Impact of staphylococcal protease expression on the outcome of infectious arthritis

Calander, Ann-Marie; Jonsson, Ing-Marie; Kanth, Anna; Arvidsson, Staffan; Shaw, Lindsey N.; Foster, Simon J.; Tarkowski, Andrej

doi:10.1016/j.micinf.2003.10.015

Cited by 22 publications

(24 citation statements)

References 18 publications

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“…The exoproteases of S. aureus have been proposed as virulence factors during S. aureus infections. Calander and colleagues [29], using wild-type S. aureus strain 8325-4 and its mutants lacking aureolysin, serine protease, and cysteine protease, demonstrated in a murine SA model that inactivation of the exoprotease genes did not affect the frequency or the severity of joint pathology. Intra-articular injection of PGN into murine joints triggered arthritis in a dose-dependent manner [17].…”

Section: Discussionmentioning

confidence: 99%

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et al. 2006

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Infections of body tissue by Staphylococcus aureus are quickly followed by degradation of connective tissue. Patients with rheumatoid arthritis are more prone to S. aureus-mediated septic arthritis. Various types of collagen form the major structural matrix of different connective tissues of the body. These different collagens are degraded by specific matrix metalloproteinases (MMPs) produced by fibroblasts, other connective tissue cells, and inflammatory cells that are induced by interleukin-1 (IL-1) and tumor necrosis factor (TNF). To determine the host's contribution in the joint destruction of S. aureus-mediated septic arthritis, we analyzed the MMP expression profile in human dermal and synovial fibroblasts upon exposure to culture supernatant and whole cell lysates of S. aureus. Human dermal and synovial fibroblasts treated with cell lysate and filtered culture supernatants had significantly enhanced expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-10, and MMP-11 compared with the untreated controls (p < 0.05). In the S. aureus culture supernatant, the MMP induction activity was identified to be within the molecularweight range of 30 to >50 kDa. The MMP expression profile was similar in fibroblasts exposed to a combination of IL-1/TNF. mRNA levels of several genes of the mitogen-activated protein kinase (MAPK) signal transduction pathway were significantly elevated in fibroblasts treated with S. aureus cell lysate and culture supernatant. Also, tyrosine phosphorylation was significantly higher in fibroblasts treated with S. aureus components. Tyrosine phosphorylation and MAPK gene expression patterns were similar in fibroblasts treated with a combination of IL-1/TNF and S. aureus. Mutants lacking staphylococcal accessory regulator (Sar) and accessory gene regulator (Agr), which cause significantly less severe septic arthritis in murine models, were able to induce expression of several MMP mRNA comparable with that of their isogenic parent strain but induced notably higher levels of tissue inhibitors of metalloproteinases (TIMPs). To our knowledge, this is the first report of induction of multiple MMP/TIMP expression from human dermal and synovial fibroblasts upon S. aureus treatment. We propose that host-derived MMPs contribute to the progressive joint destruction observed in S. aureusmediated septic arthritis. Agr = accessory gene regulator; AHO = acute hematogenous osteomyelitis; AMV = avian myeloblastoid virus; AP-1 = activation protein; ATCC = American Type Culture Collection; DMEM = Dulbecco's modified Eagle's medium; ELISA = enzyme-linked immunosorbent assay; ERK = extracellular signal regulated kinase; FBS = fetal bovine serum; GAPDH = glyceraldehyde phosphate dehydrogenase; IFN = interferon; IL = interleukin; IL-1ra = interleukin-1 receptor antagonist; JNK = c-jun N-terminal kinase; LT = lymphotoxin; mAb = monoclonal antibody; MAPK = mitogen-activated protein kinase; MMP = matrix metalloproteinase; MRSA = multidrug-resistant Staphylococcus aureus; OA = osteoarthritis; PCR = polymerase chain re...

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Section: Discussionmentioning

confidence: 99%

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et al. 2006

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“…In this context it is worth reiterating that it is no coincidence that SspB is tightly regulated both at the transcriptional level and at the posttranslational level and that additional control is guaranteed through the unique coexpression of a protease and an inhibitor from the same locus. Significantly, all these regulation mechanisms have evolved for an enzyme which is not even an essential housekeeping protein and has unproven importance as a virulence factor in mouse models of staphylococcal infections (6,55,62). Nevertheless, SspB is conserved in all of the S. aureus clinical isolates investigated to date (24).…”

Section: Discussionmentioning

confidence: 99%

“…The reduced virulence of the sspA mutant is apparently due to the polar effect of the transposon insertion in sspA on the expression of sspB, which encodes a cysteine protease, located downstream in the same operon (55,62). The inference that proteases secreted by S. aureus are crucial virulence factors was contradicted by a recent study which revealed no alteration in S. aureus virulence in a mouse model of septic arthritis when isogenic extracellular protease mutants were tested (6). However, it is typical of S. aureus that different sets of genes are important for showing a virulent phenotype in different models (12,31), and thus the significance of staphopains for S. aureus pathogenicity is still an open question.…”

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confidence: 97%

Cytoplasmic Control of Premature Activation of a Secreted Protease Zymogen: Deletion of Staphostatin B (SspC) in Staphylococcus aureus 8325-4 Yields a Profound Pleiotropic Phenotype

et al. 2005

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The cytoplasmic protein SspC of Staphylococcus aureus, referred to as staphostatin B, is a very specific, tightly binding inhibitor of the secreted protease staphopain B (SspB). SspC is hypothesized to protect intracellular proteins against proteolytic damage by prematurely folded and activated staphopain B (M. Rzychon, A. Sabat, K. Kosowska, J. Potempa, and A. Dubin, Mol. Microbiol. 49:1051-1066, 2003). Here we provide evidence that elimination of intracellular staphopain B activity is indeed the function of SspC. An isogenic sspC mutant of S. aureus 8325-4 exhibits a wide range of striking pleiotropic alterations in phenotype, which distinguish it from the parent. These changes include a defect in growth, a less structured peptidoglycan layer within the cell envelope, severely decreased autolytic activity, resistance to lysis by S. aureus phages, extensively diminished sensitivity to lysis by lysostaphin, the ability to form a biofilm, and a total lack of extracellular proteins secreted into the growth media. The same phenotype was also engineered by introduction of sspB into an 8325-4 sspBC mutant. In contrast, sspC inactivation in the SH1000 strain did not yield any significant changes in the mutant phenotype, apparently due to strongly reduced expression of sspB in the sigma B-positive background. The exact pathway by which these diverse aberrations are exerted in 8325-4 is unknown, but it is apparent that a very small amount of staphopain B (less than 20 ng per 200 g of cell proteins) is sufficient to bring about these widespread changes. It is proposed that the effects observed are modulated through the proteolytic degradation of several cytoplasmic proteins within cells lacking the inhibitor. Seemingly, some of these proteins may play a role in protein secretion; hence, their proteolytic inactivation by SspB has pleiotropic effects on the SspCdeficient mutant.

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“…The Sae-regulated protease aureolysin was found to be a key contributor for this disease by mediating the degradation of PSMs, which in turn triggered osteoblast cell death and bone destruction (168). Of note, aureolysin is not a virulence factors for S. aureus induced septic arthritis (169). …”

Section: Models Requiring Surgerymentioning

confidence: 99%

Mouse models for infectious diseases caused by Staphylococcus aureus

Kim

Missiakas

Schneewind

2014

Journal of Immunological Methods

141

130

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Staphylococcus aureus - a commensal of the human skin, nares and gastrointestinal tract - is also a leading cause of bacterial skin and soft tissue infection (SSTIs), bacteremia, sepsis, peritonitis, pneumonia and endocarditis. Antibiotic-resistant strains, designaed MRSA (methicillin-resistant S. aureus), are common and represent a therapeutic challenge. Current research and development efforts seek to address the challenge of MRSA infections through vaccines and immune therapeutics. Mice have been used as experimental models for S. aureus SSTI, bacteremia, sepsis, peritonitis and endocarditis. This work led to the identification of key virulence factors, candidate vaccine antigens or immune-therapeutics that still require human clinical testing to establish efficacy. Past failures of human clinical trials raised skepticism whether the mouse is an appropriate model for S. aureus disease in humans. S. aureus causes chronic-persistent infections that, even with antibiotic or surgical intervention, reoccur in humans and in mice. Determinants of S. aureus evasion from human innate and adaptive immune responses have been identified, however only some of these are relevant in mice. Future research must integrate these insights and refine the experimental mouse models for specific S. aureus diseases to accurately predict the failure or success for candidate vaccines and immune-therapeutics.

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Impact of staphylococcal protease expression on the outcome of infectious arthritis

Cited by 22 publications

References 18 publications

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Cytoplasmic Control of Premature Activation of a Secreted Protease Zymogen: Deletion of Staphostatin B (SspC) in Staphylococcus aureus 8325-4 Yields a Profound Pleiotropic Phenotype

Mouse models for infectious diseases caused by Staphylococcus aureus

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