genomewide characterization of host-pathogen interactions by ...

Maren Depke
Introduction
host as well as pathogen, developed mechanisms to fight or to gain some advantage against the
other. The host developed defense mechanisms to either avoid infection or to overcome it,
whereas the pathogen gained mechanisms to evade these host defense strategies. One part of
the host’s immune defense is the innate immune system, for which the detailed information is
encoded in the genome and which has been passed on and further modified and optimized
during evolution. The host as a complex organism commands two main levels of such immune
defense, non-cellular and cellular. On epithelial barriers, the host deposits antimicrobial peptides,
which are often membrane-active and pore-forming and aim to lyse the pathogen during its
attempt to enter the body (Schröder 1999). Also enzymes like lyzozyme are secreted and serve a
similar function.
A very important and complex defense system of cascade-activated components is the
complement system (Dunkelberger/Song 2010). The complement system consists of several
serum proteins, which interact and build complexes, contain several sequential and
interdependent activation steps and enzymatic activities, and finally achieves three main goals:
First, in a process called opsonization the labeling of pathogens with a molecular tag to render it
recognizable for phagocytosis, and second the lysis of the pathogen by pore-forming
components. The third function during activation of the complement is to pass the information of
occurring infection to the other immune defense systems.
Three activation pathways of the complement system exist (Fig. I.1). The first, called classical
pathway, is linked to the non-innate, i. e. adaptive immune system, because it relies in the first
step on antibodies, which recognize specific pathogenic structures. Pathogen surface bound
antibodies bind and activate the C1 factor of the complement system. The following steps of
proteolytic cleavage produce from factors C2 and C4 the smaller “a” and the bigger “b”
fragments. C2a and C4b together form the first very important complex during complement
activation, the C3-convertase, which cleaves C3 into C3a and C3b. The C3-convertase (via C4b)
and C3b will be covalently bound to the pathogen’s cell surface after reaction of an active
thioester bond and accomplish opsonization.
The second complement activation pathway leads to the same effects, but starts with a
different recognition complex including lectins (Fujita et al. 2004). This lectin-activation pathway
does not require antibodies bound to the surface of the pathogen. Here, mannose-binding lectin
(MBL) or ficolin recognize conserved carbohydrate structures of the pathogen. These molecules
belong to the so-called pattern recognition receptors (PRRs), conserved and non-variable
receptors for conserved pathogenic structures, which in turn are called pathogen-associated
molecular patterns (PAMPs). MBL or ficolin are complexed, among others, with a serine protease
(MASP), which achieves the next activation steps of C2 and C4 and formation of the C3-
convertase as described before in the classical pathway.
The third way of complement activation is named alternative pathway. For activation, it uses
the spontaneous hydrolysis of C3 in the plasma to C3(H 2 O), which exposes the molecular site for
covalent binding to pathogenic surfaces. In the presence of such surface, C3(H 2 O) binds to it and
subsequently complement factor B to C3(H 2 O). Finally, factor D cleaves factor B into the
fragments Ba and Bb. The resulting complex of C3(H 2 O)Bb constitutes the initial C3-convertase of
the alternative pathway and cleaves further C3 molecules. The resulting C3b fragments again
opsonize the pathogen, but also bind factor B and D, and form further C3-convertase complexes
C3bBb. At this step, a strong amplification takes place, also when the C3b fragments are derived
from activation of the classical and lectin pathway.
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