the potential role of chemokines in bovine mammary gland health and disease. The chemokine CCL28 has previously been shown to play a key role in the homing and accumulation of IgA antibody secreting cells to the lactating murine mammary gland. CCL28 has also been shown to act as an antimicrobial peptide with activity demonstrated against a wide range of pathogens including bacteria, fungi and protozoans. Here we describe the cloning and function of bovine CCL28 and document the concentration of this chemokine in bovine milk. Bovine CCL28 was shown to mediate cellular chemotaxis via the CCR10 chemokine receptor and exhibited antimicrobial activity against a variety of bovine mastitis causing organisms. The concentration of bovine CCL28 in milk was found to be highly correlated with the lactation cycle. Highest concentrations of CCL28 were observed soon after parturition, with levels decreasing over time. These results suggest a potential role for CCL28 in the prevention/resolution of bovine mastitis. 

Bovine CCL28 Mediates Chemotaxis via CCR10 and Demonstrates Direct Antimicrobial Activity against Mastitis Causing Bacteria.

Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe's success as a human pathogen.

Interaction of Staphylococci with Human B cells.

The ability of Staphylococcus aureus to evade killing by human neutrophils significantly contributes to disease progression. In this study, we characterize an influential role for the S. aureus SaeR/S 2-component gene regulatory system in suppressing monocyte production of tumor necrosis factor alpha (TNF-α) to subsequently influence human neutrophil priming.

Staphylococcus aureus SaeR/S-Regulated Factors Decrease Monocyte-Derived Tumor Necrosis Factor-α to Reduce Neutrophil Bactericidal Activity.

 is a common Gram-positive bacteria that is a major cause of human morbidity and mortality. The SaeR/S two-component sensory system of  is important for virulence gene transcription and pathogenesis. However, the influence of SaeR phosphorylation on virulence gene transcription is not clear. To determine the importance of potential SaeR phosphorylation sites for  virulence, we generated genomic alanine substitutions at conserved aspartic acid residues in the receiver domain of the SaeR response regulator in clinically significant  pulsed-field gel electrophoresis (PFGE) type USA300. Transcriptional analysis demonstrated a dramatic reduction in the transcript abundance of various toxins, adhesins, and immunomodulatory proteins for SaeR with an aspartic acid to alanine substitution at residue 51. These findings corresponded to a significant decrease in cytotoxicity against human erythrocytes and polymorphonuclear leukocytes, the ability to block human myeloperoxidase activity, and pathogenesis during murine soft-tissue infection. Analysis of SaeR sequences from over 8,000 draft  genomes revealed that aspartic acid residue 51 is 100% conserved. Collectively, these results demonstrate that aspartic acid residue 51 of SaeR is essential for  virulence and underscore a conserved target for novel antimicrobial strategies that treat infection caused by this pathogen.

Article	Year
The mechanism of direct heme transfer from the streptococcal cell surface protein Shp to HtsA of the HtsABC transporter. The Journal of biological chemistry\| PubMed ID: 16717094	2006
Identification and characterization of the heme-binding proteins SeShp and SeHtsA of Streptococcus equi subspecies equi. BMC microbiology\| PubMed ID: 17007644	2006
Community-associated methicillin-resistant Staphylococcus aureus skin infections: advances toward identifying the key virulence factors. Current opinion in infectious diseases\| PubMed ID: 18317037	2008
The SaeR/S gene regulatory system is essential for innate immune evasion by Staphylococcus aureus. The Journal of infectious diseases\| PubMed ID: 19374556	2009
SaeR binds a consensus sequence within virulence gene promoters to advance USA300 pathogenesis. The Journal of infectious diseases\| PubMed ID: 20001858	2010
Spectroscopic identification of heme axial ligands in HtsA that are involved in heme acquisition by Streptococcus pyogenes. Biochemistry\| PubMed ID: 20180543	2010
Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis. Molecular microbiology\| PubMed ID: 21255120	2011
Alpha-toxin induces programmed cell death of human T cells, B cells, and monocytes during USA300 infection. PloS one\| PubMed ID: 22574180	2012
Staphylococcus aureus nuclease is an SaeRS-dependent virulence factor. Infection and immunity\| PubMed ID: 23381999	2013
The role of innate immunity in promoting SaeR/S-mediated virulence in Staphylococcus aureus. Journal of innate immunity\| PubMed ID: 23816635	2014
The impact of α-toxin on host cell plasma membrane permeability and cytokine expression during human blood infection by CA-MRSA USA300. Journal of leukocyte biology\| PubMed ID: 24026286	2013
Bovine CCL28 Mediates Chemotaxis via CCR10 and Demonstrates Direct Antimicrobial Activity against Mastitis Causing Bacteria. PloS one\| PubMed ID: 26359669	2015
Interaction of Staphylococci with Human B cells. PloS one\| PubMed ID: 27711145	2016
Staphylococcus aureus SaeR/S-Regulated Factors Decrease Monocyte-Derived Tumor Necrosis Factor-α to Reduce Neutrophil Bactericidal Activity. The Journal of infectious diseases\| PubMed ID: 29272502	2018
Aspartic Acid Residue 51 of SaeR Is Essential for Virulence. Frontiers in microbiology\| PubMed ID: 30619166	2018

Tyler K. Nygaard

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