Diagnosis of sub-clinical cryptic group A streptococcal myonecrosis
EMSL Project ID
48198
Abstract
Invasive group A streptococcal (GAS) infections associated with shock, multi-organ failure, necrotizing fasciitis with myonecrosis, and death emerged worldwide in the mid-1980s prompting an official case definition of Streptococcal Toxic Shock Syndrome (StrepTSS) by the US Centers for Disease Control and Prevention. Despite decades of research on bacterial virulence factors and mechanisms of host defense, and the availability of modern antibiotic regimens and intensive care measures, the incidence of invasive, life-threatening GAS infections has remained relatively constant at ~ 3.5 cases/100,000/year with mortality ranging from 30 – 60%. Survivors often undergo repeated surgeries, including amputation. The average cost of treatment was recently estimated to be ~$60,000/patient. With an annual incidence of hospitalization of 0.5 - 1/100,000, this equates to $90-180 million/year in the US alone. Nearly half of all StrepTSS patients with necrotizing fasciitis/myonecrosis develop deep-seeded infection precisely at the site of minor trauma (bruise, muscle strain) that does not break the skin. Without an obvious portal of entry to provide clinical clues, the correct diagnosis of such “cryptic” GAS infections is often delayed until after shock and organ failure are manifested, leading to extremely high mortality rates (up to 85%) in this group.
To remedy this diagnostic shortfall and improve clinical outcomes, we will combine 1) the well-known ability of GAS to modify host proteins plus 2) the knowledge that injured muscles express unique proteins during regeneration, as the basis for a novel approach to diagnosis. Specifically, we hypothesize that a GAS exotoxin-modified form of a human injury-associated protein circulates in patients during the very earliest stages of cryptic GAS myonecrosis and that this pathogen-modified host protein (PmHP) could be exploited as a diagnostic biomarker to detect infection well before life-threatening complications develop.
We have established a unique animal model of non-penetrating muscle injury with GAS infection that mimics the salient features of cryptic GAS infection. With this model, we have shown that a moderate muscle strain causes GAS to home to the injured site and that administration of a non-selective NSAID significantly augments this process. Thus, we have at our disposal a unique animal model of muscle injury complicated by GAS infection which reproduces key factors contributing to life-threatening cryptic GAS infection. Using this experimental system combined with state-of-the-art proteomic technologies, we will pursue unique biomarkers of this infection that could be developed into a diagnostic test for use early in the disease course - well before the onset of shock and organ failure.
Our proposed project will translate basic science information gained from molecular interaction studies and a systems biology approach into a new, potentially life-saving, clinical diagnostic tool for infection due to an NIAID-designated Group II Re-emerging pathogen, the group A streptococcus. Exploiting our long-term experience in bacterial pathogenesis and extending our existing animal model of cryptic GAS infection to include state-of-the-art proteomics/bioinformatics analyses affords us the unique opportunity to identify biomarkers of cryptic GAS infection and gain insight into molecular mechanisms of host-pathogen interactions.
Project Details
Start Date
2013-11-26
End Date
2016-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Co-Investigator(s)
Team Members
Related Publications
Bryant A, MJ Aldape, CR Bayer, EJ Katahira, L Bond, CD Nicora, TL Fillmore, TRW Clauss, TO Metz, BJM Webb-Robertson, and DL Stevens. 2017. "Effects of delayed NSAID administration after experimental eccentric contraction injury – A cellular and proteomics study." PLoS One 12(12):Article No. e0172486. doi:10.1371/journal.pone.0172486