PANoptosis opens new treatment options for allergic bronchopulmonary aspergillosis

Abstract

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a rare airway disorder primarily affecting patients with asthma and cystic fibrosis. Persistent airway inflammation brought on by Aspergillus fumigatus exacerbates the underlying condition and can cause significant respiratory damage. Treatments center on reducing inflammation with the use of corticosteroids and antifungals. PANoptosis is a new concept in the field of cell death and inflammation that posits the existence of cross talk and a master control system for the 3 programmed cell death (PCD) pathways, namely, apoptosis, pyroptosis, and necroptosis. This concept has revolutionized the understanding of PCD and opened new avenues for its exploration. Studies show that Aspergillus is one of the pathogens that is capable of activating PANoptosis via the Z-DNA binding protein 1 (ZBP1) pathway and plays an active role in the inflammation caused by this organism.

Objective: This article explores the nature of inflammation in ABPA and ways in which PCD could lead to novel treatment options.

Method: PubMed was used to review the literature surrounding Aspergillus infection-related inflammation and PANoptosis.

Results: There is evidence that apoptosis and pyroptosis protect against Aspergillus-induced inflammation, whereas necroptosis promotes inflammation.

Conclusion: Experimental medications, in particular, necroptosis inhibitors such as necrosulfonamide and necrostatin-1, should be studied for use in the treatment of ABPA.

Keywords: ABPA; Aspergillus fumigatus; PANoptosis; TAK1; ZBP1; allergic bronchopulmonary aspergillosis; apoptosis; necroptosis; programmed cell death; pyroptosis.

Fig 1

PANoptosis is suspected to be induced by A fumigatus. Evidence suggests there may be a cyclopentanediol analog produced by A fumigatus that serves as an inhibitor of TAK1. In addition, direct activation can occur through an unknown Z-DNA ligand binding to ZBP1. The PANoptosome complex formed from either pathway can then go on to induce the 3 modalities of cell death, namely, apoptosis, pyroptosis, and necroptosis. ASC, Adapter apoptosis-associated speck-like protein containing a caspase recruitment domain; CASP8, caspase-8; FADD, FAS-associated via death domain.

Fig 2

A fumigatus–induced cell death. Solid lines represent known relationships, dashed lines represent suspected relationships based on studies in C albicans. A fumigatus conidia inhibits apoptosis through the secretion of dihydroxynapthalene-melanin (DHN-melanin). Once it has germinated, A fumigatus has multiple virulence factors capable of inducing the 3 different cell death pathways. Gliotoxin serves as an activator of apoptosis. Ergosterol and chitin are known virulence factors of A fumigatus but have not been directly shown to activate the pyroptosis pathway in aspergillosis. Activation of dectin-1 via β-glucan has been demonstrated to play a role in the pyroptosis pathway but is currently only suspected in necroptosis.