Drivers of Infectious Disease Seasonality: Potential Implications for COVID-19.

Not 1 year has passed since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Since its emergence, great uncertainty has surrounded the potential for COVID-19 to establish as a seasonally recurrent disease. Many infectious diseases, including endemic human coronaviruses, vary across the year. They show a wide range of seasonal waveforms, timing (phase), and amplitudes, which differ depending on the geographical region. Drivers of such patterns are predominantly studied from an epidemiological perspective with a focus on weather and behavior, but complementary insights emerge from physiological studies of seasonality in animals, including humans. Thus, we take a multidisciplinary approach to integrate knowledge from usually distinct fields. First, we review epidemiological evidence of environmental and behavioral drivers of infectious disease seasonality. Subsequently, we take a chronobiological perspective and discuss within-host changes that may affect susceptibility, morbidity, and mortality from infectious diseases. Based on photoperiodic, circannual, and comparative human data, we not only identify promising future avenues but also highlight the need for further studies in animal models. Our preliminary assessment is that host immune seasonality warrants evaluation alongside weather and human behavior as factors that may contribute to COVID-19 seasonality, and that the relative importance of these drivers requires further investigation. A major challenge to predicting seasonality of infectious diseases are rapid, human-induced changes in the hitherto predictable seasonality of our planet, whose influence we review in a final outlook section. We conclude that a proactive multidisciplinary approach is warranted to predict, mitigate, and prevent seasonal infectious diseases in our complex, changing human-earth system.

The circadian syndrome predicts cardiovascular disease better than metabolic syndrome in Chinese adults.

BACKGROUND: To compare the predictive value of the circadian syndrome (CircS) and Metabolic syndrome (MetS) for cardiovascular disease. METHOD: We used the data of 9360 Chinese adults aged ≥40 years from the 2011 China Health and Retirement Longitudinal Study (CHARLS). Of the participants, 8253 people were followed in the 2015 survey. MetS was defined using the harmonized criteria. CircS was based on the components of the International Diabetes Federation (IDF) MetS plus short sleep and depression. The cut-off for CircS was set as ≥4. Multivariable logistic regression analysis was used to examine the associations. RESULTS: The prevalence of CircS and MetS was 39.0% and 44.7%. Both MetS and CircS were directly associated with prevalent CVD. The odds ratios for prevalent CVD comparing CircS with MetS, respectively, were 2.83 (95%CI 2.33-3.43) and 2.34 (1.93-2.83) in men, and 2.33 (1.98-2.73) and 1.79 (1.53-2.10) in women. Similar associations were found for incident CVD. The five-year incidence of CVD was 15.1% in CircS and 14.0% in MetS. The number of CircS components has a better predictive power for both prevalent and incident CVD than those of Mets components as indicated by the area under the ROC (AUC). AUC values for CVD in 2011 were higher for CircS than MetS in both men (0.659 (95%CI 0.634-0.684) vs 0.635 (95%CI 0.610-0.661)) and women (0.652 (95%CI 0.632-0.672) vs 0.619 (95%CI 0.599-0.640)). CONCLUSION: The circadian syndrome is a strong and better predictor for CVD than the metabolic syndrome in Chinese adults.

The Circadian Syndrome: is the Metabolic Syndrome and much more!

The Metabolic Syndrome is a cluster of cardio-metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio-economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the 'Circadian Syndrome'. With the increased recognition of the 'Circadian Syndrome', circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

Disrupted seasonal biology impacts health, food security and ecosystems.

The rhythm of life on earth is shaped by seasonal changes in the environment. Plants and animals show profound annual cycles in physiology, health, morphology, behaviour and demography in response to environmental cues. Seasonal biology impacts ecosystems and agriculture, with consequences for humans and biodiversity. Human populations show robust annual rhythms in health and well-being, and the birth month can have lasting effects that persist throughout life. This review emphasizes the need for a better understanding of seasonal biology against the backdrop of its rapidly progressing disruption through climate change, human lifestyles and other anthropogenic impact. Climate change is modifying annual rhythms to which numerous organisms have adapted, with potential consequences for industries relating to health, ecosystems and food security. Disconcertingly, human lifestyles under artificial conditions of eternal summer provide the most extreme example for disconnect from natural seasons, making humans vulnerable to increased morbidity and mortality. In this review, we introduce scenarios of seasonal disruption, highlight key aspects of seasonal biology and summarize from biomedical, anthropological, veterinary, agricultural and environmental perspectives the recent evidence for seasonal desynchronization between environmental factors and internal rhythms. Because annual rhythms are pervasive across biological systems, they provide a common framework for trans-disciplinary research.

Spontaneous caloric restriction associated with increased leptin levels in obesity-resistant αMUPA mice.

BACKGROUND: αMUPA mice carry as a transgene the cDNA encoding urokinase-type plasminogen activator, a member of the plasminogen/plasmin system that functions in fibrinolysis and extracellular proteolysis. These mice spontaneously consume less food when fed ad libitum and live longer compared with wild-type (WT) control mice. αMUPA mice are obesity resistant and they share many similarities with calorically restricted animals. However, extensive metabolic characterization of this unique transgenic model has never been performed. METHOD: Metabolism of αMUPA mice was analyzed by measuring hormone, lipid and glucose levels in the serum, as well as gene and protein expression levels in the liver, hypothalamus and brainstem. RESULTS: αMUPA mice were found to be leaner than WT mice mainly because of reduced fat depots. Serum analyses showed that αMUPA mice have high levels of the anorexigenic hormones insulin and leptin, and low levels of the orexigenic hormone ghrelin. Analyses of brain neuropeptides showed that the transcript of the anorexigenic neuropeptide Pomc is highly expressed in the brainstem, whereas the expression of the orexigenic neuropeptides Npy, Orexin and Mch is blunted in the hypothalamus of αMUPA mice. In addition, adenosine monophosphate (AMP)-activated protein kinase (AMPK) levels were higher in the liver and lower in the hypothalamus, thus promoting simultaneously central reduction in appetite and peripheral loss of fat. The levels of SIRT1 were low in the liver, but high in the hypothalamus, a feature that αMUPA mice share with calorically restricted animals. CONCLUSION: Taken together, αMUPA mice exhibit a unique metabolic phenotype of low-calorie intake and high leptin levels, and could serve as a model for both spontaneous calorie restriction and resistance to obesity.

Hyperleptinemia in pregnant bats is characterized by increased placental leptin secretion in vitro.

Hyperleptinemia is a common feature of pregnancy in mammals. The source of increased plasma leptin is uncertain. We examined leptin secretory rates in vitro to test the hypothesis that leptin secretion is upregulated during pregnancy. Two species of insectivorous bats were examined, Myotis lucifugus and Eptesicus fuscus, because of their unique reproductive cycle. Body mass and plasma leptin significantly increased with gestation and decreased during lactation. Adiposity increased in midgestation, then decreased in late gestation and lactation and was not significantly correlated with plasma leptin in pregnant or early lactating individuals. Leptin secretion in vitro per gram of adipose tissue tended to increase with gestation but was not significantly correlated with plasma leptin in the same individuals. Leptin secretion from placentae, however, increased with gestation and was significantly correlated with plasma leptin from the same individuals. In suckling pups, plasma leptin was high shortly after birth, then decreased to low levels that were not correlated with adiposity thereafter. We conclude that in bats, the placenta is a major source of circulating leptin during pregnancy, and that adiposity and plasma leptin levels are decoupled during three different periods of intense metabolic demand (pregnancy, early lactation, and neonatal growth).

Temporal partitioning among diurnally and nocturnally active desert spiny mice: energy and water turnover costs.

Nocturnal Acomys cahirinus and diurnally active A. russatus coexist in hot rocky deserts. Diurnal and nocturnal activity exposes them to different climatic challenges. A doubly-labelled water field study revealed no significant differences in water turnover between the species at all seasons, reflecting the adaptations of A. russatus to water conservation. In summers the energy expenditure of A. russatus tended to be higher than that of A. cahirinus. Energy requirements of A. cahirinus in winter are double than that of A. russatus, and may reflect the cost of thermoregulating during cold nights.

Dissociation of leptin secretion and adiposity during prehibernatory fattening in little brown bats.

Hibernating animals deposit adipose tissue before hibernation to withstand long periods of reduced energy intake. Normally, adiposity is positively correlated with increased secretion from adipose tissue of the satiety hormone, leptin. During the prehibernatory phase of the little brown bat, Myotis lucifugus, body mass and adiposity increased to a maximum within 12 days. Leptin secretion from adipose tissue in vitro and plasma leptin, however, increased before the increase in adiposity, then significantly decreased when adiposity increased. Basal metabolic rate (BMR) decreased when plasma leptin was increasing. This was followed by an increase in nonshivering thermogenic capacity and brown adipose tissue mass. We conclude that in the early prehibernatory phase, BMR decreases despite increasing plasma leptin levels, suggesting a state of relative leptin resistance at that time. At later stages, adiposity increases as BMR continues to decrease, and plasma leptin becomes dissociated from adiposity. Thus, in M. lucifugus, hibernation may be achieved partly by removing the metabolic signal of leptin during the fattening period of prehibernation.

Steroid-dependent up-regulation of adipose leptin secretion in vitro during pregnancy in mice.

Circulating leptin levels are elevated during the later stages of pregnancy in mammals, suggesting that maternal leptin may play a role in maintenance of pregnancy and/or preparation for parturition and lactation. The regulation and source of circulating leptin during pregnancy remains undetermined, but leptin mRNA levels increase in adipose tissue during this time in some species. Considerable controversy exists whether placenta is also a leptin-secreting tissue during pregnancy. Here, we directly demonstrate that leptin secretion rates from mouse adipose tissue in vitro are decreased during early pregnancy and up-regulated during late pregnancy and lactation. Changes in leptin secretion rates in vitro paralleled those of circulating leptin in vivo during gestation. Subcutaneous implants of estradiol or corticosterone into lactating mice for 48 h stimulated adipose leptin secretion rates in vitro to the level of that in pregnant mice. However, corticosterone, but not estradiol, increased leptin secretion when added to isolated adipose tissue in vitro. Placentae obtained at two stages of pregnancy did not secrete leptin in vitro, either when acutely isolated or when dissociated into cells for long-term cultures. Placental tissue (or cells) secreted progesterone, however, demonstrating placental viability. We conclude that hyperleptinemia during late pregnancy in mice primarily results from corticosterone-dependent up-regulation of leptin secretion from adipose tissue, and that the placenta does not contribute to leptin secretion. The initial decrease in leptin secretory rates from adipose tissue during early pregnancy may facilitate energy storage for the subsequent, increased metabolic demands of later pregnancy and lactation.

Seasonal thermogenic acclimation of diurnally and nocturnally active desert spiny mice.

Diurnally active golden spiny mice (Acomys russatus) and nocturnal common spiny mice (Acomys cahirinus) coexist in hot rocky deserts of Israel. Diurnal and nocturnal activities expose these species to different climatic conditions. Nonshivering thermogenesis (NST) capacity of individuals of both species immediately upon removal from the field exhibited seasonal changes, with no significant interspecific difference. Colony-reared mice of either species transferred in the laboratory from long to short photoperiod increased NST capacity, though to a lesser extent than observed in the seasonal acclimatization. The underlying biochemical mechanisms of short photoperiod acclimation differed between the species. In both Cytochrome-c oxidase (Cox) activity was higher in short as compared to long photoperiod. In short-photoperiod-acclimated A. cahirinus uncoupling protein (UCP) content in brown adipose tissue (BAT) was significantly higher than in long photoperiod, while in A. russatus there was no significant change. In A. russatus there was a significant increase in lipoprotein lipase (LPL) activity in BAT in short-photoperiod-acclimated individuals, while in A. cahirinus LPL activity was high under both acclimations. The low LPL activity in brown adipose tissue of desert-adapted A. russatus may facilitate lipid uptake in white adipose tissue, an advantage in desert conditions where food is scarce and irregularly distributed in space and time.