Reviews and feature article
Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis

https://doi.org/10.1016/j.jaci.2009.10.039Get rights and content

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have emerged as serious health threats in the last 15 years. They are associated with large numbers of atopic dermatitis skin and soft tissue infections, but when they originate from skin and mucous membranes, have the capacity to produce sepsis and highly fatal pulmonary infections characterized as necrotizing pneumonia, purpura fulminans, and postviral toxic shock syndrome. This review is a discussion of the emergence of 3 major CA-MRSA organisms, designated CA-MRSA USA400, followed by USA300, and most recently USA200. CA-MRSA USA300 and USA400 isolates and their methicillin-sensitive counterparts (community-associated methicillin-sensitive S aureus) typically produce highly inflammatory cytolysins α-toxin, γ-toxin, δ-toxin (as representative of the phenol soluble modulin family of cytolysins), and Panton Valentine leukocidin. USA300 isolates produce the superantigens enterotoxin-like Q and a highly pyrogenic deletion variant of toxic shock syndrome toxin 1 (TSST-1), whereas USA400 isolates produce the superantigens staphylococcal enterotoxin B or staphylococcal enterotoxin C. USA200 CA-MRSA isolates produce small amounts of cytolysins but produce high levels of TSST-1. In contrast, their methicillin-sensitive S aureus counterparts produce various cytolysins, apparently in part dependent on the niche occupied in the host and levels of TSST-1 expressed. Significant differences seen in production of secreted virulence factors by CA-MRSA versus hospital-associated methicillin-resistant S aureus and community-associated methicillin-sensitive S aureus strains appear to be a result of the need to specialize as the result of energy drains from both virulence factor production and methicillin resistance.

Section snippets

Superantigens

Superantigens were originally defined by their capacities to induce fever, to amplify the lethal effects of other toxic molecules including LPS,10, 11 and in the case of SEs to cause the emesis seen in staphylococcal food poisoning.12 Their abilities to stimulate T-cell proliferation has been known for a long time,13, 14 but in 1990, Marrack and Kappler15 described the novel mechanism by which superantigens stimulate T cells and macrophages to produce massive amounts of cytokines, leading to

Cytolysins

The cytolysins, as originally described, are hemolytic for red blood cells, but variability occurs in susceptibility dependent on the species source of the red cells. However, it is more likely that the major function of cytolysins is to kill immune cells that are drawn into local areas of infection. It is useful to think of these factors as the second line of defense against the host acting locally, the first line being systemic action of superantigens to interfere with the immune system, and

Atopic dermatitis and S aureus

S aureus is a common commensal organism that colonizes as many as 40% of human beings mainly on mucous membranes.42 The organism often colonizes AD-damaged skin and anterior nares and from these sites may spread to infect any other body sites. Nearly all patients with AD may be colonized with S aureus.43, 44 This is likely the result of a combination of host factors including skin barrier dysfunction as well as impaired host immune responses in AD.45, 46 As well, there are many regulatory

Comparison of exotoxin production by USA200 CA-MRSA versus CA-MSSA

In 1982, Schlievert et al91 showed that menstrual, vaginal mucosal TSS S aureus strains produce less α-toxin and more TSST-1 than skin S aureus isolates. It was hypothesized that high levels of cytolysins are required for producing inflammation to disrupt the intact skin barrier and facilitate S aureus infection. Conversely, production of the same amounts of cytolysins on mucosal surfaces would lead to such strong host responses that the host would either quickly succumb to overwhelming

Comparison of exotoxin production by USA400 CA-MRSA versus CA-MSSA

As S aureus strains colonize human mucous membranes and skin, as observed in patients with AD, the organism is present primarily as thin biofilms of organisms growing on surfaces, rather than as planktonic (broth) cultures. As noted earlier, even in the bloodstream, it appears S aureus quickly becomes walled off from the blood into biofilms through the actions of coagulase and clumping factors.47 The data are consistent with the organism having difficulty producing secreted virulence factors

Conclusions, future research directions, and clinical implications

One purpose of this review was to emphasize that S aureus strains have become selected for their various niches within human beings as a function of secreted virulence factors produced. When they become stressed by the host, as in attempting to survive on the skin versus on mucous membranes, or when they must grow in the presence of antibiotic therapy, as in acquisition of SCC mec DNA, the organisms specialize in production of secreted virulence factors, progressively emphasizing production of

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    Supported by National Institutes of Health grants R01s AI74283, AI73366, and AR41256; U54-AI57153 (Great Lakes Regional Center of Excellence in Biodefense and Emerging Infectious Diseases, where P.M.S. is a member); and contract N01 AI40029 to D.Y.M.L.

    Disclosure of potential conflict of interest: P. M. Schlievert receives research support from the NIH and has provided legal consultation/expert witness testimony in cases related to streptococcal toxic shock syndrome. M. L. Peterson receives research support from the NIH and 3M. D. Y. M. Leung receives research support from the NIH/NIAID, the NIH/NIAMS, and Novartis Pharmaceuticals. The rest of the authors have declared that they have no conflict of interest.

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