Relationships between Staphylococcus aureus genetic background, virulence factors, agr groups (alleles), and human disease

Abstract

The expression of most Staphylococcus aureus virulence factors is controlled by the agr locus, which encodes a two-component signaling pathway whose activating ligand is an agr-encoded autoinducing peptide (AIP). A polymorphism in the amino acid sequence of the AIP and of its corresponding receptor divides S. aureus strains into four major groups. Within a given group, each strain produces a peptide that can activate the agr response in the other member strains, whereas the AIPs belonging to different groups are usually mutually inhibitory. We investigated a possible relationship between agr groups and human S. aureus disease by studying 198 S. aureus strains isolated from 14 asymptomatic carriers, 66 patients with suppurative infection, and 114 patients with acute toxemia. The agr group and the distribution of 24 toxin genes were analyzed by PCR, and the genetic background was determined by means of amplified fragment length polymorphism (AFLP) analysis. The isolates were relatively evenly distributed among the four agrgroups, with 61 strains belonging to agr group I, 49 belonging to group II, 43 belonging to group III, and 45 belonging to group IV. Principal coordinate analysis performed on the AFLP distance matrix divided the 198 strains into three main phylogenetic groups, AF1 corresponding to strains of agr group IV, AF2 corresponding to strains of agr groups I and II, and AF3 corresponding to strains of agr group III. This indicated that the agr type was linked to the genetic background. A relationship between genetic background, agr group, and disease type was observed for several toxin-mediated diseases: for instance, agr group IV strains were associated with generalized exfoliative syndromes, and phylogenetic group AF1 strains with bullous impetigo. Among the suppurative infections, endocarditis strains mainly belonged to phylogenetic group AF2 and agr groups I and II. While these results do not show a direct role of the agr type in the type of human disease caused by S. aureus, the agr group may reflect an ancient evolutionary division of S. aureus in terms of this species' fundamental biology.

FIG. 1.

PCO factor map (F1 × F2) of the 198 strains of S. aureus based on the AFLP data. The 198 strains are projected in the F1/F2 plane. This plane, obtained by computation, is defined by the two principal axes of the analysis: F1 explains most of the variance, and the second axis, F2 (orthogonal to F1), explains most of the remaining variance. Phylogenetic groups AF1, AF2, and AF3 are indicated. For clarity, when several strains are projected on the same point, only one is represented.

FIG. 2.

AFLP PCO factor map (F1 × F2) of the 198 strains, split according to the 13 disease types designated A to M: A, generalized exfoliative syndrome; B, bullous impetigo; C, enterotoxin-mediated diseases; D, TSST-1-mediated diseases; E, endocarditis; F, necrotizing pneumonia; G, cellulitis and/or myositis; H, furunculosis; I, osteitis and/or osteomyelitis; J, finger pulp infections; K, arthritis; L, enterocolitis; M, colonization. Numbers 1 to 4 in panels A to M indicate the agr group of each strain. Panel “>Fig. 1<” is a reduction of Fig. 1 showing the axes (F1 and F2) and the positions of the phylogenetic groups (AF1, AF2, and AF3).

FIG. 3.

AFLP PCO factor map (F1 × F2) of the 198 strains of S. aureus as in Fig. 1 split according to the agr groups (agr I to IV). Phylogenetic groups AF1, AF2, and AF3 are indicated.

FIG. 4.

PCA of 19 toxin genes in the 198 S. aureus strains. The variables are projected in the F1/F2 plane (defined as in Fig. 1). In each pair of axes, the variables located in a given direction relative to the origin can be considered positively associated, whereas the variables located in opposite directions can be considered antagonistic. Variables plotted near the origin cannot be interpreted. For example, the five gene toxins seg, sei, sen, sem, and seo can be considered associated with one another and negatively associated with sea. The toxin gene codes are given in Table 1.

FIG. 5.

First factor map (F1 × F2) of the CIA of the 19 toxin genes. This factor map is very similar to the PCA factor map (Fig. 4), with a few exceptions (sea and seb, for example). Genes with similar positions on this map have a similar profile of presence or absence among the 198 strains (as in Fig. 4), but they also belong to strains that have a similar AFLP profile (see Fig. 6).

FIG. 6.

First factor map (F1 × F2) of the CIA of the 198 S. aureus strains. This factor map is very similar to the PCO factor map (Fig. 1), except that the second (vertical) axis is inverted. Phylogenetic group AF1 is in the lower part of the graph, while groups AF2 and AF3 are in the upper part. Strains with similar positions on this map have genes present in the same direction on the map in Fig. 5.