Necrotizing fasciitis (NF), also known as flesh-eating disease, is a human-specific bacterial infection caused by group A streptococcus (GAS). NF is typified by extensive necrosis of parts of the body's soft tissue and is associated with 30% of patient mortality despite prompt treatments. The current treatment includes drastic surgical debridement of the affected tissue and sometimes partial or total limb amputation. As a result, survivors are facing substantial risk for long-term morbidity and reduced quality of life. Besides rapid surgical intervention, antibiotic administration and supportive care constitute the most critical adjunct therapies in NF. One major challenge in treating severe NF is the time required for diagnosis. However, NF initial symptoms might be blurred and misleading. Therefore, a delayed diagnosis could increase the mortality rate up to 70%. Thus, additional novel treatments against NF are urgently required.
Our earlier studies showed that GAS induces endoplasmic reticulum (ER) stress by delivering streptolysin toxins into infected cells. These toxins force the infected cells to synthesize high amounts of the amino acid-asparagine. Accordingly, GAS utilizes asparagine to increase its virulence and thus to spread rapidly and destroy soft tissue. ER stress is usually mitigated by activating the unfolded protein response (UPR). UPR restores normal functions of the cell by halting protein translation, degrading misfolded proteins, and activating the expression of specific molecules that can assist the cell in promoting recovery of ER function. UPR does so through several intricate signal transduction processes.
In a research published recently at Science Translational Medicine, Profs. Boaz Tirosh and Emanuel Hanski have deciphered the molecular pathway activated explicitly by GAS during UPR to produce asparagine. We hypothesized that blocking this pathway would tilt the NF infection in favor of its host. Utilizing existing specific inhibitors of the identified pathway and mouse model mimicking human NF, we showed that the inhibitors minimized mortality when mice were challenged with a lethal dose of GAS and reduced bacterial counts and lesion size when mice were challenged with a sublethal dose. Inhibitor treatment was also effective in mice when started after the onset of the infection. We hope that our therapeutic strategy can be applied soon to treating devastating NF cases.
Explanation to the image above
The upper panel shows the Microscope images of GAS-infected (left panel) and uninfected (right panel) mouse soft tissues stained with Hematoxylin and Eosin, showing changes of the various mouse soft tissue layers 48 hours after challenge. (Original magnification x100). The fascial plane is swollen because of extensive inflammation and full of GAS microcolonies similar to the histopathology observed in human tissue.
Lower panel. Immunofluorescence micrographs of stained soft tissue obtained 4 and 6 days after mice were infected with GAS and either untreated (left panels) or treated with the PERK inhibitor GSK2656157. This presentation shows that the treatment facilitates neutrophils entry into GAS-occupied fascia, removing the bacteria and healing the tissue.