The length of the protein A polymorphic region regulates inflammation: impact on acute versus chronic staphylococcal disease.

GAROFALO AILIN; GIAI CONSTANZA; LATTAR SANTIAGO; SORDELLI DANIEL; GOMEZ MARISA

Congreso; Gordon Research Conference, Staphylococcal Diseases; 2011

The length of the protein A polymorphic region regulates inflammation: impact on acute versus chronic staphylococcal disease.  Ailin Garofalo, Constanza Giai, Santiago Lattar, Daniel Sordelli and Marisa Gómez.  Staphylococcus aureus is a major human pathogen that causes a broad range of infections with high morbidity and mortality.  The increase in the prevalence of hospital and community acquired methicillin-resistant strains have raised an important concern in public health.  S. aureus pathogenesis is determined by the action of many virulence factors that mediate adhesion, inflammation and tissue damage. Among these virulence factors, protein A (SpA) is a 42 kDa conserved surface protein present in the vast majority of human isolates that plays a critical role in the development of pneumonia.  SpA induces airway inflammation through the activation of TNF-α signaling via the IgG binding domains and the induction of type I IFN by the polymorphic carboxiterminal region. The polymorphic region, named Xr, consist of a variable number (1 to 22) of 24 bp short sequence repeats (SSR).  These polymorphisms are generated by deletion, duplication and point mutation and have been extensively used as epidemiological tool for S. aureus molecular typing. The variability in the number of protein A SSRs in S. aureus clinical isolates suggests a potential role for the length of the Xr region in pathogenesis. Based on the ability of the Xr region to initiate IFN-β mediated responses and the role of this signaling cascade in S. aureus virulence, the aim of this study was to determine whether the number of SSRs in the Xr region could modulate the inflammatory response induced by protein A and the consequences in the pathogenesis of staphylococcal diseases.  Using macrophages and airway epithelial cells grown in vitro and mouse models of pneumonia and systemic inflammation, we demonstrated that the link between the highly conserved polymorphic region of SpA and S. aureus virulence is the dose-response effect in the activation of IFN-β mediated signaling according to the number of SSRs. The minimum number of SSRs required to activate type I IFN, and downstream regulated genes such as IL-6 and CXCL10, varied between airway epithelial cells and macrophages.  This finding indicates that different cell types have distinct threshold levels of activation by protein A.  We analyzed the spa type of 150 S. aureus isolates from[W1]  patients with acute (n=83) or chronic (n=67) infection and determined that a significant proportion (23/67) of isolates from patients with chronic osteomyelitys carried seven or less SSRs compared to the corresponding proportion in isolates from patients with acute infections (7/83) (p < 0.001, Fisher exact test).  Moreover, there was an inverse correlation between the number of repeated sequences and the time of chronic disease evolution.  The link between the number of repeats and the strength of the IFN-β mediated inflammatory response induced by protein A showed in this study may explain the association between longer polymorphic spa regions and complicated outcome of S. aureus infections.  On the other hand, given the importance of IFN signaling to eradicate S. aureus it seems that loss of SSRs during the course of infection could represent an advantageous mechanism to adapt and persist in the host.