genomewide characterization of host-pathogen interactions by ...

Maren Depke
Summary of Dissertation
The in vivo model of psychological stress in a complex mammalian host was performed
without additional influences of a pathogen. This additional factor was addressed in the second
study: Here, the influence of staphylococcal intra-venous infection on the host kidney gene
expression was analyzed in another murine in vivo model using the wild type strain
Staphylococcus aureus RN1HG and its isogenic sigB mutant.
S. aureus, a Gram-positive bacterium, is a persistent commensal in the anterior nares of
approximately 20 % of the human population. The bacterium is found intermittently in 30 % to
60 % of the population, and in non-carriers, which is the remaining fraction of the population,
nasal swabs are never positive for S. aureus. Normally, such carriage does not cause any
symptoms of illness. On the other hand, S. aureus can be responsible for a broad variety of
diseases: S. aureus can cause mild to severe local infections of skin or pharyngeal mucosa, but
also of inner organs (e. g. endocarditis, osteomyelitis) and systemic disease like sepsis. S. aureus
can be transmitted to the blood after body injury or by medical devices like catheters. An
elementary model to mimic blood stream infection is the i. v. infection of laboratory animals, e. g.
mice. Host reactions can be monitored by physiological, immunological or molecular readout
systems. In this study, transcriptome analysis of murine kidney samples was performed.
Although the virulence of sigB deficient strains is often reported to be similar to that of wild
type strains the pathogenesis or pathomechanism of different infection settings might vary.
Therefore, the rationale of this study was to investigate whether the deletion of sigB will lead to
a different reaction of the infected host. Gene expression profiling indicated a highly
reproducible host kidney response to infection with S. aureus. The comparison of infected with
non-infected samples revealed a strong inflammatory reaction of kidney tissue. This included e. g.
Toll-like receptor signaling, complement system, antigen presentation, interferon and IL-6
signaling, but also counter-regulatory IL-10 signaling. However, the results of this study did not
provide any hints for differences in the pathogenesis or pathomechanism of the S. aureus strains
RN1HG and ΔsigB in the selected model of i. v. infection in mice, since the host response did not
differ between infections with the two strains analyzed. If really existing, such differences might
be transient and only apparent at earlier time points. Effects of SigB might also be compensated
for in in vivo infection by the interlaced pattern of other regulators. There is also the possibility of
missing activity of SigB in vivo which could explain the similarity of host reaction to infection with
S. aureus RN1HG and its sigB mutant in this study. SigB might possess only to a lesser extent
characteristics attributed to virulence factors and might act in vivo more like a virulence
modulator and fine tune bacterial reactions, or SigB might be important in special niches during
infection. Assuming such function failure to detect differences in the host’s reaction to S. aureus
RN1HG and its isogenic sigB mutant could be explained.
Tissue expression profiling from in vivo models has the advantage of directly recording the
relevant physiological state with all its complex interactions and influences and its vicinity to
medical questions in the human. Nevertheless, it is very difficult to distinguish the different
components because the tissue samples are always a mixture of different cell types which might
even feature contrary reactions. Therefore, in vitro models were additionally analyzed in which
only one defined host cell type was studied. Macrophages are an example for an immune cell
type involved in the first steps of the encounter between the host and a pathogen. In the innate
immune system, macrophages, together with dendritic cells, hold a central position. They are
main effectors of the clearance of infections by their sentinel and phagocytic function.
Macrophages present phagocytosed antigen derived peptides on MHC-II to lymphocytes. By this
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