The Kongming defense: Host-pathogen battles take a new face

Abstract

Bacteria employ diverse immune systems, such as CRISPR-Cas, to fend off phage infections. A recent study uncovered the unprecedented mechanistic features of the Kongming bacterial defense system, which uniquely exploits phage-derived enzymes to synthesize deoxyinosine triphosphate (dITP), thereby triggering host immunity through NAD+ depletion. In response, some phages have evolved countermeasures to disrupt dITP synthesis, highlighting the ongoing evolutionary arms race between hosts and pathogens. This discovery not only deepens our understanding of bacterial defense strategies but also paves the way for new insights in biomedical research and synthetic biology.

Keywords

Kongming immunity / Deoxyinosine triphosphate (dITP) / Base modification / Bacterial immunity / Host-pathogen coevolution

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Dongchun Ni: Writing - original draft.

References

[1] S.J. Hobbs, P.J. Kranzusch, Nucleotide immune signaling in CBASS, Pycsar, Thoeris and CRISPR antiphage defense, Annu. Rev. Microbiol (2024) 78.

[2] J.S. Athukoralage, M.F. White, Cyclic nucleotide signaling in phage defense and counter-defense, Annu Rev. Virol 9 (1) (2022) 451-468.

[3] A. Bernheim, R. Sorek, The pan-immune system of bacteria: antiviral defence as a community resource, Nat. Rev. Microbiol. 18 (2) (2020) 113-119.

[4] D. Jur ėnas, N. Fraikin, F. Goormaghtigh, L. Van Melderen, Biology and evolution of bacterial toxin-antitoxin systems, Nat. Rev. Microbiol. 20 (6) (2022) 335-350.

[5] H. Georjon, A. Bernheim, The highly diverse antiphage defence systems of bacteria, Nat. Rev. Microbiol. 21 (10) (2023) 686-700.

[6] A. Lopatina, N. Tal, R. Sorek, Abortive infection: bacterial suicide as an antiviral immune strategy, Annu Rev. Virol 7 (1) (2020) 371-384.

[7] L.A. Marraffini, CRISPR-Cas immunity in prokaryotes, Nature 526 (7571) (2015) 55-61.

[8] E.R. Westra, A. Buckling, P.C. Fineran, CRISPR-Cas systems: beyond adaptive im- munity, Nat. Rev. Microbiol. 12 (5) (2014) 317-326.

[9] R. Barrangou, C. Fremaux, H. Deveau, M. Richards, P. Boyaval, S. Moineau, D. A. Romero, P. Horvath, CRISPR provides acquired resistance against viruses in prokaryotes, Sci 315 (5819) (2007) 1709-1712.

[10] M. Jinek, K. Chylinski, I. Fonfara, M. Hauer, J.A. Doudna, E. Charpentier, A pro- grammable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity, Sci. (1979) 337 (6096) (2012) 816-821.

[11] G. Gasiunas, R. Barrangou, P. Horvath, V. Siksnys, Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria, Proc. Natl. Acad. Sci. 109 (39) (2012) E2579-E2586.

[12] F.A. Ran, P.D. Hsu, J. Wright, V. Agarwala, D.A. Scott, F. Zhang, Genome engineering using the CRISPR-Cas9 system, Nat. Protoc 8 (11) (2013) 2281-2308.

[13] A. Millman, S. Melamed, G. Amitai, R. Sorek, Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems, Nat. Microbiol 5 (12)(2020) 1608-1615.

[14] J.S. Athukoralage, M.F. White, Cyclic nucleotide signaling in phage defense and counter-defense, Annu Rev. Virol 9 (1) (2022) 451-468.

[15] M.S. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of AD- P-ribosylation, Nat. Chem. Biol 14 (3) (2018) 236-243.

[16] Z. Zeng, Z. Hu, R. Zhao, J. Rao, M.R. Mestre, Y. Liu, S. Liu, H. Feng, Y. Chen, H. He, N. C.J. Zheng, D. Peng, M. Luo, Q. She, R. Pinilla-Redondo, W. Han, Base-modified nucleotides mediate immune signaling in bacteria, Science (2025) eads6055.

[17] A. Stern, R. Sorek, The phage-host arms race: shaping the evolution of microbes, Bioessays 33 (1) (2011) 43-51.

[18] T. Niault, S. van Houte, E. Westra, D.C. Swarts, Evolution and ecology of anti-defence systems in phages and plasmids, Curr. Biol. 35 (1) (2025) R32-R44.

[19] B.R. Morehouse, Phage defense origin of animal immunity, Curr. Opin. Microbiol 73 (2023) 102295.

[20] T. Wein, R. Sorek, Bacterial origins of human cell-autonomous innate immune mech- anisms, Nat. Rev. Immunol. 22 (10) (2022) 629-638.

[21] T. Li, Y. Yang, H. Qi, W. Cui, L. Zhang, X. Fu, X. He, M. Liu 1, P.-F. Li, T. Yu, CRISPR/Cas 9 therapeutics: progress and prospects, Signal Transduct. Target. Ther. 8 (1) (2023) 36.

[22] J.A. Doudna, E. Charpentier, The new frontier of genome engineering with CRISPR-Cas9, Sci. (1979) 346 (6213) (2014) 1258096.

[23] P.D. Hsu, E.S. Lander, F. Zhang, Development and applications of CRISPR-Cas9 for genome engineering, Cell 157 (6) (2014) 1262-1278.

[24] H. Wang, M. La Russa, L.S. Qi, CRISPR/Cas 9 in genome editing and beyond, Annu. Rev. Biochem 85 (1) (2016) 227-264.

[25] Y. Wu, D. Battalapalli, M.J. Hakeem, V. Selamneni, P. Zhang, M.S. Draz, Z. Ruan, Engineered CRISPR-Cas systems for the detection and control of antibiotic-resistant infections, J. Nanobiotechnology 19 (2021) 1-26.

[26] A. Mayorga-Ramos, J. Zúñiga-Miranda, S.E. Carrera-Pacheco, C. Barba-Ostria, L. P. Guamán, CRISPR-Cas-based antimicrobials: design, challenges, and bacterial mechanisms of resistance, ACS. Infect. Dis 9 (7) (2023) 1283-1302.

[27] Y. Wan, C. Zong, X. Li, A. Wang, Y. Li, T. Yang, Q. Bao, M. Dubow, M. Yang, L.A. Ro- drigo, C. Mao, New insights for biosensing: lessons from microbial defense systems, Chem. Rev 122 (9) (2022) 8126-8180.

[28] T.S. Zavvar, Z. Khoshbin, M. Ramezani, M. Alibolandi, K. Abnous, S.M. Taghdisi, CRISPR/Cas-engineered technology: innovative approach for biosensor develop- ment, Biosens. Bioelectron. 214 (2022) 114501.

[29] W.P. Smith, B.R. Wucher, C.D. Nadell, K.R. Foster, Bacterial defences: mechanisms, evolution and antimicrobial resistance, Nat. Rev. Microbiol. 21 (8) (2023) 519-534.