genomewide characterization of host-pathogen interactions by ...

Maren Depke
S U M M A R Y O F D I S S E R T A T I O N
Humans and animals regularly encounter microorganisms like bacteria and need to defend
themselves in order to avoid or limit damage. The host developed defense mechanisms to either
avoid infection or to overcome it, whereas the pathogen gained mechanisms to evade these host
defense strategies. The host’s immune system is not only influenced by its own regulatory
mechanisms and by the pathogens’ factors, but also by additional elements like physical efforts
or the psychological state of the organism. While short stressful episodes might even enhance
the immune response, the immune response can be suppressed when the stress becomes
chronic. But not only the immune system, but also metabolic processes might underlie
modification by such stressors. Therefore, the improvement of knowledge on host-pathogen
interactions helps to elucidate mechanisms which benefit either host or pathogen. It will
contribute to the establishment of new intervention strategies during infectious diseases. This
thesis contains results from transcriptome studies on different aspects of host-pathogen
interactions.
First, liver gene expression profiles from a murine chronic stress model served to elucidate
aspects of the influence of stress on the metabolism and the immune response state of the
animals. Psychological and physiological stressors can disturb neuroendocrine, immunological,
behavioral, and metabolic functions and adaptive physiological processes aim to reconstitute a
dynamic equilibrium. Recently, Kiank et al. described that BALB/c mice developed severe
systemic immune suppression, neuroendocrinological disturbances and depression-like behavior
due to 4.5 days of intermittent combined acoustic and restraint stress which served as a murine
model of severe chronic psychological stress (Kiank et al. 2006; Brain Behav Immun. 20(4):359).
Furthermore, mice subjected to chronic stress suffered from severe loss of body mass. Therefore,
gene expression profiles of the liver, which plays the major role in metabolism, were analyzed to
investigate primary causes for the observed loss of body weight. The liver fulfills an important
function as a gatekeeper between the intestinal tract and the general circulation. Thus, the
influence of psychological stress on immune regulatory processes in the liver was additionally
investigated in the gene expression data set.
Hepatic gene expression profiles of stressed mice exhibited distinct changes even after a
single acute stress session. Although metabolic disturbances were not visible yet, a regulatory
gene expression cascade started at that time point which led to the disturbances observed when
stress had become chronic. Considering chronically stressed mice, genes related to metabolic
diseases were most significantly influenced. Differential expression affected carbohydrate, amino
acid, and lipid metabolism. Chronic stress in female BALB/c mice was shown to lead to a
hypermetabolic syndrome including induction of gluconeogenesis, hypercholesteremia, and loss
of essential amino acids. Additionally, the analysis of liver homogenates of acutely and
chronically stressed mice revealed an altered mRNA expression of immune response genes.
These included the induction of the acute phase response, but also of immune suppressive
pathways. Furthermore, repression of hepatic antigen presentation was observed. In chronically
stressed mice, increased leukocyte trafficking, increased oxidative stress together with counterregulatory
gene expression changes, and an induction of apoptosis were detected.
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