Superantigens produced by catheter-associated Staphylococcus aureus elicit systemic inflammatory disease in the absence of bacteremia

Abstract

SAgs, produced by Staphylococcus aureus, play a major role in the pathogenesis of invasive staphylococcal diseases by inducing potent activation of the immune system. However, the role of SAgs, produced by S. aureus, associated with indwelling devices or tissues, are not known. Given the prevalence of deviceassociated infection with toxigenic S. aureus in clinical settings and the potency of SAgs, we hypothesized that continuous exposure to SAgs produced by catheterassociated S. aureus could have systemic consequences. To investigate these effects, we established a murine in vivo catheter colonization model. One centimeter long intravenous catheters were colonized with a clinical S. aureus isolate producing SAgs or isogenic S. aureus strains, capable or incapable of producing SAg. Catheters were subcutaneously implanted in age-matched HLA-DR3, B6, and AE o mice lacking MHC class II molecules and euthanized 7 d later. There was no evidence of systemic infection. However, in HLA-DR3 transgenic mice, which respond robustly to SSAgs, the SSAg-producing, but not the nonproducing strains, caused a transient increase in serum cytokine levels and a protracted expansion of splenic CD4 + T cells expressing SSAg-reactive TCR Vb8. Lungs, livers, and kidneys from these mice showed infiltration with CD4 + and CD11b + cells. These findings were absent in B6 and AE o mice, which are known to respond poorly to SSAgs. Overall, our novel findings suggest that systemic immune activation elicited by SAgs, produced by S. aureus colonizing foreign bodies, could have clinical consequences in humans. J. Leukoc. Biol. 98: 000-000; 2015.Abbreviations: AE˚= mice lacking all MHC class II, B6 = C57Bl/6, DC = dendritic cell, SAg = superantigen, SEA/B/C/D/E = staphylococcal enterotoxin A/B/C/D/E, SEB 2 SA = isogenic S. aureus not producing staphylococcal enterotoxin B, SEB + SA = S. aureus producing staphylococcal enterotoxin B, SSAg = staphylococcal superantigen, TSB = trypticase soy broth, Vb = variable region bThe online version of this paper, found at www.jleukbio.org, includes supplemental information. 0741-5400/15/0098-0001

Superantigen-Producing Staphylococcus aureus Elicits Systemic Immune Activation in a Murine Wound Colonization Model

“…, SEB in our model). In our experiment, as is evident from Figure 4 , the proportion of CD4 + and CD8 + T cells expressing TCR Vβ8 and Vβ6 was significantly different in the spleens of mice challenged with S. aureus SEB+ RN6734/pRN7114 compared to DR3 mice with wounds colonized with SEB− S. aureus RN6734/pRN7116, which was comparable to mice with uninfected wounds ( p < 0.001, p < 0.001; Figure 4 ) [ 17 , 18 ]. This observation combined with our finding that we were not able to culture any bacteria in blood, spleen or any tissue indicated that SEB produced in the skin was able to cause systemic immune activation.…”

“…Histopathological evaluation of tissues from different mice groups showed the presence of inflammatory cell infiltrates in the livers, kidneys and lungs only in mice challenged with SEB+ S. aureus RN6734/pRN7114 compared to uninfected controls. Tissues from mice challenged with SEB− S. aureus RN6734/pRN7116 showed minimal or no inflammation ( Figure 5 ) [ 17 , 18 ]. The presence of these inflammatory changes only in mice challenged with SEB-producing S. aureus RN6734/pRN7114, but not its isogenic RN6734/pRN7116 strain not producing SEB, strongly suggests the involvement of SEB in eliciting this systemic inflammatory process.…”

Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producingStaphylococcus aureus

“…The S. aureus strain IDRL-7420 [RN6734, containing a derivative with a large 3 0 deletion in SEB, pRN5543::seb(b.2) (pRN7116), referred to as SEB-SA], is an isogenic control for IDRL-7419 and does not produce any SAg including SEB. 54,64,65 RN6734 produces a-toxin and d-toxin. 66 We have shown previously that IDRL-7419 produces equivalent levels of SEB compared with clinical isolates 65 Only the SEBCSA, but not the SEB-SA, induces lethal pneumonia in HLA-DR3 transgenic at the inoculum tested, whereas C57Bl/B6 mice are not susceptible to lethal pneumonia.…”

“…54,64,65 RN6734 produces a-toxin and d-toxin. 66 We have shown previously that IDRL-7419 produces equivalent levels of SEB compared with clinical isolates 65 Only the SEBCSA, but not the SEB-SA, induces lethal pneumonia in HLA-DR3 transgenic at the inoculum tested, whereas C57Bl/B6 mice are not susceptible to lethal pneumonia. 54 Experimental pneumonia was induced following our previously published protocol.…”

Mini-Osmotic Pump Infusion Model to Investigate the Systemic Effects of Chronic Continuous Exposure to Staphylococcal Superantigen in Mice

“…This is termed as systemic inflammatory response syndrome and generally culminates in multiple organ dysfunction syndrome, which can be lethal (8). However, in certain clinical situations, chronic exposure to small amounts of SSAg can occur e.g., chronic S. aureus carriers, chronic or recurrent staphylococcal skin and soft tissue infections or catheter-associated biofilm infection (9, 10). The immunopathology ensuing from chronic immune activation mediated by SSAg could be distinct from that resulting from acute exposures.…”