Morales, D. K. | bioRxiv Science

bioRxiv2022

Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis

Recognition of pathogen-associated molecular patterns can trigger the IRE1 arm of the endoplasmic reticulum (ER) stress response in immune cells. IRE1 activation has been shown to maintain ER homeostasis while simultaneously coordinating diverse immunomodulatory programs in the setting of bacterial and viral infections. However, the role of IRE1 signaling in innate immune responses to fungal pathogens is unknown. Here we report that systemic infection with the fungus Candida albicans causes severe renal immunopathology by triggering inflammatory IRE1 hyperactivation in host myeloid cells. Mechanistically, sensing of fungal {beta}-glucans by the C-type lectin receptor Dectin-1 induced Src-Syk-NOX-dependent accumulation of intracellular reactive oxygen species and the ensuing generation of lipid peroxidation byproducts that sustained IRE1 activation. Selective deletion of IRE1 in leukocytes, or treatment with an IRE1 pharmacological inhibitor, reduced detrimental inflammatory responses in the kidney and extended survival in mice systemically infected with C. albicans. Hence, controlling IRE1 overactivation may be useful to impede the fatal immunopathogenic progression of disseminated candidiasis. One sentence summaryInnate IRE1 signaling in disseminated candidiasis

immunology↗

bioRxiv2022

Light/dark and temperature cycling modulate metabolic electron flow in Pseudomonas aeruginosa biofilms

Sunlight drives phototrophic metabolism, which affects redox conditions and produces substrates for non-phototrophs. These environmental parameters fluctuate daily due to Earths rotation, and non-phototrophic organisms can therefore benefit from the ability to respond to, or even anticipate, such changes. Circadian rhythms, such as daily changes in body temperature, in host organisms can also affect local conditions for colonizing bacteria. Here, we investigated the effects of light/dark and temperature cycling on biofilms of the opportunistic pathogen Pseudomonas aeruginosa PA14. We grew biofilms in the presence of a respiratory indicator dye and found that greater dye reduction occurred in biofilm zones that formed during dark intervals and at lower temperatures. This pattern formation occurred with cycling of blue, red, or far-red light, and a screen of mutants representing potential sensory proteins identified two with defects in pattern formation, specifically under red light cycling. We also found that the physiological states of biofilm subzones formed under specific light and temperature conditions were retained during subsequent condition cycling. Light/dark and temperature cycling affected expression of genes involved in primary metabolic pathways and redox homeostasis, including those encoding electron transport chain components. Consistent with this, we found that cbb3-type oxidases contribute to dye reduction under light/dark cycling conditions. Together, our results indicate that cyclic changes in light exposure and temperature have lasting effects on redox metabolism in biofilms formed by a non-phototrophic, pathogenic bacterium. IMPORTANCEOrganisms that do not obtain energy from light can nevertheless be affected by daily changes in light exposure. Many aspects of animal and fungal physiology fluctuate in response to these changes, including body temperature and the activities of antioxidant and other redox enzymes that play roles in metabolism. Whether redox metabolism is affected by light/dark and temperature cycling in bacteria that colonize such circadian organisms has not been studied in detail. Here we show that growth under light/dark and temperature cycling leads to rhythmic changes in redox metabolism in Pseudomonas aeruginosa and identify proteins involved in this response. P. aeruginosa is a major cause of healthcare-associated infections and designated as a serious threat by the CDC due to its recalcitrance during treatments. Our findings have the potential to inform therapeutic strategies that incorporate controlled light exposure or consider P. aeruginosas responses to conditions in the host.

microbiology↗