Immunosuppressive effect and global dysregulation of blood transcriptome in response to psychosocial stress in vervet monkeys (Chlorocebus sabaeus)

Abstract

Psychosocial stressors-life events that challenge social support and relationships-represent powerful risk factors for human disease; included amongst these events are relocation, isolation and displacement. To evaluate the impact of a controlled psychosocial stressor on physiology and underlying molecular pathways, we longitudinally studied the influence of a 28-day period of quarantine on biomarkers of immune signalling, microbial translocation, glycaemic health and blood transcriptome in the wild-born vervet monkey. This event caused a coordinated, mostly transient, reduction of circulating levels of nine immune signalling molecules. These were paralleled by a massive dysregulation of blood transcriptome, including genes implicated in chronic pathologies and immune functions. Immune and inflammatory functions were enriched among the genes downregulated in response to stress. An upregulation of genes involved in blood coagulation, platelet activation was characteristic of the rapid response to stress induction. Stress also decreased neutrophils and increased CD4 + T cell proportions in blood. This model of psychosocial stress, characterised by an immune dysregulation at the transcriptomic, molecular and cellular levels, creates opportunities to uncover the underlying mechanisms of stress-related diseases with an immune component, including cardiovascular diseases and susceptibility to infections. Psychosocial stress is a key risk factor for numerous chronic diseases, particularly cardiovascular (e.g., hypertension and atherosclerosis), metabolic (e.g., diabetes), and neuro-psychiatric morbidity (e.g., depression and anxiety, substance use disorders, neurodegenerative disease and psychosis) 1-8. Stress responses constitute an adaptive strategy for maintaining bodily homeostasis in physically or psychologically challenging situations and are, in part, orchestrated by the hypothalamus-pituitary-adrenal (HPA) axis and controlled by its end products, glucocorticoids, through a negative feedback loop. However, prolonged exposure to stress, chronic activation of the HPA, and continuous secretion of glucocorticoids exert maladaptive effects and lead to the wide range of health complications mentioned above. Cortisol is regarded as a major mediator of a range of stress responses affecting many body systems, including the suppression of HPA activity, regulation of immune functions, glucose metabolism, and gene expression across different organ systems and, if chronically elevated, is a key driver of stress-related pathologies. Cortisol is commonly used physiological indicator of an individual's response to stress; 9,10 notably, however, this relationship is moderated by multiple biological and environmental variables (including-but not limited to

Epigenetic clock and methylation studies in vervet monkeys

“…Vervets exhibit some aspects of human aging, including neurodegeneration [29][30][31][32], and reproductive senescence and menopause [33]. Vervets have also been used in studies of reproductive physiology and obesity [34], the effects of genes and diet on growth and obesity [35], cardiometabolic health [36], physiological and behavioral stress responses [37][38][39], and multi-tissue genetic regulation of gene expression, including that in tissues involved in stress responses [40]. Because it is a natural host of simian immunodeficiency virus, which typically does not progress to immunodeficiency upon infection, the vervet is an established model for AIDS research [41][42][43][44].…”

Epigenetic clock and methylation studies in vervet monkeys

“…Vervets exhibit some aspects of human aging, including neurodegeneration (Postupna et al 2017;Kalinin et al 2013;Chen et al 2018;Latimer et al 2019), reproductive senescence and menopause (Atkins et al 2014). Vervets have also been used in studies of reproductive physiology and obesity (Kuokkanen et al 2016), the effects of genes and diet on growth and obesity (Schmitt et al 2018), cardiometabolic health (Voruganti et al 2013), physiological and behavioral stress responses Jasinska, Pandrea, et al 2020), and multi-tissue genetic regulation of gene expression, including that in tissues involved in stress responses (Jasinska et al 2017). Because it is a natural host of simian immunodeficiency virus, which typically does not progress to immunodeficiency upon infection, the vervet is an established model for AIDS research (Pandrea et al 2006;Chahroudi et al 2012;Ma et al 2013;Ma et al 2014).…”