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glycans, but may also bind GlcNAc-containing glycans as well (
Zhang et al., 2006
).
DC-SIGN promotes phagocytosis and MHC class II antigen presentation of
bacteria, viruses, fungi, and parasites, including
Helicobacter pylori
and
Myco-
bacterium tuberculosis
. In response to LPS from
E. coli
O55 (which contains
GlcNAc, Gal, GalNAc, and colitose (
Stenutz et al., 2006
)), a subpopulation
of monocytes differentiate into DC-SIGN
+
dendritic cells in a TLR4/CD14-
dependent manner (
Cheong et al., 2010
). These cells then migrate to lymph
nodes where they can interact with T cells, involved in adaptive immunity.
Serum sensitivity and phagocytosis
In contrast to the membrane-bound TLRs, the complement system is a soluble
network of proteins which respond to the presence of bacteria in the blood-
stream. There are three main pathways for complement activation: the alterna-
tive pathway, the classical pathway, and the lectin pathway (
Figure 17.6
). The
alternative pathway is activated by carbohydrates, lipids, and proteins on foreign
surfaces. The classical pathway is activated by IgG or IgM binding to pathogens
and is similar to the lectin pathway, which is activated by mannose-binding lec-
tin (MBL) and MBL-associated proteins (MASPs). The three pathways follow
different sequences that converge at the deposition of C3 protein on the bacte-
rial surface and lead to opsonization, formation of membrane attack complexes,
and formation of anaphylatoxins (reviewed in
Sarma and Ward, 2011
). When
C3 is cleaved, it forms C3a and C3b. C3a is an anaphylatoxin, a small protein
that causes a number of inflammatory responses, including acting as a chemo-
attractant for neutrophils and monocytes (phagocytes). C3b is an opsonin, which
helps with phagocytosis. C3b also binds to either of the two C3 convertases to
form a C5 convertase, C4bC2aC3b or C3bBbC3b. The C5 convertases cleave
C5 into C5a and C5b. C5a is another anaphylatoxin while C5b interacts with
C6, C7, C8, and multiple copies of C9 to form the membrane attack complex
(MAC). The MAC inserts itself into the bacterial membrane, forming a pore and
resulting in cell lysis.
Pathogens have evolved ways of circumventing the complement cascade in
order to survive in the bloodstream. O antigens and capsules contribute to the
virulence of pathogens by preventing phagocytosis and complement-mediated
killing (
Weiss et al., 1982
;
Johnson, 1991
;
Russo et al., 1993, 1994
;
Burns and
Hull, 1999
;
Schneider et al., 2004
;
Buckles et al., 2009
). One method for evasion
of complement involves preventing complement activation. At the simplest level,
this may be achieved by masking underlying antigens that would otherwise acti-
vate complement. Alternatively these surface glycans can prevent killing by com-
plement, through decreasing attachment and internalization of the bacteria by
PMNs, or by preventing formation of the membrane attack complex. However, in
many cases the exact mechanism by which this is achieved is not clear and it may
vary depending on the particular O or K antigen (or combination thereof) as well
as the underlying cell surface (
Cross et al., 1986
;
Falkenhagen et al., 1991
). K5
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