M. fortuitum-induced CNS-pathology: Deciphering the role of canonical Wnt signaling, blood brain barrier components and cytokines. (September 2021)

• Record Type: Journal Article
• Authors: Sharma, Shagun; Kumar, Manmohan; Kumar, Jai; Srivastava, Nidhi; Hussain, Md Arafat; Shelly, Asha; Mazumder, Shibnath
• Is Part Of: Developmental and comparative immunology. Volume 122(2021)
• Publication Date: 2021-09
• Subjects: Mycobacterium fortuitum -- Zebrafish -- Wnt-signaling -- CNS-pathology -- Cytokines; M. fortuitum Mycobacterium fortuitum -- GSK3β Glycogen synthase kinase 3β -- TJ Tight junction -- AJC Adherens junction complex -- BBB Blood Brain Barrier -- ZN Zeihl-Neelson -- CFU Colony forming units -- DEPC Diethyl pyrocarbonate; Immunology -- Periodicals; Developmental immunology -- Periodicals; 616.079
• DOI: 10.1016/j.dci.2021.104111
• Languages: English
• ISSNs: 0145-305X

Abstract

Abstract: Molecular underpinning of mycobacteria-induced CNS-pathology is not well understood. In the present study, zebrafish were infected with Mycobacterium fortuitum and the prognosis of CNS-pathogenesis studied. We observed M. fortuitum triggers extensive brain-pathology. Evans blue extravasation demonstrated compromised blood-brain barrier (BBB) integrity. Further, decreased expression in tight-junction (TJ) and adherens junction complex (AJC) genes were noted in infected brain. Wnt-signaling has emerged as a major player in host-mycobacterial immunity but its involvement/role in brain-infection is not well studied. Sustained expression of wnt2, wnt3a, fzd5, lrp5/6 and β-catenin, with concordant decline in degradation complex components axin, gsk3β and β-catenin regulator capn2a were observed. The surge in ifng1 and tnfa expression preceding il10 and il4 suggested cytokine-interplay critical in M. fortuitum -induced brain-pathology. Therefore, we suggest adult zebrafish as a viable model for studying CNS-pathology and using the same, conclude that M. fortuitum infection is associated with repressed TJ-AJC gene expression and compromised BBB permeability. Our results implicate Wnt/β-catenin pathway in M. fortuitum -induced CNS-pathology wherein Th1-type signals facilitate bacterial clearance and Th2-type signals prevent the disease sequel. Highlights: Adult zebrafish ( Danio rerio ) used to model M. fortuitum -induced CNS-pathology. M. fortuitum invades zebrafish brain inducing extensive pathological alterations. Reduced BBB permeability and inhibited TJ-AJC gene expression observed in infected brain. Canonical Wnt-signaling was discerned in M. fortuitum -infected brain. Interplay of cytokines regulate the sequel of CNS-pathology.