Stress-induced Susceptibility Research Articles

Stress-Induced Susceptibility to Sudden Cardiac Death in Mice with Altered Serotonin Homeostasis

In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT1A receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5-HT1A receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress.

Intergranular δ-hydride nucleation and orientation in zirconium alloys

A theoretical understanding of the intergranular δ-hydrides is still lacking, although hydride-related degradation of the mechanical properties of zirconium alloys has been studied for many years. In this paper a thermodynamic model is developed to analyze the nucleation and orientation of intergranular δ-hydrides. The results show that the grain boundary structure and zirconium grain orientation simultaneously govern hydride precipitation. An electron backscatter diffraction study of hydrided Zircaloy-4 provides direct evidence supporting theoretical predictions. A criterion is proposed to reveal the inherent relation between hydride precipitation at the grain boundaries and in the zirconium grains. Stress-induced susceptibility to hydride precipitation at the radial grain boundaries of zirconium alloy tubes is theoretically analyzed. This work provides a general framework based on which the correlation between the grain boundary structure, the grain orientation, the stress and their effects on the nucleation and orientation of the intergranular δ-hydrides can be clarified.

Corticotropin-releasing hormone receptor-1 and 2 activity produces divergent resistance against stress-induced pulmonary Streptococcus pneumoniae infection

Utilizing a murine model of S. pneumoniae infection and restraint stress, we determined how corticotropin releasing hormone (CRH-R) receptors impacts disease. CRH-R1 (antalarmin) and CRH-R2 (astressin2B) antagonists were administered intraperitoneally prior to restraint stress followed by pulmonary S. pneumoniae infection. CRH-R1 inhibition is not protective against pneumococcal disease induced by stress. Conversely, CRH-R2 inhibition attenuates stress-induced bacterial growth and significantly prevented severe sepsis. Neutrophillic responses were associated with CRH receptor-specific disease outcome providing a potential cellular target for stress-induced susceptibility to the development of severe pneumococcal disease. CRH receptor-mediated effects on immune responses could prove valuable for novel therapeutics.

Stressed and Depressed? Check Your GDNF for Epigenetic Repression

Some adults fail to adapt to chronic stress, developing symptoms of depression and anxiety. In this issue of Neuron, Uchida and colleagues link maladaptive stress responses to GDNF through a comprehensive investigation of the neurotrophic factor's regulation. Further, this study is an excellent example for investigators interested in neuroepigenetics research.

Abscisic Acid in Salt Stress Predisposition to Phytophthora Root and Crown Rot in Tomato and Chrysanthemum

Plants respond to changes in the environment with complex signaling networks, often under control of phytohormones that generate positive and negative crosstalk among downstream effectors of the response. Accordingly, brief dehydration stresses such as salinity and water deficit, which induce a rapid and transient systemic increase in levels of abscisic acid (ABA), can influence disease response pathways. ABA has been associated with susceptibility of plants to bacteria, fungi, and oomycetes but relatively little attention has been directed at its role in abiotic stress predisposition to root pathogens. This study examines the impact of brief salinity stress on infection of tomato and chrysanthemum roots by Phytophthora spp. Roots of plants in hydroponic culture exposed to a brief episode of salt (sodium chloride) stress prior to or after inoculation were severely diseased relative to nonstressed plants. Tomato roots remained in a predisposed state up to 24 h following removal from the stress. An increase in root ABA levels in tomato preceded or temporally paralleled the onset of stress-induced susceptibility, with levels declining in roots prior to recovery from the predisposed state. Exogenous ABA could substitute for salt stress and significantly enhanced pathogen colonization and disease development. ABA-deficient tomato mutants lacked the predisposition response, which could be restored by complementation of the mutant with exogenous ABA. In contrast, ethylene, which exacerbates disease symptoms in some host-parasite interactions, did not appear to contribute to the predisposition response. Thus, several lines of evidence support ABA as a critical and dominant factor in the salinity-induced predisposition to Phytophthora spp. infection.

Stress-Induced Susceptibility to Bacterial Infection During Cutaneous Wound Healing

Psychological stress delays wound healing and decreases immune/inflammatory responses required for bacterial clearance. To determine if stress increases the susceptibility to wound infection, female SKH-1 mice were subjected to restraint stress (RST) beginning 3 days prior to the placement of cutaneous wounds. Viable bacteria were quantified from harvested wounds. RST delayed healing by 30% and caused a 2- to 5-log increase in opportunistic bacteria (e.g., Staphylococcus aureus) when compared to wounds from control animals (p < .05). By day 7, 85.4% of the wounds from RST mice had bacterial counts predictive of infection compared to 27.4% from control mice (p < .001). To assess the role of RST-induced glucocorticoids in bacterial clearance, mice were treated with the glucocorticoid receptor antagonist RU486. RU486 reduced opportunistic bacteria by nearly 1 log in wounds from RST mice (p < .05). Thus, stress impairs bacterial clearance during wound healing, resulting in a significant increase in the incidence of opportunistic infection.

Genetic Variation in Bovine Neutrophil Sensitivity to Glucocorticoid Challenge

Blood neutrophils use CD62L and CD18 adhesion molecules to contact and migrate rapidly through blood vessels in defense against infections in underlying tissues. Previous work showed that glucocorticoid hormones repress expression of CD62L and CD18, causing neutrophilia and increased mastitis susceptibility in dairy cows. The aim of this study was to determine whether bovine neutrophil sensitivity to glucocorticoids exhibits genetic variability. Test animals included 60 pedigreed Holstein bulls treated on 3 consecutive days with a synthetic glucocorticoid (dexamethasone) and five untreated control bulls. Five indicator traits of neutrophil glucocorticoid sensitivity were monitored, including circulating neutrophil counts and two measures on each of CD62L and CD18 expression. Random regression models with treatment-specific serial correlation were used to estimate genetic and non-genetic sources of variation before, during and after glucocorticoid administration. Significant genetic variation was observed for neutrophil CD18 expression, with longitudinal heritability estimates ranging from 0.10 to 0.54 and influenced by dexamethasone. Significant genetic variation was also observed for blood neutrophil counts (heritability estimates ranging from 0.11 to 0.24) but was not influenced by dexamethasone administration. Estimated genetic correlations between circulating neutrophil counts and various indicators of CD62L and CD18 expression were large and negative (-0.44 to - 0.78). These results imply significant genetic variability and pleiotropic effects for neutrophil traits that are important for stress-induced disease susceptibility in dairy cattle and might be exploited by genetic selection.

Protective effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to), on the restraint stress-induced susceptibility against Listeria monocytogenes

In this study, the effect of traditional Japanese (Chinese) medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to, HOT), on the restraint stress treatment (RST)-induced susceptibility against Listeria monocytogenes (L. monocytogenes) was examined. When RST was performed every day for 10 h from the day of infection, the bacterial numbers were increased at 3 and 5 days after the infection. Oral pretreatment with HOT for 7 days prevented such increases. Pretreatment with HOT prevented the suppression of antigen-specific IFN-γ production by RST. HOT also prevented suppression of macrophage accumulation, including MHC-class II positives, in the peritoneal cavity and their bactericidal activity by RST. HOT suppressed the serum corticosterone level elevated by RST in infected mice. Taken together, the suppression of corticosterone using HOT participates in the prevention of suppressions of the bactericidal activity of macrophages, migration of macrophages and antigen-specific IFN-γ production of Th1 cells by RST. Our findings suggest that HOT is a useful drug for patients suffering from stress disease to reduce the susceptibility to bacterial infection.

The effect of a second dexamethasone treatment on turkeys previously challenged in an experimental Escherichia coli respiratory model of turkey osteomyelitis complex

In two separate experiments, turkeys that had survived immunosuppression with dexamethasone (DEX) and air sac inoculation with low numbers of Escherichia coli at 5 wk of age were maintained until 13 wk of age, at which time they were given a second treatment with DEX. All mortalities and birds that were necropsied 8 and 15 d (Experiment 1) and 21 d (Experiment 2) after the last DEX injection were scored for air sacculitis/pericarditis and turkey osteomyelitis complex (TOC). In both experiments, all of the lesions that characterize TOC were reproduced, including osteomyelitis of the proximal tibia, synovitis/tendonitis, abscesses in the soft tissues, and green liver. In Experiment 1, all mortalities after Day 7 had TOC lesions, whereas 44% of mortalities had green livers. Staphylococcus aureus was isolated from 90% of all TOC lesions cultured. In Experiment 2, the incidence of mortality, air sacculitis, TOC, and green liver as well as the heterophil:lymphocyte ratio were significantly higher in birds that had previously been treated with DEX but had never been challenged with E. coli than in birds that had survived both treatment with DEX and challenge with 25 or 50 cfu of E. coli. Staphylococcus aureus was isolated from 73% of TOC lesions cultured, whereas E. coli was isolated from only 5.4% of the lesions. These studies suggest that TOC incidence may be related to a stress-induced susceptibility to opportunistic infection.

Susceptibility of larvae of the mushroom fly Megaselia halterata to the entomopathogenic nematode Steinernema feltiae in bioassays

Bioassays were initially conducted in Petri-dishes to screen the efficacy of four Heterorhabiditis and Steinernema species against the mushroom phorid Megaselia halterata. Control rates of 61 to 70% control were obtained at a dosage of 1500 infective juveniles (IJs) per 30 larvae. In order to avoid stress-induced susceptibility, an improved bioassay system in micro-wells, filled with 0.6 ml of compost agar and 0.2 of compost colonized by Agaricus bisporus, was developed. In a screening of different species of Heterorhabiditis and Steinernema with applications of 30 IJs per phorid larva, a highest parasitization rate of 20% was obtained with S. feltiae. Bioassays were continued with S. feltiae in dosage-mortality assays in which larvae of the sciarid Lycoriella auripila and the phorid M. halterata were challenged. At the lowest dosage of 30 IJs per sciarid larva, 78% control was obtained. Increasing the dosage from 30 to 1000 led to only small increases of the phorid mortality. At 1000 IJs per larva a significant mortality of 18% was obtained. The nature of the substrate, compost or casing did not greatly influence the parasitization rates. The sex ratio of nematodes that were able to penetrate and establish in the phorid larvae appeared to be female-skewed. Males were only present at a mean of 19%. Low susceptibility of the phorid larva was ascribed to the inaccessibility of its small mouth opening.