Pathogen induced subversion of NAD metabolism mediating host cell death: a target for development of chemotherapeutics
Authors: Niharika Singh
Ayushi Chaurasiya
Pallavi Srivastava
Chintam Narayana
Nishant Joshi
Jhalak Singhal
Gobardhan Das
Shailja Singh
Santosh Kumar
Zill E Anam
Shikha Kaushik
Akshay Munjal
Amandeep Kaur Kahlon
Soumya Pati
Swati Garg
Anand Ranganathan
Mukesh Kumar
Ram Sagar
Manisha Marothia
Ved Prakash Dwivedi
Ashish Khanna
Geeta Kumari
Preeti Singh
Sonal Gupta
Journal: Cell Death Discovery (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: pathogen dissemination; NAD+ modulation; necroptosis; eryptosis; M. tuberculosis
Affiliations: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India., Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India., International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India., Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, 201314, India., Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India. ., Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India. .

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. 

Retracted: No

PubPeer comments:
 In Figure 4b, the merged micrograph does not correspond with the DIC and FITC micrographs. ![file] , 
 #1 Dear Indigofera Tanganyikensis Thank you for your comment. These micrographs are from the same erythrocyte only but they are taken at different z-positions. Please see the accompanying image. For microscopic images, the best focus for DIC (to see the morphology of the cell) and fluorescence (to check the staining of corresponding dye, in this case FITC-Annexin) is usually different and hence to provide the best view of the images (which is the best focus) to the reader, we provided micrographs of different z-positions. To be sure, if there are multiple fluorescent dye stainings they may be depicted at the same z-section. But since in our case, there is only FITC-Annexin staining, therefore, we provided micrographs of different z-positions for better clarity. Thank you. ![file] ,