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In the mid-1980s, a flurry of new techniques for working with
proteins and DNA led to identification of a key malaria antigen.
Palmer and McElwain, just beginning their careers on the WSU
faculty, immediately applied the new techniques to their
organisms.
When Palmer used the new tools to search for Anaplasma
antigens, he found Msp2 (major surface protein 2). Msp2 is the most
abundant protein on the surface of the pathogen. Both ends of Msp2
are embedded in the Anaplasma cell membrane, and the middle
portion loops out into the extracellular space. Since the loop is
exposed to the bloodstream, whenever Anaplasma goes looking
for new red blood cells to infect, it is the part of the protein
the host’s antibodies have a chance to recognize and grab onto.
In other words, Msp2 looked like a perfect candidate as a
vaccine antigen.
Then why doesn’t the host’s immune system target Msp2 and knock
out the infection? That part still didn’t make sense. Palmer’s lab
found that infected cows do make antibody against Msp2, a lot of
it; that’s likely what drives down the number of pathogen cells and
allows the cow to recover from acute illness. But why do pathogen
numbers rise again a couple of weeks later? Why doesn’t the cow
clear the infection completely?
After months of protein and gene analysis, Palmer’s team reached
a stunning conclusion. The pathogen persists because the host no
longer recognizes it—because Msp2 changes. It’s still present, but
it doesn’t look like the Msp2 that was there before. Palmer’s group
found that at any given stage of the infection, several forms of
Msp2 are present—and none of them are recognized by antibodies the
host made in earlier stages. By altering the most abundant protein
in its surface coat, Anaplasma avoids detection by
antibodies the host has already made.
“That’s why the immune system can never catch up with what’s
going on,” says molecular biologist Kelly Brayton. She describes
Msp2 as throwing up a smokescreen that allows Anaplasma
cells to escape direct attack by the immune system. “Part of the
job of this molecule is to be this thing that’s going, ‘Hey! Look
at me!’ Because it can change. So it’s trying to attract the
attention of the immune system, and then as soon as the host makes
a response to that particular variant, it’s moved on.”
So how did Anaplasma do it?
Palmer calculated that a cow infected early in life might see
more than 1,000 variants of Msp2 over its lifetime. The
Anaplasma genome codes for fewer than 1,000 proteins.
There’s no way it could have 1,000 genes for Msp2 alone. The
pathogen had to be doing something unusual with its genes to
generate that many variants.
Brayton sequenced the entire Anaplasma genome and looked for
something that would explain the diversity of Msp2 forms. What she
found is a process called “gene conversion,” a masterwork of
deception in which a handful of “pseudogenes” mix and mingle to
continually change the identity of Msp2—and of Anaplasma
itself. (See illustration.)
It was a major finding. Gene conversion explained how
Anaplasma escapes detection by the immune system. It also
led to the discovery, by researchers elsewhere, that a similar
process occurs in the pathogen that causes relapsing fever in
humans.
And yet, figuring out how gene conversion works was a bit like
finally bursting into the room of a con man you’ve been hunting for
years, to find only a trunk full of wigs and false noses. The team
still wasn’t in sight of a vaccine. And the culprit himself had
fled again.
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