Biology subjects

Hall, A. G.

Publications and source records attributed to Hall, A. G..

3 recordsLinked to original sources

bioRxiv2025

Activation of the Spx redox sensor counters cysteine-driven Fe(II) depletion under disulfide stress

In many low G+C Gram-positive bacteria, the global regulator Spx helps maintain thiol homeostasis during disulfide stress, when protein thiols form aberrant disulfide bonds that can lead to misfolding and oxidative damage. Spx-dependent gene expression is triggered when an intramolecular disulfide bond forms between two cysteines in its redox switch. Surprisingly, some Spx functions persist even in the absence of an active redox switch, highlighting the need to better understand the physiological significance of maintaining this regulatory feature. Here, we utilize a spxC10A mutant that encodes a redox-insensitive Spx variant to study the role of the Spx redox switch in Staphylococcus aureus. We show that the spxC10A mutant is hypersensitive to diamide-induced disulfide stress and exhibits widespread transcriptional dysregulation of genes that contribute to thiol maintenance and disulfide repair. Remarkably, the spxC10A mutant rapidly adapts to disulfide stress by increasing its intracellular pool of L-cysteine (L-Cys) through enhanced uptake, which helps restore a reduced intracellular environment. However, during this process increased L-Cys inadvertently depletes cytosolic Fe(II), leading to growth inhibition of the spxC10A mutant. Finally, we show that the Spx-dependent control of intracellular L-Cys is critical for S. aureus survival when it encounters human neutrophils. Overall, these findings suggest that staphylococcal adaptation to disulfide stress through intracellular L-Cys accumulation imposes significant fitness costs that S. aureus overcomes by rapid regulatory control of thiol homeostasis through a functional Spx redox switch. SignificanceAll cells have a pool of low molecular weight thiols, such as cysteine, glutathione, bacillithiol, and coenzyme A, to maintain redox balance under oxidative and disulfide stress. Among these, cysteine is a very effective thiol but is highly reactive, and its intracellular concentration must be tightly regulated. In S. aureus, we found that cysteine accumulates intracellularly during disulfide stress and if left unchecked, can inadvertently deplete cytosolic Fe(II), leading to growth inhibition. To prevent cysteine toxicity, S. aureus activates the global regulator Spx, which rapidly induces genes that restore thiol homeostasis and limits cysteine accumulation.

microbiology↗

bioRxiv2025

Correspondence between sleep patterns and anhedonia in adult male mice exposed to early-life stress

Early-life stress (ELS) can produce long-lasting effects that increase the risk for mood and anxiety disorders. Transdiagnostic symptoms include anhedonia (reduced reward sensitivity) and sleep disruption, both of which are quantifiable via objective endpoints that can be utilized across species. Here we used a mouse model for ELS--exposure to juvenile chronic social defeat stress (jCSDS)--together with translationally-applicable endpoints to examine correspondence between sleep patterns and anhedonia. These initial studies focused on males, which typically show robust defeat-induced anhedonia phenotypes. Exposure to jCSDS produced reductions in open-field social behavior, an endpoint commonly used in mice to quantify stress effects, during adulthood. Mice were then implanted with wireless transmitters that enable continuous EEG-derived analysis of sleep architecture. Following assessment of baseline sleep patterns, mice were tested in a rodent version of the Probabilistic Reward Task (PRT), a procedure used to quantify reward responsiveness in humans, during the light phase of their diurnal cycle. These studies revealed significant associations between baseline sleep architecture and anhedonic phenotypes in jCSDS-exposed mice: higher anhedonia correlated with less time awake and more time in slow wave sleep (SWS) during the light phase, and more time awake and less time in rapid eye movement (REM) sleep and SWS during the dark (active) phase. Our findings suggest that sleep patterns represent a biomarker that can predict stress-susceptible (higher anhedonia) and resilient (lower anhedonia) phenotypes. This work enhances our understanding of relationships between sleep and anhedonia, and may provide a basis for precision approaches to treat ELS-induced pathophysiology.

animal behavior and cognition↗

bioRxiv2024

Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture

As a syndrome, chronic pain comprises physical, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. A rodent model of long-term inflammatory pain, induced by complete Freunds adjuvant (CFA) injection, has previously been shown to cause anhedonia and dysregulated naturalistic behaviors, in a manner similar to animal models of stress. We examined whether this extended to alterations in circadian rhythms and sleep, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG. CFA-induced inflammatory pain profoundly altered sleep architecture in male and female mice. Injection of the hind paw, whether with CFA or saline, reduced some measures of circadian rhythmicity such as variance, period, and amplitude. CFA increased sleep duration primarily in the dark phase, while sleep bout length was decreased in the light and increased in the dark phase. Additionally, CFA reduced wake bout length, especially during the dark phase. Increases in REM and SWS duration and bouts were most significant in the dark phase, regardless of whether CFA had been injected at its onset or 12 hours prior. Taken together, these results indicate that inflammatory pain acutely promotes but also fragments sleep.

neuroscience↗