Mini Review
Community-associated MRSA: What makes them special?

https://doi.org/10.1016/j.ijmm.2013.02.007Get rights and content

Abstract

While infections with methicillin-resistant Staphylococcus aureus (MRSA) were traditionally restricted to the hospital setting, novel MRSA strains emerged over the last two decades that have the capacity to infect otherwise healthy people outside of the hospital setting. These community-associated (CA-)MRSA strains combine methicillin resistance with enhanced virulence and fitness. Interestingly, CA-MRSA strains emerged globally and from different backgrounds, indicating that the “trade-off” between maintaining sufficient levels of methicillin resistance and obtaining enhanced virulence at a low fitness cost was achieved on several occasions in convergent evolution. However, frequently this process comprised similar changes. First and foremost, all CA-MRSA strains typically carry a novel type of methicillin resistance locus that appears to cause less of a fitness burden. Additionally, acquisition of specific toxin genes, most notably that encoding Panton-Valentine leukocidin (PVL), and adaptation of gene expression of genome-encoded toxins, such as alpha-toxin and phenol-soluble modulins (PSMs), further contributed to the evolution of CA-MRSA. Finally, the exceptional epidemiological success of the USA300 CA-MRSA clone in particular may have been due to yet another gene acquisition, namely that of the speG gene, which is located on the arginine catabolic mobile element (ACME) and involved in detoxifying harmful host-derived polyamines.

Introduction

Antibiotic resistance is a big problem during the treatment of bacterial infections. While antibiotics are an effective means to control such infections, antibiotic overuse triggers the spread of resistant strains in the population. As a result, many strains of dangerous bacterial pathogens nowadays are resistant to antibiotics, with some strains combining even multiple resistances to different antibiotics.

Possibly the most infamous example of an antibiotic-resistant pathogen is Staphylococcus aureus (Lowy, 2003). This bacterium asymptomatically colonizes about a third of the population and may cause moderately severe to severe and occasionally life-threatening infections (Lowy, 1998). Notably, it is the most common cause of nosocomial infections and a leading cause of death in hospitalized patients. This extreme morbidity and mortality is due largely to the fact that many S. aureus strains carry genes that provide resistance to a variety of antibiotics, including the most efficient and widely used anti-staphylococcal drugs.

Penicillin and its derivatives are very effective against staphylococci. However, soon after the introduction of penicillin intro clinical use, penicillin-resistant, penicillinase-containing S. aureus strains spread all over the world (Barber and Rozwadowska-Dowzenko, 1948, Kirby, 1944). As a response to the fact that penicillin became ineffective against many infectious S. aureus strains, the penicillinase-resistant penicillin derivative methicillin was introduced in 1959. However, methicillin-resistant S. aureus (MRSA) was found within a year (Barber, 1961). Beginning in the 1980s, MRSA spread globally to such an extent that many countries now report MRSA rates of 50% or higher among infective S. aureus isolates in hospitals (Diekema et al., 2001). Only some countries, such as the Netherlands and the Scandinavian countries, which have effective search-and-destroy policies and/or control antibiotic overuse, have so far succeeded in keeping MRSA rates at a low level.

Until the mid 1990s, MRSA infections were limited to hospitals, infecting primarily the elderly, very young, and patients with weakened immune systems or undergoing surgery. However, within the last ∼15 years, MRSA outbreaks were reported in healthy individuals without connection to health care institutions, such as sports teams, army recruits, or prisoners (Chambers, 2001). It soon became clear that these infections were due to the rise of new, distinct strains of MRSA, now called CA-MRSA strains. In the present review I will address the question what makes these strains different from hospital-associated (HA-)MRSA, enabling them to spread sustainably in the population and cause disease in otherwise healthy people.

Section snippets

Epidemiology and CA-MRSA disease manifestations

The first well documented CA-MRSA cases appeared in the upper midwestern United States between 1997 and 1999 in children (CDC, 1999). These infections, which were fatal cases of sepsis and severe pneumonia, were caused by strain MW2 (pulsed-field type USA400). In the meantime, strains belonging to pulsed-field type strain USA300 have replaced USA400 strains in the U.S. (Moran et al., 2006), but USA400 CA-MRSA infections are still observed in Alaska (David et al., 2008). While the U.S. has

Antibiotic resistance

With respect to antibiotic resistance, CA-MRSA strains are distinguished from HA-MRSA strains by three characteristics: first, CA-MRSA harbor different types of SCCmec elements, the mobile genetic elements (MGEs) encoding methicillin resistance genes. Traditional SCCmec elements found in HA-MRSA are most frequently of types I, II, and III; in contrast, CA-MRSA have SCCmec elements of types IV and V, which are shorter and thus believed to cause less of a fitness burden (Daum et al., 2002,

Virulence characteristics

The observation that CA-MRSA strains have the capacity to infect otherwise healthy people indicates enhanced virulence. Accordingly, Voyich et al. showed in 2005 that the CA-MRSA strains MW2 and LAC are more virulent in a mouse infection model than common HA-MRSA strains such as COL and MRSA252 (Voyich et al., 2005). Furthermore, these authors found that the enhanced virulence of CA-MRSA strains was accompanied by enhanced survival in human neutrophils, suggesting that the interaction of the

Toxins

The species S. aureus is infamous for producing a plethora of toxins, some of which are found virtually in all S. aureus, while others are linked to MGEs and restricted to a subset of strains. Therefore, a specific toxin repertoire or an enhanced production of toxins appeared as a likely basis for the enhanced virulence characteristics of CA-MRSA. As evasion of neutrophil killing was at least one of the predominant factors assumed to be associated with that enhanced virulence, staphylococcal

Gene expression versus gene acquisition

The evolution of virulence in S. aureus clones and lineages is frequently only analyzed in terms of acquisition or loss of virulence-associated genes. However, significant changes in virulence may arise from minute changes in the genome, for example in regulatory loci such as Agr (DeLeo et al., 2011, Kennedy et al., 2008), which may remain unrecognized in such analyses. PSMs and alpha-toxin are expressed at high levels in CA- compared to HA-MRSA strains (Li et al., 2009), in accordance with the

Fitness

The epidemiological success of pathogenic S. aureus is not solely due to virulence factors in the stricter sense, such as toxins. It is also dependent on factors enhancing what can be called “fitness”, i.e. the capacity to grow and persist in the human host. S. aureus is a colonizer at least in parts of the human population (Wertheim et al., 2005) and infections commonly originate from colonizing strains (von Eiff et al., 2001). Whether this is always true for CA-MRSA infection is not entirely

Conclusions

Recent research revealed that CA-MRSA strains have increased virulence and fitness properties compared to traditional HA-MRSA strains. Mechanistically, this is likely due to a combination of (i) the acquisition of novel genes on MGEs, such as novel SCCmec elements, the PVL-encoding phage or, in case of USA300, ACME, and (ii) adaptations in gene expression, most importantly resulting in enhanced toxin expression (Fig. 1).

The development of high virulence and the acquisition of methicillin

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH.

References (76)

  • J.R. Mediavilla et al.

    Global epidemiology of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA)

    Curr. Opin. Microbiol.

    (2012)
  • J.A. Otter et al.

    The emergence of community-associated methicillin-resistant Staphylococcus aureus at a London teaching hospital, 2000–2006

    Clin. Microbiol. Infect.

    (2008)
  • P.N. Panton et al.

    Staphylococcal toxin

    Lancet

    (1932)
  • S.Y. Queck et al.

    RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus

    Mol. Cell

    (2008)
  • S. Szmigielski et al.

    Leukocidal toxins of staphylococci

    Zentralbl. Bakteriol.

    (1999)
  • H.F. Wertheim et al.

    The role of nasal carriage in Staphylococcus aureus infections

    Lancet Infect. Dis.

    (2005)
  • C. Badiou et al.

    Rapid detection of Staphylococcus aureus Panton-Valentine leukocidin in clinical specimens by enzyme-linked immunosorbent assay and immunochromatographic tests

    J. Clin. Microbiol.

    (2010)
  • M. Barber

    Methicillin-resistant staphylococci

    J. Clin. Pathol.

    (1961)
  • A.H. Bartlett et al.

    Alpha-toxin facilitates the generation of CXC chemokine gradients and stimulates neutrophil homing in Staphylococcus aureus pneumonia

    J. Infect. Dis.

    (2008)
  • S. Bhakdi et al.

    Alpha-toxin of Staphylococcus aureus

    Microbiol. Rev.

    (1991)
  • J. Bubeck Wardenburg et al.

    Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia

    Nat. Med.

    (2007)
  • J. Bubeck Wardenburg et al.

    Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease

    J. Infect. Dis.

    (2008)
  • J. Bubeck Wardenburg et al.

    Vaccine protection against Staphylococcus aureus pneumonia

    J. Exp. Med.

    (2008)
  • CDC

    From the Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus – Minnesota and North Dakota, 1997–1999

    JAMA

    (1999)
  • H.F. Chambers

    The changing epidemiology of Staphylococcus aureus?

    Emerg. Infect. Dis.

    (2001)
  • G.Y. Cheung et al.

    Staphylococcus epidermidis strategies to avoid killing by human neutrophils

    PLoS Pathog.

    (2010)
  • G.Y. Cheung et al.

    Role of the accessory gene regulator agr in community-associated methicillin-resistant Staphylococcus aureus pathogenesis

    Infect. Immun.

    (2011)
  • R.R. Craven et al.

    Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells

    PLoS ONE

    (2009)
  • A.C. Cremieux et al.

    Panton-valentine leukocidin enhances the severity of community-associated methicillin-resistant Staphylococcus aureus rabbit osteomyelitis

    PLoS ONE

    (2009)
  • R.S. Daum et al.

    A novel methicillin-resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds

    J. Infect. Dis.

    (2002)
  • M.Z. David et al.

    Molecular epidemiology of methicillin-resistant Staphylococcus aureus, rural southwestern Alaska

    Emerg. Infect. Dis.

    (2008)
  • P. Del Giudice et al.

    Panton-Valentine leukocidin-positive Staphylococcus aureus strains are associated with follicular skin infections

    Dermatology

    (2011)
  • F.R. DeLeo et al.

    Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus

    Proc. Natl. Acad. Sci. U.S.A.

    (2011)
  • D.J. Diekema et al.

    Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999

    Clin. Infect. Dis.

    (2001)
  • B. Diep

    Relative effects of Panton Valentine Leukocidin, alpha-hemolysin and alpha-type phenol-soluble modulins in pathogenesis of community-associated MRSA necrotizing pneumonia

  • B.A. Diep et al.

    Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men

    Ann. Intern. Med.

    (2008)
  • B.A. Diep et al.

    Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • B.A. Diep et al.

    The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus

    J. Infect. Dis.

    (2008)
  • Cited by (240)

    View all citing articles on Scopus
    View full text