Chapter 129. Staphylococcal Infections (Part 3)

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Regulation of Virulence Gene Expression In both toxin-mediated and non-toxin-mediated diseases due to S. aureus, the expression of virulence determinants associated with infection depends on a series of regulatory genes [e.g., accessory gene regulator (agr) and staphylococcal accessory regulator (sar)] that coordinately control the expression of many virulence genes. The regulatory gene agr is part of a quorum-sensing signal transduction pathway that senses and responds to bacterial density. Staphylococcal surface proteins are synthesized during the bacterial exponential growth phase in vitro. In contrast, many secreted proteins, such as α toxin, the enterotoxins, and assorted enzymes, are released during the postexponential...

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Nội dung Text: Chapter 129. Staphylococcal Infections (Part 3)

Chapter 129. Staphylococcal Infections (Part 3) Regulation of Virulence Gene Expression In both toxin-mediated and non-toxin-mediated diseases due to S. aureus, the expression of virulence determinants associated with infection depends on a series of regulatory genes [e.g., accessory gene regulator (agr) and staphylococcal accessory regulator (sar)] that coordinately control the expression of many virulence genes. The regulatory gene agr is part of a quorum-sensing signal transduction pathway that senses and responds to bacterial density. Staphylococcal surface proteins are synthesized during the bacterial exponential growth phase in vitro. In contrast, many secreted proteins, such as α toxin, the enterotoxins, and assorted enzymes, are released during the postexponential growth phase. It has been hypothesized that these regulatory genes serve a similar function in vivo. Successful invasion requires the sequential expression of these different bacterial elements. Bacterial adhesins are needed to initiate colonization
of host tissue surfaces. The subsequent release of various enzymes enables the colony to obtain nutritional support and permits bacteria to spread to adjacent tissues. Studies with mutant strains in which these regulatory genes are inactivated show reduced virulence in several animal models of S. aureus infection. Pathogenesis of Invasive S. aureus Infection Staphylococci are opportunists. For these organisms to invade the host and cause infection, some or all of the following steps are necessary: inoculation and local colonization of tissue surfaces, invasion, evasion of the host response, and metastatic spread. The initiation of staphylococcal infection requires a breach in cutaneous or mucosal barriers. Colonizing strains or strains transferred from other individuals are inoculated into damaged skin, a wound, or the bloodstream. Recurrences of S. aureus infections are common, apparently because of the capacity of these pathogens to survive, to persist in a quiescent state in various tissues, and then to cause recrudescent infections when suitable conditions arise. Nasal Colonization The anterior nares is the principal site of staphylococcal colonization in humans. Colonization appears to involve the attachment of S. aureus to both nasal mucin and keratinized epithelial cells of the anterior nares. Other factors that may contribute to colonization include the influence of other resident nasal flora and
their bacterial density, nasal mucosal damage (e.g., that resulting from inhalational drug use), and the antimicrobial properties of nasal secretions. Inoculation and Colonization of Tissue Surfaces Staphylococci may be introduced into tissue as a result of minor abrasions, administration of medications such as insulin, or establishment of IV access with catheters. After their introduction into a tissue site, bacteria replicate and colonize the host tissue surface. A family of structurally related S. aureus surface proteins referred to as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) plays an important role as a mediator of adherence to these sites. MSCRAMMs such as clumping factor and collagen-binding protein enable the bacteria to colonize different tissue surfaces; these proteins contribute to the pathogenesis of invasive infections such as endocarditis and arthritis by facilitating the adherence of S. aureus to surfaces with exposed fibrinogen or collagen. Although CoNS are classically known for their ability to elaborate a biofilm and colonize prosthetic devices, S. aureus also possesses genes responsible for biofilm formation, such as the intercellular adhesion (ica) locus. Binding to these devices often involves staphylococcal adherence to serum constituents that have coated the device surface. As a result, S. aureus is frequently isolated from biomedical-device infections. Invasion
After colonization, staphylococci replicate at the initial site of infection, elaborating enzymes that include serine proteases, hyaluronidases, thermonucleases, and lipases. These enzymes facilitate bacterial survival and local spread across tissue surfaces, although their precise role in infections is not well defined. The lipases may facilitate survival in lipid-rich areas such as the hair follicles, where S. aureus infections are often initiated. The S. aureus toxin Panton-Valentine leukocidin is cytolytic to PMNs, macrophages, and monocytes. Strains elaborating this toxin have been epidemiologically linked with cutaneous and more serious infections caused by community-associated MRSA. The toxin's biologic role is uncertain. Constitutional findings may result from either localized or systemic infections. The staphylococcal cell wall—consisting of alternating N-acetyl muramic acid and N-acetyl glucosamine units in combination with an additional cell wall component, lipoteichoic acid—can initiate an inflammatory response that includes the sepsis syndrome. Staphylococcal α toxin, which causes pore formation in various eukaryotic cells, can also initiate an inflammatory response with findings suggestive of sepsis.