Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1290 Chapter 23: Pathogens and Infection
inactive Vsg genes
a f b c
expression
site
anti-VSG a
anti-VSG b
anti-VSG c
gene b copied to
expression site
x1000
VSG a
number of parasites
VSG a VSG b VSG c
levels of antibodies
(A)
gene c copied to
expression site
x1000
x1000
manages a 2% change in its genome in 5 days—about the time it takes the virus
to pass from the human mouth to the gut. Second, selective pressures act rapidly
on this genetic variation. The host’s adaptive immune system and modern microbicidal
drugs, both of which destroy pathogens that fail to change, are the main
sources of these selective pressures.
MBoC5 m24.41/23.30
An example of an adaptation to the selective pressure imposed by the adaptive
immune system is the phenomenon of antigenic variation. An important
adaptive immune response against many pathogens is the host’s production of
antibodies that recognize specific molecules (antigens) on the pathogen’s surface
(discussed in Chapter 24). Many pathogens have evolved mecanisms that deliberately
change these antigens during the course of an infection, enabling them to
evade antibodies. Some eukaryotic parasites, for example, undergo programmed
rearrangements of the genes encoding their surface antigens. A striking example
occurs in Trypanosoma brucei, a protozoan parasite that causes African sleeping
sickness and is spread by tsetse flies. (T. brucei is a relative of T. cruzi—see Figure
23–21—but it replicates extracellularly rather than intracellularly.) T. brucei
is covered with a single type of glycoprotein, called variant-specific glycoprotein
(VSG), which elicits in the host a protective antibody response that rapidly clears
most of the parasites. The trypanosome genome, however, contains about 1000
different Vsg genes or pseudogenes, each encoding a VSG with a distinct amino
acid sequence. Only one of these genes is expressed at any one time, from one of
approximately 20 possible expression sites in the genome. Gene rearrangements
that copy different Vsg genes into expression sites repeatedly change the VSG protein
displayed on the surface of the pathogen. In this way, a few trypanosomes
with an altered VSG escape the initial antibody-mediated clearance, replicate,
and cause the disease to recur, leading to a chronic cyclic infection (Figure 23–30).
Bacterial pathogens can also rapidly change their surface antigens. As discussed
in Chapter 5, Salmonella enterica bacteria switch between expressing
either of two versions of the protein flagellin, the structural component of the bacterial
flagellum (see Figure 23–3D), in a process called phase variation (see Figure
5–65). Species of the genus Neisseria are also champions at this. These Gram-negative
cocci can cause meningitis and sexually transmitted diseases. They undergo
genetic recombination very similar to that just described for eukaryotic pathogens,
which enables them to vary the pilin protein they use to attach to host cells.
By inserting one of the multiple silent copies of variant pilin genes into a single
expression locus, they can express many slightly different versions of the protein
and repeatedly change the amino acid sequence over time. Neisseria bacteria are
VSG b
VSG c
infection
(B)
time (weeks)
Figure 23–30 Antigenic variation in
trypanosomes. (A) There are about 1000
distinct Vsg genes in Trypanosoma brucei,
and they are expressed one at a time from
approximately 20 expression sites in the
genome. To be expressed, an inactive
gene is copied and the copy is moved
into an expression site through DNA
recombination. Each Vsg gene encodes a
different surface protein (antigen). These
switching events allow the trypanosome
to repeatedly change the surface antigen
it expresses. (B) A person infected with
trypanosomes expressing VSG a mounts
a protective antibody response, which
clears most of the parasites expressing
this antigen. However, a few of the
trypanosomes will have switched to
expression of VSG b , which can now
proliferate until anti-VSG b antibodies
clear them. By that time, however, some
parasites will have switched to VSG c , and
so the cycle continues.