Co-ordinated mechanisms of plasma membrane repair responses adopted by mammalian cells against pore forming toxins

Date

2022-12

Authors

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

Pore forming toxins (PFTs) play an integral part of the virulence arsenal of both bacterial and fungal pathogens such as Streptococcus pyogenes, Clostridiun perfringens, Aeromonas hydrophila or Candida albicans. These pathogens utilize PFTs to cause localized to systemic lethal infections including septic cardiomyopathy, ne-crotizing soft tissue infections (NSTIs) or candidiasis. PFTs bind to specific receptor on membrane, oligomerize and insert to form large transmembrane lytic pores that causes rapid ionic imbalance and leakage of intracellular components. Pore insertion and subsequent plasma membrane damage leads to cell death. Most nucleated mamma-lian cells are able to resist cell death and subsequent infections to some extent by mounting plasma membrane repair responses. Membrane repair responses are inherently calcium dependent and are best described for cholesterol dependent cytolysins (CDCs). To resist CDCs, cells might utilize toxin removal by “caveolar endocytosis”, “clogging” the pores by annexins, “shedding” of pores and damaged membrane on mi-crovesicles known as intrinsic repair, and/or “patch repair”. However, the repair mech-anisms to clear other non-CDC pores is poorly known. Similarly, the coordinated mechanism of these repair responses is not clear. Repair may be triggered by toxin binding which activate several host cell protein families like Annexins, ESCRTs and Dysferlin to execute repair. Similarly, toxin oligomerization is sufficient to trigger in-trinsic repair however, the molecular mechanism of intrinsic repair is not known. Here, we utilized two non-CDC toxins aerolysin and candidalysin along with CDCs to study the membrane repair responses and their coordinated mechanism. We found that Ca2+ flux triggered by aerolysin was lethal to cell. Contrary to that, candidalysin triggered cell death based on K+ efflux. Though ion flux has been identified as a hallmark for the activation of repair responses, our findings established their roles as a death effec-tor. However, cells still activated and utilize coordinated response of Ca2+ dependent repair mechanisms but the co-ordination of repair mechanisms were different based on the type of the toxin.

Description

Keywords

Pore forming toxins, necrotizing soft tissue infections, Membrane repair, Annexins, Dysferlin, clogging, patching, shedding

Citation