Pathogenic Staphylococci Lessons from Comparative Genomics

Knut Ohlsen, Martin Eckart, Christian Hüttinger, and Wilma Ziebuhr 9.1

Introduction

Staphylococci are gram-positive bacteria usually living as commensals on the skin of mammals and birds. The most important species from the human point of view are Staphylococcus aureus and S. epidermidis. In recent years, both these species have become a serious health problem, causing more than 50% of all nosocomial infections. At the same time, the treatment options to combat infections due to these pathogens have dramatically declined. In particular the emergence and spread of multiresistant strains of methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE) arouses substantial fear in physicians.

Staphylococci are spherical bacteria with a diameter of approx. 1 im. They are nonmotile, do not form spores, and are unencapsulated or form a special type of capsule (approx. 75% of clinical S. aureus isolates form a uronic acid-containing microcapsule). Most species are facultative anaerobes and react positively to cata-lase and benzidine tests. Staphylococci appear under the microscope as grape-shaped clusters, for which reason the Scottish surgeon Ogston named the bacteria in 1881 after the Greek words for grape (staphyle) and berry (kokkos). In a first attempt to classify staphylococci 3 years later, Rosenbach distinguished between the yellow-orange pigmented S. aureus and the white S. albus. The latter was later renamed S. epidermidis. Rosenbach recognized that S. aureus is the pathogenic form responsible for wound infections and furunculosis, and that S. epidermidis is a normal colonizer of the skin [1]. This simple classification reflected for a long time a useful categorization of staphylococci in pathogenic and nonpathogenic forms.

Later again, staphylococci were classified on the basis of their ability to clot plasma and divided into coagulase-positive and coagulase-negative species. Until the early 1970s, the genus Staphylococcus consisted of three species: the coagulase-positive species S. aureus and the coagulase-negative species S. epidermidis and S. saprophyticus. Molecular typing methods and biochemical properties of staphy-lococci have led to the identification of many new staphylococcal species. Currently, 36 species and several subspecies belong to the genus Staphylococcus [2].

Most species are nonpathogenic, but the coagulase-positive species S. aureus, S. intermedius, S. delphini, S. schleiferi subsp. coagulans, and the coagulase-variable species S. hyicus have been recognized as potentially serious pathogens. Until recently, the coagulase-negative staphylococcal species (CoNS) have been regarded as nonpathogenic constituents of the normal microflora in humans, but the proportion of CoNS causing nosocomial infections has been steadily increasing during the last 20 years. S. epidermidis especially is now a leading cause of bacteremia in hospitals [3]. The growth in numbers of infections by S. epidermidis has been paralleled by increased use of prosthetic and indwelling devices and the growing number of immunocompromised patients.

The enormous clinical relevance of staphylococci has driven several genome projects aimed at answering questions about virulence, resistance, epidemiology, genetic flexibility, and physiology. There is substantial hope that understanding the nature of staphylococcal infections can be achieved by comparing the genome sequences of the principal pathogenic species S. aureus with the genomes of less virulent forms such as S. epidermidis and the nonpathogenic species S. carnosus.

In this review, we summarize the findings of comparative genomics based on the availability of six complete S. aureus genomes and two S. epidermidis genomes, focusing on virulence and resistance traits, and discuss the implications of these studies for the evolution of staphylococcal pathogenicity. Not surprisingly, the whole-genome studies revealed that, as has been described for other pathogens, staphylococci have a relative stable core genome encoding factors essential for growth in a specific environment, and a flexible gene pool encoding virulence-associated factors, resistance determinants, and genes that confer gene mobility such as transposons, integrases, and insertion sequences. The flexible part of the genome presumably determines the virulence of a particular strain. This became especially evident through the discovery of several pathogenicity islands which carry superantigen toxins including toxic shock syndrome toxin (tst), enterotoxins (seb, sec, sem, sen, seo), several exotoxins (set cluster), and bacteriophages. However, correlation of a particular disease type with a specific genotype is still a challenge, and much efforts is still needed if we are to understand the complex nature of staphylococcal infections.

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