Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine

Aparna Anand, Abhinay Sharma, Miriam Ravins, Debabrata Biswas, Poornima Ambalavanan, Kimberly Xuan Zhen Lim, Rachel Ying Min Tan, Atul Kumar Johri, Boaz Tirosh, Emanuel Hanski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Group A streptococcus (GAS) is among the top 10 causes of mortality from an infectious disease, producing mild to invasive life-threatening manifestations. Necrotizing fasciitis (NF) is characterized by a rapid GAS spread into fascial planes followed by extensive tissue destruction. Despite prompt treatments of antibiotic administration and tissue debridement, mortality from NF is still high. Moreover, there is no effective vaccine against GAS, and early diagnosis of NF is problematic because its clinical presentations are not specific. Thus, there is a genuine need for effective treatments against GAS NF. Previously, we reported that GAS induces endoplasmic reticulum (ER) stress to gain asparagine from the host. Here, we demonstrate that GAS-mediated asparagine induction and release occur through the PERK-eIF2α-ATF4 branch of the unfolded protein response. Inhibitors of PERK or integrated stress response (ISR) blocked the formation and release of asparagine by infected mammalian cells, and exogenously added asparagine overcame this inhibition. Moreover, in a murine model of NF, we show 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. Immunohistopathology studies demonstrated that PERK/ISR inhibitors protected mice by enabling neutrophil infiltration into GAS-infected fascia and reducing the pro-inflammatory response that causes tissue damage. Inhibitor treatment was also effective in mice when started at 12 hours after infection. We conclude that host metabolic alteration induced by PERK or ISR inhibitors is a promising therapeutic strategy to treat highly invasive GAS infections.

Original languageAmerican English
Article numbereabd7465
JournalScience Translational Medicine
Volume13
Issue number605
DOIs
StatePublished - 4 Aug 2021

Bibliographical note

Funding Information:
Funding: This work was supported by grants from the Israeli Science Foundation

Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.

Fingerprint

Dive into the research topics of 'Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine'. Together they form a unique fingerprint.

Cite this