Corneal Virulence of<i>Staphylococcus aureus</i>in an Experimental Model of Keratitis

Dajcs, Joseph J.; Thibodeaux, Brett A.; Girgis, Dalia O.; O’Callaghan, Richard J.

doi:10.1089/10445490260099656

Cited by 57 publications

(51 citation statements)

References 27 publications

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“…Tissue destruction in S. aureus endophthalmitis results partially from combined effects of several exotoxins that contribute to severity of endophthalmitis by accelerating the rate of retinal damage onset. The toxic effect of the expression of PVL and leukotoxins has been demonstrated in rabbit eye (14), where they (including α-hemolysin) participate in inflammation and virulence (15,(36)(37)(38). Here, we show that HCAbs are also biologically active in vivo by neutralizing the PVL effect in rabbit eye vitreous.…”

Section: Discussionmentioning

confidence: 56%

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

Laventie

Rademaker

Saleh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Panton-Valentine leukocidin (PVL) is a pore-forming toxin associated with current outbreaks of community-associated methicillin-resistant strains and implicated directly in the pathophysiology of Staphylococcus aureus-related diseases. Humanized heavy chain-only antibodies (HCAb) were generated against S. aureus PVL from immunized transgenic mice to neutralize toxin activity. The active form of PVL consists of the two components, LukS-PV and LukF-PV, which induce osmotic lysis following pore formation in host defense cells. One anti-LukS-PV HCAb, three anti-LukF-PV HCAbs with affinities in the nanomolar range, and one engineered tetravalent bispecific HCAb were tested in vitro and in vivo, and all prevented toxin binding and pore formation. Anti-LukS-PV HCAb also binds to γ-hemolysin C (HlgC) and inhibits HlgC/HlgB pore formation. Experiments in vivo in a toxin-induced rabbit endophthalmitis model showed that these HCAbs inhibit inflammatory reactions and tissue destruction, with the tetravalent bispecific HCAb performing best. Our findings show the therapeutic potential of HCAbs, and in particular, bispecific antibodies.

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Section: Discussionmentioning

confidence: 56%

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

Laventie

Rademaker

Saleh

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The proinflammatory and pathological characteristics associated with the administration of purified toxin imply a functional role for the toxin in mediating intraocular pathogenesis. Experiments conducted with live bacteria confirm this supposition, as S. aureus gamma-hemolysin mutants exhibit reduced pathology and inflammation in a keratitis model of ocular infection as well as reduced eyelid inflammation and CFU recovered from infected vitreous fluid (223,224,226). However, hla is believed to contribute to an even greater degree to the pathogenesis of ocular infection and causes significant epithelial erosion during corneal infection (224).…”

Section: Gamma-hemolysin (Hlgab and Hlgcb)mentioning

confidence: 97%

“…The remaining studies evaluating the contribution of gammahemolysin to pathogenesis concern ocular models of infection and inflammation (Table 1) (223)(224)(225)(226). Intraocular injection of purified gamma-hemolysin into rabbit eyes leads to increased inflammation, hemorrhage, swelling, and retinal necrosis (225).…”

Section: Gamma-hemolysin (Hlgab and Hlgcb)mentioning

confidence: 99%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

239

290

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SUMMARY The ability to produce water-soluble proteins with the capacity to oligomerize and form pores within cellular lipid bilayers is a trait conserved among nearly all forms of life, including humans, single-celled eukaryotes, and numerous bacterial species. In bacteria, some of the most notable pore-forming molecules are protein toxins that interact with mammalian cell membranes to promote lysis, deliver effectors, and modulate cellular homeostasis. Of the bacterial species capable of producing pore-forming toxic molecules, the Gram-positive pathogen Staphylococcus aureus is one of the most notorious. S. aureus can produce seven different pore-forming protein toxins, all of which are believed to play a unique role in promoting the ability of the organism to cause disease in humans and other mammals. The most diverse of these pore-forming toxins, in terms of both functional activity and global representation within S. aureus clinical isolates, are the bicomponent leucocidins. From the first description of their activity on host immune cells over 100 years ago to the detailed investigations of their biochemical function today, the leucocidins remain at the forefront of S. aureus pathogenesis research initiatives. Study of their mode of action is of immediate interest in the realm of therapeutic agent design as well as for studies of bacterial pathogenesis. This review provides an updated perspective on our understanding of the S. aureus leucocidins and their function, specificity, and potential as therapeutic targets.

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“…The fact that UAMS-1 does not make a-toxin, yet is virulent in animal models of osteomyelitis (Smeltzer et al, 1997) and septic arthritis (Blevins et al, 2003), is interesting in light of studies indicating that a-toxin makes an important contribution to staphylococcal virulence (Jonsson et al, 1985;Nilsson et al, 1999;Dajcs et al, 2002). While this could reflect the use of different animal models, there has also been a report indicating that the loss of haemolytic activity in S. aureus agr mutants is correlated with increased survival in vivo (Schwan et al, 2003).…”

Section: Transcriptional Profiling Of a Uams-1 Sara Mutantmentioning

confidence: 99%

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Cassat

Dunman

Murphy³

et al. 2006

Microbiology

147

157

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The production of Staphylococcus aureus virulence factors is under the control of complex regulatory circuits. Most studies aimed at defining these regulatory networks have focused on derivatives of the strain NCTC 8325, most notably RN6390. However, all NCTC 8325 derivatives, including RN6390, possess an 11 bp deletion in rsbU. This deletion renders NCTC 8325 derivatives naturally sigma-factor-B deficient. Recent studies have shown that RN6390 is also deficient, in comparison to clinical isolates, with respect to biofilm formation, a process which is important for both pathogenesis and antimicrobial resistance. Based on these considerations, the authors carried out genome-scale transcriptional profiling, comparing RN6390 with the virulent rsbU-positive clinical isolate UAMS-1. The results revealed significant genome-wide differences in expression patterns between RN6390 and UAMS-1, and suggested that the overall transcriptional profile of UAMS-1 is geared toward expression of factors that promote colonization and biofilm formation. In contrast, the transcriptional profile of RN6390 was heavily influenced by RNAIII expression, resulting in a phenotype characterized by increased production of exoproteins, and decreased capacity to form a biofilm. The greater influence of agr in RN6390 relative to UAMS-1 was also evident when the transcriptional profile of UAMS-1 was compared with that of its isogenic sarA and agr mutants. Specifically, the results indicate that, in contrast to NCTC 8325 derivatives, agr plays a limited role in overall regulation of gene expression in UAMS-1, when compared with sarA. Furthermore, by defining the sarA regulon in a biofilm-positive clinical isolate, and comparing the results with transcriptional profiling experiments defining biofilm-associated gene expression patterns in the same strain, the authors identified a sarA-regulated operon (alsSD) that is also induced in biofilms, and demonstrated that mutation of alsSD results in reduced capacity to form a biofilm.

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Corneal Virulence ofStaphylococcus aureusin an Experimental Model of Keratitis

Cited by 57 publications

References 27 publications

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

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