Immune or stressed? This is the question

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We are surrounded by bacteria, viruses, and fungi. Some of them may cause serious harm. At the same time, people and animals are exposed to stress, which is an element of daily life. Thus, it is worth asking about the connection between stress and immune response. This issue is the subject of research conducted by scientists from the Department of Evolutionary Immunology at the Institute of Zoology of the Jagiellonian University.

Stress is often defined as a reaction of the body to each adverse change. The occurrence of a so-called stressor, i.e., a stressing factor, activates the HPA axis (hypothalamus-pituitary-adrenal glands). A stressor stimulates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which in turn stimulates the pituitary gland to release corticotropin, thus stimulating the adrenal glands to produce cortisol. This last hormone prepares our body for an effective response to stress by increasing the level of glucose and free amino acids in the blood and by raising the blood pressure.

Stress is not our only concern. We are surrounded by an enormous number of pathogenic microorganisms – bacteria, viruses and fungi – which multiply very quickly after infecting the body. Thus, one of the fundaments of our existence must also be the skillful fight with constantly invading pathogens. However, the course of a specific infection is the result not only of the functioning of the immune system, but also depends on mutual interactions between the host, the pathogen, the environment, and, in particular, stressors originating from this environment.

Viruses "wake up" during stress

For a long time the prevailing view was that the neuroendocrine system (responsible for the functioning of the nervous and hormonal systems) and the immune system functioned independently. It was believed that the neuroendocrine system, by acting through hormones and neurotransmitters, enables maintaining of the body balance and influences growth and reproduction, while the immune system, by utilizing leukocytes and regulating factors such as cytokines, fights only with pathogens. However, increased information about the fact that stress influences the pace of healing wounds, the course of cancer, etc., led to these views being modified. A characteristic example illustrating the influence of stress on immunity is the occurrence of sores caused by the herpes virus precisely in situations of stress, e.g., during the exam session. This virus remains "asleep" when stress levels are low.

However, it should be remembered that information on this issue published in the media and online is very often unsupported by reliable scientific research. The main aim of such news is to convince potential customers that various handbooks, relaxation therapies, herbs, aromatic oils, and diet supplements are cure-alls for even the most serious illnesses and will allow such customers to maintain good health forever. Although it cannot be excluded that some of the proposed therapies may prove valuable, even if only by supporting conventional treatment, it should be remembered that many of them are currently based on unsubstantiated claims, not on actual knowledge.

Are fish stressed? What are the results of such stress?

Scientists from the Department of Evolutionary Immunology of the Institute of Zoology of the Jagiellonian University have been studying the influence of the neural and hormonal system on immunity for more than a decade. They are particularly interested in finding an answer to the question of whether factors participating in stress response, such as cortisol and adrenalin released after stress, can influence the immunity of animals in such way that makes them more susceptible to pathogens. Research initially conducted mainly with laboratory mice was soon complemented by experiments with cold-blooded vertebrates, including fish. This approach enables the detection of evolutionarily old but important mechanisms regulating immune response. Additionally, it has practical value, as it might contribute to the development of a new fish breeding strategy, in which instead of high doses of chemotherapeutics and antibiotics, the natural ability of the body to fight pathogens will be utilized to limit animal mortality due to infection. It is worth mentioning here that the intensification of animal breeding results more often in excessive population density, which causes serious stress and facilitates the spreading of infection.

The objective of the research project "Links between sensitivity to stress and the effectiveness of immune response in fish" carried out since 2010 at the Department of Evolutionary Immunology and financed by the National Centre of Science is to determine whether different sensitivity to stress is responsible for varied susceptibility to pathogens and thus for varied mortality rates in carp from several breeding lines. The project is conducted in cooperation with the Institute of Ichtyobiology and Aquaculture of the Polish Academy of Sciences in Gołysz and the Cell Biology and Immunology Group at Wageningen University in Holland. The first of these centers has a unique collection of various lines of carp, differing not only in respect to genetic structure, but also by growth rates, survival rates, and immune response to infections, both in ponds and in laboratory conditions. In addition, Wageningen University is the world leader in research on immunity in carp.

The research focuses on the determination of whether changes in levels of hormones responsible for activation of the HPA axis (e.g., cortisol) and their receptors influence the course of the immune response (e.g., the level of cytokines and their receptors). The levels of all these factors are measured both in the organs constituting the HPA axis(hypothalamus, pituitary and head kidney (pronephros), which in fish is the equivalent of mammalian adrenal glands) and in the organs and cells that constitute the immune system. Scientists analyze changes in these factors both in animals subject to stress and in infected animals, thus enabling the scientists to determine the nature and intensity of the link between the activity of the HPA axis and the observed immune response.

Thus far, it has been proven that carp originating from the breeding line characterized by the highest sensitivity to bacterial and parasitic infections (Dutch line R3xR8) also have a significantly higher cortisol level (both in stressed and non-stressed individuals) as compared to fish from lines characterized by lower sensitivity to infection (carp from Polish line R2). Moreover, it has been proven than the level of expression of genes encoding stress hormone receptors in the hypothalamus of carp from the R2 line is lower than that of fish from the R3xR8 line. In other words, genetic information connected with response to stress in these fish is activated to a lesser degree.

The obtained knowledge will enable us to select individuals characterized by low susceptibility to stress and high resistance to pathogens. This then will constitute a basis for starting innovative selection programs.

Moreover, scientists hope that the knowledge of mechanisms that regulate response to stress and the immune response obtained in the course of research will enable us to strengthen natural immunity in humans and to limit the use of pharmaceutical products in the future.

Research team from the Jagiellonian University: Magdalena Chadzińska, PhD – Project Manager; Elżbieta Kołaczkowska, PhD; Magdalena Kępka, MSc; Łukasz Pijanowski, MSc; Małgorzata Klimek, PhD Scientific coperation: Lidy Verburg-van Kemenade, PhD - Cell Biology and Immunology Group, Wageningen University, The Netherlands; Ilgiz Irnazarow, PhD; Patrycja Jurecka, PhD - Institute of Ichtyobiology and Aquaculture of the Polish Academy of Sciences in Gołysz