genomewide characterization of host-pathogen interactions by ...

Maren Depke
Results
Kidney Gene Expression Pattern in an in vivo Infection Model
An essential part of the immune response to infection is the presentation of antigens to
immune cells to direct the defense against the specific pathogen in the adaptive part of the
immune system. Antigens belong to two main groups, extracellular and intracellular antigens,
which are processed in separate pathways. Extracellular antigens are taken up by
phagocytosis/endocytosis and digested in vesicles after fusion with lysosomes. Finally, peptides
are bound to MHC-II molecules originating from exocytic Golgi vesicles and presented on the cell
surface. Intracellular antigens are digested by cytosolic proteasome with sequential transport of
peptides into the endoplasmatic reticulum (ER). These peptides are loaded to MHC-I molecules
and transported via the Golgi to the cell surface for presentation. Presentation of extracellular
antigens preferentially occurs by professional antigen presenting cells (APC) like dendritic cells
(DC), macrophages and B cells. The peptide-MHC-II complex is recognized by CD4 + helper T cells,
which leads to initiation of mechanisms fighting extracellular infection or disposing extracellular
antigens. Immune cells and other cells of the body are capable of presenting intracellular
antigens via MHC-I. They present the antigenic peptide to CD8 + cytotoxic T cells and thereby
activate processes to destroy cells and kill pathogen in case of intracellular infection.
For both pathways an increase in transcription of associated genes was observed after
infection (Fig. R.2.12). The immune-proteasome genes Psmb9, Psmb10, and Psmb8 (LMP2,
LMP7), coding for proteins in the 20S-core of the proteasome, were induced leading to an
immune-response specific reorganization of the proteasomes’ catalytic center. For the genes
Psme1 and Psme2, which contribute to the 11S regulatory complex of the proteasome, a trend of
induction was visible. Induced were also the peptide transporters Tap1 and Tap2 and the TAPbinding
protein tapasin/TPN (Tapbp), which attaches the TAP molecules to the MHC-I complex.
The ER aminopeptidase Erap1, which is responsible for N-terminal trimming of the peptide in the
ER, was induced in tendency. Finally, MHC-I molecules (H2-D1, H2-K1, H2-Q6, H2-Q7, H2-Q8) and
Beta-2-microglobulin (MHC-I-β; B2m) were induced, too.
In the pathway for presentation of extracellular antigens MHC-II molecules (H2-Aa, H2-Ab1,
H2-DMa, H2-DMb1, H2-Ea, H2-Eb1) and the invariant chain Cd74 (CLIP) were increased. Induction
of lysosomal enzymes, particularly of cathepsins, was also observed (Chi3l1, Chi3l3, Hpse, Ctsc,
Ctse, Ctss; induced by trend: Gla, Ctsd, Ctsk, Ctsl).
Fig. R.2.12: Antigen Presentation (modified from IPA, www.ingenuity.com). Red color indicates increase of expression.
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