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bioRxiv · 10.64898/2026.02.26.708173

Distinct Regulation of Host Defences by CRISPR-Cas in Typhoidal and Non-Typhoidal Salmonella serovars

DAS, A.·SHARMA, N.·Bhattacharyya, S.·MARATHE, S.·Negi, V. D.
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Abstract

CRISPR-Cas systems are best known for their role in adaptive immunity, but emerging evidence suggests broader regulatory functions. Here, we show that the CRISPR-Cas system acts as a serovar-specific regulator of stress adaptation in Salmonella enterica, exerting opposing effects in host-restricted (S. Typhi) and broad-host-range (S. Typhimurium) serovars. In S. Typhi, CRISPR-Cas system deletion reduces acid and bile tolerance by impairing envelope integrity and repressing key stress-response regulators (envZ, cadB, phoPQ, lexA, ruvB, wecD), while increasing resistance to cationic antimicrobial peptides via pmr activation and reduced oxidative damage. Conversely, CRISPR-Cas system loss in S. Typhimurium enhances acid survival-partly through speF upregulation but increases sensitivity to antimicrobial peptides. Spacer-1 of S. Typhi CRISPR-I array as the main regulator of gene expression, and its reintroduction partially restored stress tolerance, supporting spacer-dependent control of physiological pathways. These findings establish the CRISPR-Cas system as a non-canonical, spacer-dependent regulator of stress response networks in S. enterica, revealing its contribution to the evolutionary divergence of survival strategies between S. Typhi and S. Typhimurium.

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DAS, A., SHARMA, N., Bhattacharyya, S., MARATHE, S., Negi, V. D.. 2026-02-26. Distinct Regulation of Host Defences by CRISPR-Cas in Typhoidal and Non-Typhoidal Salmonella serovars. https://doi.org/10.64898/2026.02.26.708173

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