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PERK Pathway Inhibitors Cure Group A Streptococcal Necrotizing Fasciitis in a Murine Model
Aparna Anand1, Abhinay Sharma1, Miriam Ravins1
1Department of Microbiology and Molecular Genetics, The Institute for Medical Research, Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Abstract:
Group A streptococcus (GAS) is a Gram-positive human pathogen that causes invasive infections with mild to life-threatening severity, like toxic shock syndrome, rheumatic heart disease, and necrotizing fasciitis (NF). NF is characterized by a clinical presentation of widespread tissue destruction due to the rapid spread of GAS infection into fascial planes. Despite quick medical interventions, mortality from NF is high. The early onset of the disease is difficult to diagnose because of non-specific clinical symptoms. Moreover, the unavailability of an effective vaccine against GAS warrants a genuine need for alternative treatments against GAS NF. One endoplasmic reticulum stress signaling pathway (PERK pathway) gets triggered in the host upon GAS infection. Bacteria utilize asparagine release as an output of this pathway for its pathogenesis. We reported that the combination of sub-cutaneous (SC) and intraperitoneal (IP) administration of PERK pathway inhibitors (GSK2656157 and ISRIB) cures local as well as systemic GAS infection in a NF murine model, by reducing asparagine release at the infection site. This protocol's methodology is detailed below. This protocol was validated in: Sci Transl Med (2021), DOI: 10.1126/scitranslmed.abd7465.
Insights
PERK pathway inhibitors effectively treat Group A Streptococcus (GAS) necrotizing fasciitis in mice by blocking bacterial asparagine release. This novel therapeutic approach offers hope for treating severe GAS infections lacking vaccines.
Area of Science:
- Microbiology
- Pathogenesis
- Pharmacology
Background:
- Group A Streptococcus (GAS) causes severe invasive infections, including necrotizing fasciitis (NF), with high mortality rates.
- Current treatments for GAS NF are limited, and effective vaccines are unavailable.
- GAS infection triggers the host's PERK endoplasmic reticulum stress pathway, which bacteria exploit by releasing asparagine for pathogenesis.
Purpose of the Study:
- To investigate the therapeutic potential of PERK pathway inhibitors against GAS NF.
- To determine if inhibiting the PERK pathway can reduce bacterial asparagine release and treat GAS infection.
Main Methods:
- Utilized a murine model of GAS necrotizing fasciitis.
- Administered PERK pathway inhibitors (GSK2656157 and ISRIB) via subcutaneous (SC) and intraperitoneal (IP) routes.
- Assessed the reduction of asparagine release at the infection site and overall infection cure.
Main Results:
- Combination therapy with SC and IP administration of PERK inhibitors successfully cured both local and systemic GAS infections in the NF murine model.
- Treatment significantly reduced asparagine release, a key bacterial virulence factor dependent on the PERK pathway.
- The study provides a validated protocol for this therapeutic approach.
Conclusions:
- Inhibiting the PERK pathway is a promising strategy for treating severe GAS infections like NF.
- Targeting host-pathogen interactions, specifically asparagine release mediated by the PERK pathway, offers a novel therapeutic avenue.
- This research supports the development of new treatments for GAS infections in the absence of vaccines.
