Cell State Transition Analysis Identifies Interventions That Improve Control of Infection by Susceptible Macrophages

Overview

Journal bioRxiv

Date 2023 Feb 17

PMID 36798271

Authors

Shivraj M Yabaji

Oleksii S Rukhlenko

Sujoy Chatterjee

Bidisha Bhattacharya

Emily Wood

Marina Kasaikina

Boris Kholodenko

Alexander A Gimelbrant

Igor Kramnik

Affiliations

Soon will be listed here.

Abstract

Understanding cell state transitions and purposefully controlling them to improve therapies is a longstanding challenge in biological research and medicine. Here, we identify a transcriptional signature that distinguishes activated macrophages from TB-susceptible and TB-resistant mice. We then apply the cSTAR (cell State Transition Assessment and Regulation) approach to data from screening-by-RNA sequencing to identify chemical perturbations that shift the. transcriptional state of the TB-susceptible macrophages towards that of TB-resistant cells. Finally, we demonstrate that the compounds identified with this approach enhance resistance of the TB-susceptible mouse macrophages to virulent .

References

Su Y, Ko M, Cheng H, Zhu R, Xue M, Wang J . Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line. Nat Commun. 2020; 11(1):2345. PMC: 7214418. DOI: 10.1038/s41467-020-15956-9. View

Bhattacharya B, Xiao S, Chatterjee S, Urbanowski M, Ordonez A, Ihms E . The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas. J Clin Invest. 2020; 131(3). PMC: 7843230. DOI: 10.1172/JCI130319. View

Yabaji S, Chatterjee S, Waligursky E, Gimelbrant A, Kramnik I . Medium throughput protocol for genome-based quantification of intracellular mycobacterial loads and macrophage survival during infection. STAR Protoc. 2022; 3(2):101241. PMC: 8931439. DOI: 10.1016/j.xpro.2022.101241. View

Fey D, Halasz M, Dreidax D, Kennedy S, Hastings J, Rauch N . Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients. Sci Signal. 2015; 8(408):ra130. DOI: 10.1126/scisignal.aab0990. View

Arish M, Naz F . Macrophage plasticity as a therapeutic target in tuberculosis. Eur J Immunol. 2022; 52(5):696-704. DOI: 10.1002/eji.202149624. View

Kramnik I, Dietrich W, Demant P, Bloom B . Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000; 97(15):8560-5. PMC: 26987. DOI: 10.1073/pnas.150227197. View

Chatterjee S, Yabaji S, Rukhlenko O, Bhattacharya B, Waligurski E, Vallavoju N . Channeling macrophage polarization by rocaglates increases macrophage resistance to . iScience. 2021; 24(8):102845. PMC: 8333345. DOI: 10.1016/j.isci.2021.102845. View

McHenry M, Williams S, Stein C . Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches. Infect Genet Evol. 2020; 81:104204. PMC: 7192760. DOI: 10.1016/j.meegid.2020.104204. View

Ji D, Witt K, Kotov D, Margolis S, Louie A, Chevee V . Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons. Elife. 2021; 10. PMC: 8248984. DOI: 10.7554/eLife.67290. View

10.

Rukhlenko O, Halasz M, Rauch N, Zhernovkov V, Prince T, Wynne K . Control of cell state transitions. Nature. 2022; 609(7929):975-985. PMC: 9644236. DOI: 10.1038/s41586-022-05194-y. View

11.

Pichugin A, Yan B, Sloutsky A, Kobzik L, Kramnik I . Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol. 2009; 174(6):2190-201. PMC: 2684184. DOI: 10.2353/ajpath.2009.081075. View

12.

Chandra P, Grigsby S, Philips J . Immune evasion and provocation by Mycobacterium tuberculosis. Nat Rev Microbiol. 2022; 20(12):750-766. PMC: 9310001. DOI: 10.1038/s41579-022-00763-4. View

13.

Ryu H, Chung M, Dobrzynski M, Fey D, Blum Y, Lee S . Frequency modulation of ERK activation dynamics rewires cell fate. Mol Syst Biol. 2015; 11(11):838. PMC: 4670727. DOI: 10.15252/msb.20156458. View

14.

DiNardo A, Gandhi T, Heyckendorf J, Grimm S, Rajapakshe K, Nishiguchi T . Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes. Eur Respir J. 2022; 60(3). PMC: 9474892. DOI: 10.1183/13993003.02263-2021. View

15.

Pan H, Yan B, Rojas M, Shebzukhov Y, Zhou H, Kobzik L . Ipr1 gene mediates innate immunity to tuberculosis. Nature. 2005; 434(7034):767-72. PMC: 1388092. DOI: 10.1038/nature03419. View

16.

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

17.

DiNardo A, Nishiguchi T, Grimm S, Schlesinger L, Graviss E, Cirillo J . Tuberculosis endotypes to guide stratified host-directed therapy. Med. 2021; 2(3):217-232. PMC: 8530349. DOI: 10.1016/j.medj.2020.11.003. View

18.

Darrah P, Zeppa J, Maiello P, Hackney J, Wadsworth 2nd M, Hughes T . Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature. 2020; 577(7788):95-102. PMC: 7015856. DOI: 10.1038/s41586-019-1817-8. View

19.

Cronan M . In the Thick of It: Formation of the Tuberculous Granuloma and Its Effects on Host and Therapeutic Responses. Front Immunol. 2022; 13:820134. PMC: 8934850. DOI: 10.3389/fimmu.2022.820134. View

20.

Holscher C, Heitmann L, Owusu-Dabo E, Horstmann R, Meyer C, Ehlers S . A Mutation in IL4RA Is Associated with the Degree of Pathology in Human TB Patients. Mediators Inflamm. 2016; 2016:4245028. PMC: 4764744. DOI: 10.1155/2016/4245028. View