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Abstract: Accurately measuring fluctuating pH levels in bacterial cells is vital for understanding their signaling pathways and pathogenesis, which is hindered by the lack of effective pH probes. We employed mCherryTYG, a genetically-encoded fluorescent probe, coupled with Fluorescence Lifetime Imaging Microscopy (FLIM) to map pH changes in bacteria and their associated bacterial lifestyles. We measured pH fluctuations in diverse environments, including Salmonella-containing vacuoles, in biofilms, and in heterologous hosts the nematode C. elegans, and zebrafish Danio rerio1.

Salmonella enterica serovar Typhi is the causative agent of typhoid fever, a human-restricted systemic infection. We compared the H58 response (a rapidly expanding serovar) in vitro and during infection of THP-1 human macrophages with the well-characterized Salmonella Typhimurium, which causes gastroenteritis. In response to acid stress, the sulfur assimilation pathway was highly upregulated and unique to H58. In acidic pH, H58 was more oxidized; the sulfur assimilation pathway mitigated the redox stress. We emphasize the importance of studying S. Typhi strains directly to understand their unique behavior during pathogenesis2.

The presence of senescent cells causes age-related pathologies, since their removal by genetic or pharmacological means improves outcomes in animal models. An alternative to depleting such cells is to rejuvenate them to promote their return to a replicative state. Treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenated cells for growth. Notably, 15 characteristics of senescent cells were reversed by LFU. Mechanistically, LFU causes Ca2+ entry and increased actin dynamics, increases autophagy and inhibits mTORC1 signaling. LFU treatment increased mouse lifespan and healthspan3. Mice fed a high fat, high sucrose diet combined with streptozotocin developed insulin resistance and diabetes. Transcriptomic analysis indicated that LFU primarily reduced inflammatory and immune-related gene expression, by promoting a shift toward an anti-inflammatory (M2) macrophage profile4. Elderly populations are susceptible to infection due to immune senescence; we explored the effect of LFU prior to infecting aged mice with Salmonella. Colonization was significantly reduced when old mice were treated with LFU. Chemokine analysis revealed a significant increase in ICAM-1, SDF-1, and KC/CXCL1 in aged, treated mice. Ultrasound treatment rejuvenated the immune system in old mice, reducing their susceptibility to Salmonella infection5. Taken together, these results indicate that mechanically induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.

1. Singh, M. K.; Fernandez, M.; Dilawari, R.; Zangoui, P.; Kenney, L. J., FLIM of mCherryTYG Deciphers pH Dynamics and Lifestyles of Salmonella Typhimurium. ACS Sens 2025, 10 (6), 4232-4243.

2. Fernandez, M.; Yamanaka, Y.; Zangoui, P.; White, M. A.; Kenney, L. J., The sulfur assimilation pathway mitigates redox stress from acidic pH in Salmonella Typhi H58. mBio 2025, 16 (7), e0046725.

3. Kureel, S. K.; Maroto, R.; Aniqua, M.; Powell, S.; Singh, E.; Margadant, F.; Blair, B.; Rasmussen, B. B.; Sheetz, M. P., Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound. Aging Cell 2025, e70008.

4. Marchant, E. D.; Singh, E.; Kureel, S.; Blair, B.; Kalenta, H.; Von Ruff, Z. D.; Weldon, K. S.; Lai, Z.; Sheetz, M. P.; Rasmussen, B. B., Low-Frequency Ultrasound Reverses Insulin Resistance and Diabetes Induced Changes in the Muscle Transcriptome in Aged Mice. Am J Physiol Endocrinol Metab 2025.

5. Zangoui, P.; Singh, E.; Sheetz, M. P.; Kenney, L. J., Low-frequency ultrasound treatment reduces susceptibility to Salmonella infection in aged mice. J Bacteriol 2025, e0017625.