Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

Ayushi Chaurasiya, Swati Garg, Ashish Khanna, Chintam Narayana, Ved Prakash Dwivedi, Nishant Joshi, Zill e Anam, Niharika Singh, Jhalak Singhal, Shikha Kaushik, Amandeep Kaur Kahlon, Pallavi Srivastava, Manisha Marothia, Mukesh Kumar, Santosh Kumar, Geeta Kumari, Akshay Munjal, Sonal Gupta, Preeti Singh, Soumya PatiGobardhan Das, Ram Sagar, Anand Ranganathan, Shailja Singh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

Original languageEnglish (US)
Article number10
JournalCell Death Discovery
Volume7
Issue number1
DOIs
StatePublished - Jan 13 2021

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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