MRSA virulence and spread

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most frequent causes of hospital- and community-associated infections. Resistance to the entire class of β-lactam antibiotics, such as methicillin and penicillin, makes MRSA infections difficult to treat. Hospital-associated MRSA strains are often multi-drug-resistant, leaving only lower efficiency drugs such as vancomycin as treatments options. Like many other S. aureus strains, MRSA strains produce a series of virulence factors, such as toxins and adhesion proteins. Recent findings have shed some new light on the molecular events that underlie MRSA epidemic waves. Newly emerging MRSA clones appear to have acquired phenotypic traits that render them more virulent or able to colonize better, either via mobile genetic elements or via adaptation of gene expression. Acquisition of Panton-Valentine leukocidin genes and increased expression of core genome-encoded toxins are being discussed as potentially contributing to the success of the recently emerged community-associated MRSA strains. However, the molecular factors underlying the spread of hospital- and community-associated MRSA strains are still far from being completely understood, a situation calling for enhanced research efforts in that area.

Fig. 1. Important global MRSA clones

Shown are MRSA lineages or clones that are currently predominant in large geographical locations around the world. Most clones belong to clonal complexes 5 (shown in blue) or 8 (shown in red). Other predominant clones belong to CCs 22, 30, and 45. Although spreading globally, pronounced numbers of CA-MRSA infections are only seen in the U.S., where almost all CA-MRSA infections are caused by clone USA300 (CC8, shown in red).

Fig. 2. Potential factors contributing to the pathogenic success of CA-MRSA

Molecular factors being discussed as potential contributors to the sustained spread and pathogenic success of CA-MRSA, especially the USA300 clone, can be categorized into those facilitating pathogen virulence, fitness, or colonization. CA-MRSA may show unique gene presence after acquisition of genes via MGEs (shown in blue) or increased expression of core genome-encoded genes (shown in red). Increased expression of virulence determinants may at least in part be due to higher activity of the virulence regulator Agr. The PVL genes were acquired by many CA-MRSA strains via acquisition of an MGE, but PVL expression is also dependent on Agr. Both mechanisms may thus account for the discussed exceptional role of PVL in CA-MRSA virulence (shown in purple). In animal models, Agr, α-toxin, PSMα peptides, and SelX showed significant contributions to virulence. In the case of PVL, virulence contribution may depend on the type of infection. The contribution of PVL to skin infections as the most frequent type of CA-MRSA disease is controversial. SCCmec type 4 does not appear to lead to increased fitness compared to other SCCmec types during infection, but its contribution to increased fitness during colonization has not yet been investigated in appropriate models. No animal data are available for the role of speG in infection or colonization.