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

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

doi:10.1038/s41420-020-00366-z

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.

Highlights

Intracellular pathogens have evolved strategies to manipulate host cell pathways for dissemination and infection propagation
Stabilizing host NAD+ homeostasis is a key factor in determining the fate of intracellular infection[3]
Our study shows that inhibiting host intracellular NAD+ depletion by using TNT’s natural inhibitor IFT restores NAD+ levels, prevents cell death, and negatively influences the survival of M. tuberculosis inside the macrophage (Fig. 3)

Summary

Introduction

Intracellular pathogens have evolved strategies to manipulate host cell pathways for dissemination and infection propagation. D Intracellular NAD+ levels of bacterial cells expressing rIFT or rTNT, or both, in comparison to control cells, was determined by an enzyme-coupling assay. These data indicate that restoration of intracellular NAD+ levels by IFT inhibits TNT induced macrophage cell death.

Results

Conclusion