The FCT regions of Streptococcus pyogenes strains encode a variety of cell wall-anchored surface proteins that bind the extracellular matrix of the human host and/or give rise to pilus-like appendages. Strong linkage is evident between transcription-regulatory loci positioned within the FCT and emm regions and the emm pattern genotype marker for preferred infection of the throat or skin. These findings provide a basis for the hypothesis that FCT region gene products contribute to tissue-specific infection. In an initial series of steps to address this possibility, the FCT regions of 13 strains underwent comparative sequence analysis, the gene content of the FCT region was characterized for 113 strains via PCR, and genetic linkage was assessed. A history of extensive recombination within FCT regions was evident. The emm pattern D-defined skin specialist strains were highly homogenous in their FCT region gene contents, whereas the emm pattern A-C-defined throat specialist strains displayed a greater variety of forms. Most pattern A-C strains harbored prtF1 (75%) but lacked cpa (75%). In contrast, the majority of emm pattern D strains had cpa (92%) but lacked prtF1 (79%). Models based on FCT and emm region genotypes revealed the most parsimonious pathways of evolution. Using niche-determining candidate genes to infer phylogeny, emm pattern E strains-the so-called generalists, which lack a strong tissue site preference-occupied a transition zone separating most throat specialists from skin specialists. Overall, population genetic analysis supports the possibility that the FCT region gives rise to surface proteins that are largely necessary, but not always sufficient, to confer tissue site preference for infection.
FCT region genes of Streptococcus pyogenes encode surface proteins that include fibronectin-and collagenbinding proteins and the serological markers known as T antigens, some of which give rise to pilus-like appendages. It remains to be established whether FCT region surface proteins contribute to virulence by in vivo models of infection. In this study, a highly sensitive and ecologically relevant humanized mouse model was used to measure superficial skin infection. Three genes encoding FCT region surface proteins essential for Tserotype specificity were inactivated. Both the ⌬cpa and ⌬prtF2 mutants were highly attenuated for virulence when topically applied to the skin following exponential growth but were fully virulent when delivered in stationary phase. In contrast, the ⌬fctA mutant was virulent at the skin, regardless of its initial growth state. Immunoblots of cell extracts revealed anti-FctA-reactive, ladder-like polymers characteristic of streptococcal pili. In addition, FctA formed a heteropolymer with the putative collagen-binding protein Cpa. The ⌬fctA mutant showed a loss in anti-Cpa-reactive polymers, whereas anti-FctA-reactive polymers were reduced in the ⌬cpa mutant. The findings suggest that both FctA and Cpa are required for pilus formation, but importantly, an intact pilus is not essential for Cpa-mediated virulence. Although it is an integral part of the T-antigen complex, the fibronectin-binding protein PrtF2 is not covalently linked to the FctA-and Cpa-containing heteropolymer derived from cell extracts. The data provide direct evidence that streptococcal T antigens function as virulence factors in vivo, but they also reveal that a pilus-like structure is not essential for the most common form of streptococcal skin disease.Pili can function to mediate bacterial adherence to host surfaces and facilitate horizontal gene transfer (14,31,43). Although well studied among many gram-negative organisms, pilus-like surface structures are becoming increasingly recognized as a component of gram-positive bacteria (26,42,45). Included among pilus-bearing bacteria are at least three species of Streptococcus that are important human pathogens (3,23,24,28).Genes encoding pilus-associated proteins map to the FCT region of Streptococcus pyogenes (28), a highly diversified portion of the genome that contains several well-studied genes (cpa, prtF1, and prtF2) encoding microbial surface cell recognition adhesion matrix molecules (MSCRAMMs) (5,12,21,32). The gene encoding the T6 antigen, which is an antigenic target of a major serological typing scheme, maps to the FCT regions of some isolates, where it forms part of the pilus structure (5, 28, 34). The T6 protein and other FCT region gene products are anchored to the peptidoglycan cell wall via specialized sortases, whose genes also lie within the FCT region (1, 2). Some isolates of S. pneumoniae have a genomic region, called a pathogenicity islet, that is similar in its general layout to the FCT region of S. pyogenes (16,40); at least two of these pneumococcal ...
Primary infection by group A streptococci (GAS) takes place at either the throat or skin of the human host, often leading to pharyngitis or impetigo, respectively. Many GAS strains differ in their preference for throat and skin tissue sites. Previous epidemiological findings show that many of the strains displaying strong tropism for the skin have a high-affinity binding site for plasminogen, located within M protein (PAM), a prominent surface fibril. Plasminogen bound by PAM interacts with streptokinase, a plasminogen activator secreted by GAS, to yield bacterial-bound plasmin activity. In this study, PAM and streptokinase were tested for their roles in infection using an experimental model that closely mimics human impetigo. Inactivation of genes encoding either PAM or streptokinase led to a partial, but significant, loss of virulence in vivo, as measured by net growth of the bacteria and pathological alterations. The relative loss in virulence in vivo was greater for the streptokinase mutant than for the PAM mutant. However, the PAM mutant, but not the streptokinase mutant, displayed a partial loss in resistance to phagocytosis in vitro. The combined experimental and epidemiological data provide evidence that PAM and streptokinase play a key role in mediating skinspecific infection by GAS. In addition, secreted cysteine proteinase activity due to SpeB leads to degradation of streptokinase in stationary phase broth cultures. Since SpeB is also a determinant of tissue-specific GAS infection at the skin, direct interactions between these two proteolytic pathways may constitute an important pathogenic mechanism. An integrated model for superficial infection at the skin is presented.
ABSTRACT. Background. It has been proposed that infection by group A -hemolytic streptococci (GABHS) can trigger acute symptom exacerbations among patients with Tourette's syndrome (TS) or obsessive-compulsive disorder (OCD), via autoimmune mechanisms.Objective. To examine the temporal relationship between newly acquired GABHS infections (and other immunologic indices) and acute exacerbations of tics and obsessive-compulsive symptoms.Methods. Pediatric patients (7-17 years of age) with TS and/or OCD (N ؍ 47) and healthy control subjects (N ؍ 19) were prospectively monitored for newly acquired GABHS infections, nonspecific markers of acute inflammatory responses, and D8/17-reactive cells (a marker of rheumatic fever). Objective monthly ratings of tic and obsessive-compulsive symptom severity were used to determine the timing of symptom exacerbations.Results. The overall rate of acute exacerbations of neuropsychiatric symptoms was 0.56 exacerbations per patient per year. The average rate of new GABHS infections, using a stringent definition, was 0.42 infections per subject per year among patients, compared with 0.28 infections per subject per year for control subjects. The association between symptom exacerbations and new GABHS infections among patients was no greater than that expected on the basis of chance. At baseline, patients demonstrated significantly higher levels of D8/17-reactive cells and neopterin, compared with control subjects, but there was no consistent pattern of change when exacerbation time points were compared with baseline or follow-up time points.Conclusions. The results suggest no clear relationship between new GABHS infections and symptom exacerbations in an unselected group of patients with TS and/or OCD. Pediatrics 2004;113:e578 -e585. URL: http://www. pediatrics.org/cgi/content/full/113/6/e578; Tourette's syndrome, obsessive-compulsive disorder, PANDAS, group A -hemolytic streptococci, D8/17, neopterin, C-reactive protein.ABBREVIATIONS. ADHD, attention-deficit/hyperactivity disorder; ASO, anti-streptolysin O; BRR, B repeat region; CRP, C-reactive protein; CRR, C repeat region; Y-BOCS, Yale-Brown Obsessive-Compulsive Scale; GABHS, group A -hemolytic streptococci; OCD, obsessive-compulsive disorder; OC, obsessive compulsive; PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; RF, rheumatic fever; TS, Tourette's syndrome; YGTSS, Yale Global Tic Severity Scale; IgG, immunoglobulin G.T ic disorders, obsessive-compulsive disorder (OCD), and related conditions affect as many as 3% of children and adolescents. [1][2][3][4][5][6] The factors that contribute to the pathogenesis of these disorders are poorly defined. The hypothesis that infections can modulate the clinical appearance of tic disorders dates from the 1800s. 7 The past decade has seen the reemergence of the hypothesis that postinfectious immune mechanisms account for at least some cases of Tourette's syndrome (TS) and OCD.It is well known that group A -hemolytic streptococci (GABHS...
Transcription of several key virulence factors of Streptococcus pyogenes is under the control of Mga and Nra/RofA. In an M serotype 49 (M49) strain, Nra is a negative regulator of pilus gene transcription; also, Nra represses mga expression, leading to downregulation of the M protein surface fibril and secreted cysteine protease SpeB. In this report, the role of Nra in the virulence of an M53 classical skin strain was investigated. In contrast to the case for the M49 strain, Nra functions as a positive regulator of pilus gene transcription in the M53 strain, and inactivation of nra leads to loss of virulence in a humanized mouse model of superficial skin infection. Furthermore, Nra has no measurable effect on mga transcription in the M53 strain; this finding is further supported by a lack of detectable Nra effects on M protein-and SpeB-dependent phenotypes. Whereas MsmR is reported to activate nra and pilus gene transcription in the M49 strain, in the M53 strain it acts as a repressor of these genes. In both strains, MsmR and Nra form a feed-forward loop network motif for pilus gene transcription, but their effects have opposite signs. The findings demonstrate key strain-specific differences in the transcriptional circuitry governing virulence gene expression in S. pyogenes and its impact on pathogenesis.Pilus surface structures were recently identified as potentially important virulence factors for several species of pathogenic streptococci and closely related organisms, such as en-
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