Dobson, B. | Search bioRxiv

bioRxiv2025

Differential disease tolerance mediates sex-biased illness severity in sepsis

Sepsis in humans, as well as mouse models of infection, demonstrates sex-biased outcomes in which males tend to have a higher incidence, higher severity, and higher mortality compared to females. Despite this important sex-bias in sepsis outcomes, little is known about its mechanistic drivers nor therapeutic implications, as much of the foundational data on sepsis pathogenesis is derived from animal studies that included only male subjects, potentially contributing to the notable paucity of successful mouse-to-human translation of sepsis therapeutics. In this study, we demonstrate that male-biased illness severity and organ dysfunction in mouse models of bacterial sepsis is mediated by impaired disease tolerance in males, involving impaired tolerogenic shifts in mitochondrial oxidative metabolism compared to females. Microbiological analyses and systems immunology characterization of sepsis between males and females revealed that sex-biased disease tolerance was independent of infection resistance mechanisms, as well as canonical immune/inflammatory dysregulation. Therapeutic potentiation of mitochondrial tolerance with doxycycline neutralized sexual dimorphism of illness severity and organ dysfunction through a male-predominant treatment effect. These data reveal that biological sex is a fundamental determinant of illness severity and treatment-responsiveness in sepsis through modulation of disease tolerance, which may be harnessed therapeutically to address sex-biased outcomes in sepsis. One sentence summarySex-biased illness severity in bacterial sepsis is caused by impaired disease tolerance in males that can be rescued by therapeutic potentiation of mitochondrial tolerance

pathology↗

bioRxiv2022

Predicting catchment suitability for biodiversity at national scales

Biomonitoring of water quality and catchment management are often disconnected, due to mismatching scales. Great effort and money is spent each year on routine reach-scale surveying across many sites, particularly in the UK, and typically with a focus on pre-defined indicators of organic pollution to compare observed vs expected subsets of common macroinvertebrate indicator species. Threatened species are often ignored due to their rarity as are many invasive species, which are seen as undesirable even though they are increasingly common in freshwaters, especially in urban ecosystems. However, these taxa are monitored separately for reasons related to biodiversity concerns rather than for gauging water quality. Repurposing such monitoring data could therefore provide important new biomonitoring tools that can help catchment managers to directly link the water quality that they aim to control with the biodiversity that they are trying to protect. Here we used the England Non-Native and Rare/Protected species records that track these two groups of species as a proof-of-concept for linking catchment scale management of freshwater ecosystems and biodiversity to a range of potential drivers across England. We used national land use (Centre for Ecology and Hydrology land cover map) and water quality indicator (Environment Agency water quality data archive) datasets to predict the presence or absence of 48 focal threatened or invasive species of concern routinely sampled by the English Environment Agency at catchment scale, with a median accuracy of 0.81 area under the receiver operating characteristic curve. A variety of water quality indicators and land-use types were useful in predictions, highlighting that future biomonitoring schemes could use such complementary measures to capture a wider spectrum of drivers and responses. In particular, the percentage of a catchment covered by freshwater was the single most important metric, reinforcing the need for space/habitat to support biodiversity. We show how our method could inform new catchment management approaches, by highlighting how key relationships can be identified and how to understand, visualise and prioritise catchments that are most suitable for restorations or water quality interventions. The scale of this work, in terms of number of species, drivers and locations, represents a step towards a new approach to catchment management that enables managers to link drivers they can control (water quality and land use) to the biota they are trying to protect (biodiversity).

ecology↗