Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus

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Abstract

Although Staphylococcus aureus is a bacterial species of medical significance, only approximately 30% of all humans carry staphylococcal cells persistently but asymptomatically in their nasopharynx and/or other body sites. This goes largely unnoticed by the host, which shows that in the natural situation the human ecosystem is hospitable or at least receptive to the bacteria and that by a process of co-evolution this has lead to a state of mutual acceptance or tolerance. However, upon disturbance of this balanced, neutral state, localized or disseminated invasive infection can occur. Unfortunately, the events leading to infection are still largely unknown and especially the causal events leading to the transition from colonization to infection are ill-defined in vivo. Whether certain genotypes of S. aureus are more prone to colonise and/or infect humans is still quite heavily debated. The genetic population structure of S. aureus has been largely solved by using a number of different DNA polymorphism-interrogating laboratory methods. However, even this major effort has not (yet) revealed major clues with respect to colonisation and infection potency of the clonal lineages that were thus identified, except for the fact that certain lineages are highly epidemic. The overall picture is that in principle all S. aureus strains can become invasive given the proper circumstances. What these, primarily host-defined circumstances are is still enigmatic. However, a large variety of staphylococcal virulence and colonization factors have been identified as well as a number of host’ colonisation and infection susceptibility traits. How these are specifically involved in colonisation and infection has been experimentally substantiated in only a limited number of cases. The present review paper will explore the relevance of these and other, for instance environmental factors that define the colonisation or infection state in humans. When the nature of these states would be known in more detail, this knowledge could be used to design novel and empirical, knowledge-driven means of preventing colonisation from proceeding into S. aureus infection.

Introduction

Staphylococcus aureus was discovered in Aberdeen, Scotland, in 1880 by the surgeon Sir Alexander Ogston. He systematically viewed stained slide preparations of pus from patients with post-operative wound suppuration and abscesses under a microscope and observed grape-like clusters of bacteria, which he therefore named Staphylococcus from the Greek expression staphylé (a “bunch of grapes”) (Ogston, 1882). In 1884, Rosenbach was able to isolate and grow these bacteria from abscesses and called them Staphyloccocus aureus because of the yellow-orange or “gold” pigmented appearance of the colonies, “aureus” meaning golden in Latin (Rosenbach, 1884). Subsequently, S. aureus was demonstrated to be a major human pathogen capable of causing a wide range of infections, from relatively mild skin infections such as folliculitis and furunculosis to life-threatening conditions, including sepsis, deep abscesses, pneumonia, osteomyelitis, and infective endocarditis (Lowy, 1998, Moreillon et al., 2005). S. aureus is currently part of the genus Staphylococcus, which contains more than 30 species. S. aureus is by far the most human-pathogenic species in the genus Staphylococcus. In contrast to most other Staphylococcus species, S. aureus is capable of being pathogenic in the absence of overt predisposing host conditions such as general immune suppression or local immune-deficiency due to the presence of foreign body material (Moreillon et al., 2005, van Belkum and Melles, 2005).

Numbers of both community- and hospital-acquired (CA and HA) S. aureus infections have increased over the past 25 years (Lowy, 1998, Staphylococcus Laboratory, 2004, Steinberg et al., 1996). S. aureus ranks second as the cause of nosocomial blood stream infections that lead to increased morbidity, mortality, length of hospital stay, and costs (Pittet and Wenzel, 1995, Richards et al., 2000, Wisplinghoff et al., 2004, Wertheim et al., 2004). S. aureus has demonstrated extensive adaptability and has developed or acquired resistance mechanisms to almost all antibiotics that were introduced over the past decades. Epidemic methicillin-resistant S. aureus (E-MRSA) strains have emerged and novel strains are still emerging regularly. Currently, many of these strains pose a major problem in hospitals and other medical care institutions all over the world. More recently, highly pathogenic MRSA strains have apparently established themselves in the community outside the hospital setting and these strains are again causing serious infections in otherwise healthy individuals (Fridkin et al., 2005, Tristan et al., 2007, Gonzalez et al., 2005, Moran et al., 2006). Some determinants for this apparently enlarged infectious potential have been identified but there surely still is a lack of a clear and complete explanation for this infectious potency of the strains involved.

In apparent contrast with its infectious potential, S. aureus normally is a ubiquitous but relatively innocent commensal and colonizer of the skin and mucosa of humans and several animal species (Moss et al., 1948, Lowy, 1998, Wertheim et al., 2005b). Although multiple body sites can be colonized in human beings, the anterior nares (foremost parts of the nose, covered by fully keratinized squamous epithelium containing hair follicles) are the most frequent carriage site for S. aureus (Aly and Levit, 1987, Hoefnagels-Schuermans et al., 1999). The mechanisms leading to S. aureus nasal carriage appear to be multi-factorial. Bacterial factors (e.g. staphylococcal toxins and cell wall-associated proteins) (Lowy, 1998, Weidenmaier et al., 2004), environmental factors (e.g. hospitalization and crowding) (Peacock et al., 2003, Bogaert et al., 2004, Goslings and Buchli, 1958) as well as host susceptibility factors (e.g. immune suppression or other serious underlying diseases) play an important role (Bogaert et al., 2004, Williams, 1963). Nasal colonization of S. aureus in human beings can be viewed as the net result of repellent and attracting forces that can be imposed by either of the interacting parties. Obviously, an optimal ecological fit between host and bacteria must be essential for long term colonization. This precise fit must have developed through long term co-evolutionary processes.

Interestingly, nasal carriage appears to play a key role in the epidemiology and pathogenesis of infection (Kluytmans et al., 1997, Peacock et al., 2001). It must be admitted, however, that the clinical relevance of throat or perineal carriage has not been as extensively investigated (Acton et al., 2008). The association between S. aureus nasal carriage and staphylococcal disease was first reported in 1931 on the basis of a study on predisposing factors of furunculosis, quite some time after the recognition of the significant infectious potential of S. aureus (reviewed by Solberg in 1965). Nasal application of an anti-staphylococcal drug temporarily decolonizes the nose and other body sites, which prevents such infectious episodes (Perl et al., 2002). Furthermore, several studies have confirmed that the majority of the (nosocomial) S. aureus infections are of endogenous origin (i.e. the nasal S. aureus strain and the infecting strain share the same phage type or genotype) (Luzar et al., 1990, Von Eiff et al., 2001, Yu et al., 1986). Nasal carriage increases the risk of nosocomial auto-infection by a factor three (Wertheim et al., 2004). This poses a clear warning that S. aureus nasal carriage should be taken seriously.

It is obvious that S. aureus is able to interact with its host in a wide variety of manners. This requires the availability and usage of bacterial colonisation factors on the one hand and host's susceptibility or resistance features on the other. These features, including environmental factors such as co-colonisation with other bacterial species and invasive surgical procedures leaving large wounds, need to be understood in order to develop innovative and general measures to counteract colonization. This review will describe the current state of affairs concerning the population structure and population dynamics of S. aureus as a clinically important bacterial species and, most importantly, the interaction between S. aureus and its human host during colonisation and infection. For that reason first the technologies used for population structure mapping will be described, in combination with a description of the current opinion on the nature of this structure and associated dynamics. Subsequently, virulence factors, environmental features (bacterial interference) and host determinants of carriage and infection will be defined in more detail.

Section snippets

Technical aspects of molecular typing and molecular evolution of S. aureus

It is essential to document whether effective colonisation and infection is limited to certain individual bacterial isolates or to major clusters of strains. In the first scenario the selective presence or absence of genes probably is important for the processes to develop. When major clusters are identified there must be components common to these strains and quite generally present in the population that define colonisation or invasion success. Genetic profiling of invasive or colonising

Staphylococcal virulence factors important in the development of invasive disease

Many microbial features have been implicated in the host pathogen interaction. Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), e.g. clumping factor B and S. aureus surface protein SasG, were demonstrated to be adhesins involved in nasal colonization (O’Brien et al., 2002, Roche et al., 2003). In addition, a recent study of mutant strains defective in wall teichoic acid (WTA) in a rat model of nasal colonization also implicated WTA in colonization (Weidenmaier et

Bacterial interference: an “environmental” determinant of staphylococcal carriage

Bacterial interference has been postulated to be a major determinant of the S. aureus carrier or, rather, non-carrier state. When an ecological niche is already occupied by certain bacteria, other bacteria do not seem to have the means to replace this resident bacterial population (Bibel et al., 1983). The resident flora interferes and protects against acquisition of new strains, and must be reduced or eliminated before other bacteria can successfully “interfere” with the resident bacterial

Host factors

The anterior nares (of the nose) are the primary ecological reservoir of S. aureus in humans (Moss et al., 1948), and it has been suggested that most infections result from endogenous nasal carriage (Luzar et al., 1990, Nguyen et al., 1999, Von Eiff et al., 2001, Wertheim et al., 2005a, Wertheim et al., 2005b, Wertheim et al., 2006, Yu et al., 1986). Longitudinal studies show that about 20% of individuals are persistent S. aureus nasal carriers, approximately 30% are intermittent carriers, and

Concluding remarks

In conclusion, the population structure of S. aureus carried by people in the community at large has been largely solved. Evidence was generated that essentially any S. aureus genotype carried by humans can transform into a life-threatening human pathogen but that certain clones are more virulent than others. This additional virulence can be associated with differences in the gene complement as defined by core-variable and variable domains in the staphylococcal genome. Such differences will

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    Present address: Oxford University Clinical Research Unit, National Institute for Infectious Tropical Diseases, Bach Mai Hospital, Hanoi, Vietnam.

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