Mortality Response Research Articles

Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model.

Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Predicting key ectotherm population mortality in response to dynamic marine heatwaves: A Bayesian‐enhanced thermal tolerance landscape approach

Abstract As climate change intensifies heatwaves, quantifying associated mortality within ectothermic populations is crucial for effective conservation. Thermal tolerance landscape (TTL) models are useful predictive tools that assume exponentially decreasing survival durations in individuals with increasing temperatures. This assumption has been validated through regression analyses on data from constant temperature experiments, primarily focusing on adult‐stage individuals. However, this approach does not allow for direct model validation with data from dynamic, real‐world heatwave events and overlooks early recruitment stage vulnerabilities. This study aimed to address these gaps using the blue mussel Mytilus, a foundation species forming extensive reefs along temperate coasts, as a model organism. We monitored survival rates of mussels (juveniles and adults) under constant heatwave (CHW) conditions in a laboratory experiment and under dynamic heatwave (DHW) scenarios simulated in an outdoor mesocosm experiment. Post‐heatwaves, we also assessed recruitment rates within the mesocosms. TTL models were parametrised by employing Approximate Bayesian Computation with Sequential Monte Carlo (ABC‐SMC) on each dataset separately. The parameter distributions were similar across both experiments, and the ABC‐SMC model predictions closely matched the observed survival declines, validating these models. In comparison, we found a lower predictive performance when using a Bayesian regression approach. Additionally, our best‐fit model predicted that warming across the non‐fatal DHW regimes would increase sublethal effects on mussels. The observed impact on the recruitment stage was more pronounced, with the recruitment rate following an exponential decay as sublethal effects increased. Our model projected minor (<4%) sublethal effects in adult mussels during the century's five warmest summer temperature regimes, corresponding to 0%–32% declines in recruitment rates. Our research extends the TTL model validation, demonstrates the resilience of subtidal Baltic Mytilus to future extreme heatwaves and offers an approach to predict heatwave‐induced population mortalities, applicable to other species and sensitive systems. Read the free Plain Language Summary for this article on the Journal blog.

Drought- and heat-induced mortality of conifer trees is explained by leaf and growth legacies.

An increased frequency and severity of droughts and heat waves have resulted in increased tree mortality and forest dieback across the world, but underlying mechanisms are poorly understood. We used a common garden experiment with 20 conifer tree species to quantify mortality after three consecutive hot, dry summers and tested whether mortality could be explained by putative underlying mechanisms, such as stem hydraulics and legacies affected by leaf life span and stem growth responses to previous droughts. Mortality varied from 0 to 79% across species and was not affected by hydraulic traits. Mortality increased with species' leaf life span probably because leaf damage caused crown dieback and contributed to carbon depletion and bark beetle damage. Mortality also increased with lower growth resilience, which may exacerbate the contribution of carbon depletion and bark beetle sensitivity to tree mortality. Our study highlights how ecological legacies at different time scales can explain tree mortality in response to hot, dry periods and climate change.

Body size mediates latitudinal population differences in the response to chytrid fungus infection in two amphibians

Factors behind intraspecific variation in sensitivity to pathogens remain poorly understood. We investigated how geographical origin in two North European amphibians affects tolerance to infection by the chytrid fungus Batrachochytrium dendrobatidis (Bd), a generalist pathogen which has caused amphibian population declines worldwide. We exposed newly metamorphosed individuals of moor frog Rana arvalis and common toad Bufo bufo from two latitudinal regions to two different BdGPL strains. We measured survival and growth as infections may cause sub-lethal effects in fitness components even in the absence of mortality. Infection loads were higher in B. bufo than in R. arvalis, and smaller individuals had generally higher infection loads. B. bufo had high mortality in response to Bd infection, whereas there was little mortality in R. arvalis. Bd-mediated mortality was size-dependent and high-latitude individuals were smaller leading to high mortality in the northern B. bufo. Bd exposure led to sub-lethal effects in terms of reduced growth suggesting that individuals surviving the infection may have reduced fitness mediated by smaller body size. In both host species, the Swedish Bd strain caused stronger sublethal effects than the British strain. We suggest that high-latitude populations can be more vulnerable to chytrids than those from lower latitudes and discuss the possible mechanisms how body size and host geographical origin contribute to the present results.

A Bayesian network model to disentangle the effects of stand and climate factors on tree mortality of Chinese fir plantations

Tree mortality is a complex process that not only be affected by the various factors, such as stand and climate factors, but also the various long-term effects of the factors to each other. In this study, based on the long-term spacing trials of Chinese fir in four regions of southern China, a Bayesian network was used to model tree mortality in response to stand and climate factors, as well as comparing this approach with logistic regression and random forest method. The results showed that the Bayesian network method had the highest accuracy in predicting tree mortality. In addition, the Bayesian network approach could find the dependency in the relationship between data and provide a theoretical framework for modeling uncertainty by using probabilistic calculus and underlying graph structure. Sensitivity analysis showed relative diameter was the most important factor, and temperature was the most important climate factor. Furthermore, climate factors not only directly affected tree mortality, but also indirectly affected tree mortality through affecting relative diameter, stand density and Gini coefficient. We also found that stand competition, structural heterogeneity and age affected tree mortality under climate change, and a moderate level of competition condition and stand structure heterogeneity weakened the negative impact of climate factors on tree mortality. Old trees were more sensitive to climate change than young trees, especially under extreme climate conditions. Besides, we found that tree mortality was negatively correlated with moderate annual precipitation, winter mean minimum temperature, and stand structure (Gini), and low age, but positively correlated with low relative diameter, high density and age. The results will provide adaptive options for effective forest management of Chinese fir plantations under the backdrop of global climate change in the future.

Time of death: behavioral responses of an oceanic whitetip shark, Carcharhinus longimanus, to capture by a longline fishing vessel

BackgroundBycatch mortality in longline fisheries is a major contributor to global declines in shark populations. The duration of time that an animal is hooked and the impacts of hooking on behavior affect the likelihood of mortality. However, limited information exists on the behavior of sharks to longline capture because of difficulties observing hooking events. Using a fortuitous recovery of an archival satellite tag, we describe the movement of an oceanic whitetip shark (Carcharhinus longimanus) and examine the behavior prior to its mortality in response to hooking on a longline.ResultsA 1.5 m (fork length) C.longimanus was tagged and released in good condition by a fisheries observer following initial capture on a US longline fishing vessel. After release, the shark resumed normal vertical behavior within 5 h. Over 198 days, the shark undertook wide-ranging movements throughout the Pacific between Samoa, Niue, and Tonga. The shark was hooked by a second longline vessel while conducting routine yo-yo diving between 0 and 120 m depth. For the first hour after being hooked the shark exhibited high swimming activity with rapid vertical movements between 20 and 40 m indicative of an initial struggle against the line. After this, the shark struggled at the surface for approximately 5 h, until it succumbed to exhaustion and died on the line.ConclusionFight time has a strong influence on the mortality rates of sharks captured in commercial longline fishing operations. Data obtained from this shark offers further understanding of capture behavior and time to mortality on a longline for C.longimanus which may assist managers as they work on options to reduce mortality rates for this threatened species.

High Summer Temperatures and Heat Stroke Mortality in Spain.

Heat stroke is a significant cause of mortality in response to high summer temperatures. There is limited evidence on the pattern and magnitude of the association between temperature and heat stroke mortality. We examined this association in Spain, using data from a 27-year follow-up period. We used a space-time-stratified case-crossover design. We analyzed data using conditional quasi-Poisson regression with distributed lag nonlinear models. Spain recorded a total of 285 heat stroke deaths between 1990 and 2016. Heat stroke deaths occurred in 6% of the days in the summer months. The mean temperature was, on average, 5 °C higher on days when a heat stroke was recorded than on days without heat stroke deaths. The overall relative risk was 1.74 (95% confidence interval = 1.54, 1.96) for a 1 °C rise in mean temperature above the threshold of 16 °C, at which a heat stroke death was first recorded. We observed lagged effects as long as 10 days. Although heat stroke represents a small fraction of total heat-attributable mortality during the summer, it is strongly associated with high temperatures, providing an immediately visible warning of heat-related risk.

The adrenal stress response is an essential host response against therapy-induced lethal immune activation.

Cytokine release syndrome (CRS) is a systemic inflammatory syndrome associated with infection- or drug-induced T cell activation and can cause multiple organ failure and even death. Because current treatments are ineffective in some patients with severe CRS, we set out to identify risk factors and mechanisms behind severe CRS that might lead to preventive therapies and better clinical outcomes in patients. In mice, we found that deficiency in the adrenal stress response-with similarities to such in patients called relative adrenal insufficiency (RAI)-conferred a high risk for lethal CRS. Mice treated with CD3 antibodies were protected against lethal CRS by the production of glucocorticoids (GC) induced by the adrenal stress response in a manner dependent on the scavenger receptor B1 (SR-BI), a receptor for high-density lipoprotein (HDL). Mice with whole-body or adrenal gland-specific SR-BI deficiency exhibited impaired GC production, more severe CRS, and increased mortality in response to CD3 antibodies. Pretreatment with a low dose of GC effectively suppressed the development of CRS and rescued survival in SR-BI-deficient mice without compromising T cell function through apoptosis. Our findings suggest that RAI may be a risk factor for therapy-induced CRS and that pretreating RAI patients with GC may prevent lethal CRS.

Editorial: Forests under pressure: The need for interdisciplinary approaches to address forest vulnerability to tree mortality in response to drought

Editorial: Forests under pressure: The need for interdisciplinary approaches to address forest vulnerability to tree mortality in response to drought

Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca2+ Handling After Myocardial Infarction.

Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+ overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+ leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.

Assessing the Dynamics of COVID-19 Morbidity and Mortality in Response to Mass Vaccination: A Comparative Study Between Saudi Arabia and the United Kingdom.

Background Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, efforts have been in place to tackle the infection. Mass vaccination programs were regarded as the sole solution to end the pandemic. Here, we compare the differential impact of mass vaccination programs in Saudi Arabia (SA) and the United Kingdom (UK) on COVID-19 morbidity and mortality to determine whether vaccines were solely responsible for the changes observed in the disease dynamics. Methodology We retrospectively collected the number of new cases and deaths throughout 2021 in both SA and the UK. Similarly, the number of vaccine doses delivered in both countries was collected and compared. Results Through 2021, the percentage of daily COVID-19 cases was significantly less in SA than in the UK; however, the percentage of deaths was higher in SA. Interestingly, the percentage of daily cases was significantly reduced in SA upon vaccination. The vaccination coverage of both the first and second doses was higher in the UK compared to SA, and, consequently, the percentage of deaths was significantly reduced in the UK compared to SA. Conclusions The UK vaccination program succeeded in curbing the number of daily deaths compared to SA. SA had better control over the percentage of daily cases, primarily due to the restrictive measures and vaccination, such as the imposed social distancing and mandatory face masks.

Binding characterization of anthraquinone derivatives by stabilizing G-quadruplex DNA leads to an anticancerous activity

G-quadruplex is a non-canonical secondary structure identified in the telomeric region and the promoter of many oncogenes. Anthraquinone derivatives, a well-known inducer of telomere disruption in malignant cells and activate the apoptotic pathway. We used biophysical and biochemical studies to confirm the interaction of synthesized anthraquinone derivatives with the human telomeric G-quadruplex sequence. The binding affinity of N-2DEA and N-1DEA are K b= 4.8×106 M-1 and K b= 7.6×105 M-1, respectively, leading to hypochroism, fluorescence quenching with minor redshift and ellipticity variations indicating ligand binding in the external groove. We found that sodium ions induced stabilization more rather than potassium ions. Molecular docking of complex demonstrates a molecule's exterior binding to a quadruplex. The investigation of ROS activity indicated that the cell initiates mortality in response to the IC50 concentration. Cellular morphology, nuclear condensation, and fragmentation were altered in the treated cell, impairing cellular function. Finally, the transcriptional regulatory study paves the way for drug design as an anti-cancer agent because of the tremendous possibilities of changing substituent groups on anthraquinones to improve efficacy and selectivity for G-quartet DNA. Our research focused on how ligand binding to telomere sequences induces oxidative stress and inhibits the growth of malignant cells.

Pioglitazone Modifies Kupffer Cell Function and Protects against Escherichia coli-Induced Bacteremia in Burned Mice.

Infectious complications and subsequent sepsis in severely burned patients lead to high morbidity and mortality in response to uncontrolled innate immune responses mediated by macrophages. Peroxisome proliferator-activated receptor gamma (PPARγ) has anti-inflammatory activity and acts as a master regulator of macrophage polarization. In this study, we investigated whether the administration of a PPARγ agonist could modulate the Kupffer cell phenotype and thereby ameliorate the dysregulated innate response during post-burn bacterial infection. C57BL/6 mice were subjected to severe burns and randomized to receive either the PPARγ agonist, pioglitazone, or the vehicle control five days after injury, followed by the subsequent analysis of hepatic macrophages. Survival from the bacterial infection was monitored for seven days. Pioglitazone protected burned mice against bacterial infection. A single treatment with pioglitazone significantly enhanced phagocytosis, phagosome acidification, bacterial clearance, and reduction in inflammatory mediators in Kupffer cells. In conclusion, PPARγ activation by pioglitazone prevents clinical deterioration due to post-burn bacterial infection and improves survival. Our findings suggest that pioglitazone may be an effective therapeutic candidate for post-burn infectious complications.

Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.

Trained immunity is an innate immune memory response that is induced by a primary inflammatory stimulus that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Dietary fatty acids can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli to induce trained immunity. Here we find mice fed a diet enriched exclusively in saturated fatty acids (ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and hyperglycemia. We find KD alters the composition of the hematopoietic stem cell compartment and enhances the response of bone marrow macrophages, monocytes, and splenocytes to secondary LPS challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in KD-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA induces a hyper-inflammatory response to LPS in macrophages, and this was dependent on the synthesis of ceramide. In vivo, we found systemic PA confers enhanced inflammation and mortality in response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. Conversely, we find PA exposure enhanced clearance of Candida albicans in Rag1-/- mice. Lastly, we show that oleic acid, which depletes intracellular ceramide, reverses PA-induced hyper-inflammation in macrophages and enhanced mortality in response to LPS. These implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory and highlight the plasticity of this innate immune reprogramming by dietary constituents.

Dry forest decline is driven by both declining recruitment and increasing mortality in response to warm, dry conditions

AbstractAimAnticipating when and where changes in species' demographic rates will lead to range shifts in response to changing climate remains a major challenge. Despite evidence of increasing mortality in dry forests across the globe in response to drought and warming temperatures, the overall impacts on the distribution of dry forests are largely unknown because we lack comparable large‐scale data on tree recruitment rates. Here, our aim was to develop range‐wide population models for dry forest tree species (pinyon pine and juniper), quantifying both mortality and recruitment, to better understand where and under what conditions species range contractions are occurring.LocationWestern United States.Major taxa studiedTwo pinyon pine (Pinus spp.) and three juniper (Juniperus spp.) species.MethodsWe developed range‐wide demographic models for five species using forest inventory data from across the western United States and estimated population trends and climate vulnerability.ResultsWe find that four of the five species are declining in parts of their range, with Pinus edulis having the largest proportion of populations declining (24%). Population vulnerability increases with aridity and temperature, with up to ~50% of populations declining in the warmest and driest conditions. Mortality and recruitment were both essential to explaining where populations are declining.Main conclusionsOur results suggest that dry forest species are undergoing an active range shift driven by both changing recruitment and mortality, and that increasing temperatures and drought threaten the long‐term viability of many of these species in their current range. While four of the five species examined were experiencing some declines, P. edulis is currently most vulnerable. Management actions such as reducing tree density may be able to mitigate some of these impacts. The framework we present to estimate range‐wide demographic rates can be applied to other species to determine where range contractions are most likely.

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis.

Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. Nicotinamide adenine dinucleotide (NAD+) is an important regulator of oxidative stress and immunoinflammatory responses. However, the effects of NAD+ replenishment during inflammatory activation are still poorly defined. Hence, we investigated whether the administration of β-nicotinamide mononucleotide (β-NMN), a natural biosynthetic precursor of NAD+, could modulate the macrophage phenotype and thereby ameliorate the dysregulated inflammatory response during sepsis. For this purpose, C57BL6 mice were subjected to the cecal ligation and puncture (CLP) model to provoke sepsis or were injected with thioglycolate to induce sterile peritonitis with recruitment and differentiation of macrophages into the inflamed peritoneal cavity. β-NMN was administered for 4 days after CLP and for 3 days post thioglycolate treatment where peritoneal macrophages were subsequently analyzed. In the CLP model, administration of β-NMN decreased bacterial load in blood and reduced clinical signs of distress and mortality during sepsis. These results were supported by transcriptomic analysis of hearts and lungs 24 h post CLP-induction, which revealed that β-NMN downregulated genes controlling the immuno-inflammatory response and upregulated genes involved in bioenergetic metabolism, mitochondria, and autophagy. In the thioglycolate model, a significant increase in the proportion of CD206 macrophages, marker of anti-inflammatory M2 phenotype, was detected on peritoneal exudate macrophages from β-NMN-administered mice. Transcriptomic signature of these macrophages after bacterial stimulation confirmed that β-NMN administration limited the pro-inflammatory M1 phenotype and induced the expression of specific markers of M2 type macrophages. Furthermore, our data show that β-NMN treatment significantly impacts NAD + metabolism. This shift in the macrophage phenotype and metabolism was accompanied by a reduction in phagolysosome acidification and secretion of inflammatory mediators in macrophages from β-NMN-treated mice suggesting a reduced pro-inflammatory activation. In conclusion, administration of β-NMN prevented clinical deterioration and improved survival during sepsis. These effects relied on shifts in the metabolism of organs that face up an increased energy requirement caused by bacterial infection and in innate immunity response, including reprogramming of macrophages from a highly inflammatory phenotype to an anti-inflammatory/pro-resolving profile.

A diminished immune response underlies age-related SARS-CoV-2 pathologies.

Morbidity and mortality in response to SARS-CoV-2 infection are significantly elevated in people of advanced age. To understand the underlying biology of this phenotype, we utilize the golden hamster model to compare how the innate and adaptive immune responses to SARS-CoV-2 infection differed between younger and older animals. We find that while both hamster cohorts showed similar virus kinetics in the lungs, the host response in older animals was dampened, with diminished tissue repair in the respiratory tract post-infection. Characterization of the adaptive immune response also revealed age-related differences, including fewer germinal center B cells in older hamsters, resulting in reduced potency of neutralizing antibodies. Moreover, older animals demonstrate elevated suppressor T cells and neutrophils in the respiratory tract, correlating with an increase in TGF-β and IL-17 induction. Together, these data support that diminished immunity is one of the underlying causes of age-related morbidity.

AKT2 reduces IFNβ1 production to modulate antiviral responses and systemic lupus erythematosus

Interferon regulatory factor 3 (IRF3)‐induced type I interferon (I‐IFN) production plays key roles in both antiviral and autoimmune responses. IRF3 phosphorylation, dimerization, and nuclear localization are needed for its activation and function, but the precise regulatory mechanisms remain to be explored. Here, we show that the serine/threonine kinase AKT2 interacts with IRF3 and phosphorylates it on Thr207, thereby attenuating IRF3 nuclear translocation in a 14‐3‐3ε‐dependent manner and reducing I‐IFN production. We further find that AKT2 expression is downregulated in viral‐infected macrophages or in monocytes and tissue samples from systemic lupus erythematosus (SLE) patients and mouse models. Akt2‐deficient mice exhibit increased I‐IFN induction and reduced mortality in response to viral infection, but aggravated severity of SLE. Overexpression of AKT2 kinase‐inactive or IRF3‐T207A mutants in zebrafish supports that AKT2 negatively regulates I‐IFN production and antiviral response in a kinase‐dependent manner. This negative role of AKT2 in IRF3‐induced I‐IFN production suggests that AKT2 may be therapeutically targeted to differentially regulate antiviral infection and SLE.

T cell activation and IFNγ modulate organ dysfunction in LPS-mediated inflammation.

LPS challenge is used to model inflammation-induced organ dysfunction. The effects of T cell activation on LPS-mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti-CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high-dose LPS (LPSHi; 600μg) was 60%; similar mortality was observed with a 10-fold reduction in LPS dose (LPSLo; 60μg) when administered with CD3 (CD3LPSLo). LPSHi and CD3LPSLo cohorts suffered severe organ dysfunction. CD3LPSLo led to increased IFNγ and IL12p70 produced by T cells and dendritic cells (cDCs) respectively. CD3LPSLo caused cDC expression of CD40 and MHCII and prevented PD1 expression in response to CD3. These interactions led to the generation of CD4 and CD8 cytolytic T cells. CD3LPSLo responded to IFNγ or IL12p40 blockade, in contrast to LPSHi. The combination of TCR activation and LPS (CD3LPSLo) dysregulated T cell activation and increased LPS-associated organ dysfunction and mortality through T cell and cDC interactions.

Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory CD8 T-Cell Dysfunction.

Type 2 diabetes (T2D) causes an increased risk of morbidity and mortality in response to viral infection. T2D is characterized by hyperglycemia and is typically associated with insulin resistance and compensatory hyperinsulinemia. CD8 T cells express the insulin receptor, and previously, we have shown that insulin is able to directly modulate effector CD8 T-cell function. We therefore hypothesized that memory CD8 T-cell responsiveness in the context of T2D is negatively impacted by hyperinsulinemia or hyperglycemia. Using a mouse model for T2D, we could show that memory CD8 T-cell function was significantly reduced in response to rechallenge by viral infection or with melanoma cells. Basal insulin injection of mice increased GLUT-1 expression and glucose uptake in memory CD8 T-cell precursors early after infection, which was prevented when these cells were deficient for the insulin receptor. However, neither insulin injection nor insulin receptor deficiency resulted in a difference in metabolism, memory formation, cytokine production, or recall responses of memory CD8 T cells compared with controls. Importantly, in context of obesity, insulin receptor deficiency on CD8 T cells did not affect the functional capacity of memory CD8 T cells. In contrast, we could show in vitro and in vivo that hyperglycemia significantly impairs the antiviral capacity of memory CD8 T cells. Our findings indicate that obesity impairs the memory CD8 T-cell response against viral infection and cancer through the detrimental effects of hyperglycemia rather than hyperinsulinemia.