Friend mouse leukemia virus (yellow) budding from infected T-lymphocyte (blue). Credit: Elizabeth Fischer and Kim Hasenkrug, NIH |
Biologists
have found new evidence of why mice, people and other vertebrate
animals carry thousands of varieties of genes to make immune-system
proteins named MHCs—even though some of those genes make vertebrate
animals susceptible to infections and to autoimmune diseases.
“Major
histocompatibility complex” (MHC) proteins are found on the surfaces of
most cells in vertebrate animals. They distinguish proteins like
themselves from foreign proteins, and trigger an immune response against
these foreign invaders.
MHCs
recognize invading germs, reject or accept transplanted organs and play
a role in helping vertebrates smell compatible mates.
“Results
of this study explain why there are so many versions of the MHC genes,
and why the ones that cause susceptibility to diseases are being
maintained and not eliminated,” says biologist Wayne Potts of the
University of Utah.
“They
are involved in a never-ending ‘arms race’ that causes them, at any
point in time, to be good against some infections but bad against other
infections and autoimmune diseases.”
By
allowing a disease virus to evolve rapidly in mice, Potts, Jason
Kubinak and other University of Utah scientists produced new
experimental evidence for the arms race between genes and germs—known
technically as “antagonistic co-evolution.”
The findings are published online this week in the journal Proceedings of the National Academy of Sciences (PNAS).
In
addition to Potts and Kubinak, the paper’s lead author, the paper’s
co-authors are James Ruff, Cornelius Whitney Hyzer, and Patricia Slev,
all of the University of Utah.
The research was funded by the National Science Foundation (NSF) and the National Institute of Allergy and Infectious Diseases.
“The
genetic diversity of the MHC complex is critical for vertebrates,
including humans, to mount a defense against novel pathogens,” says
George Gilchrist, acting deputy director of NSF’s Division of
Environmental Biology, which funded the research.
“This
study demonstrates that trade-offs between MHC genotypes and the
severity of pathogen effects are key factors maintaining that
diversity,” says Gilchrist. “The work has important implications for
agricultural practice and conservation genetics, as well as human
health.”
Most genes in humans and other vertebrates have only one or two “alleles,” varieties or variants of a single gene.
Although
any given person carries no more than 12 varieties of the six human MHC
genes, the human population has anywhere from hundreds to 2,300
varieties of each of the six human genes that produce MHC proteins.
“The
mystery is why there are so many different versions of the same [MHC]
genes in the human population,” Kubinak says, especially because many
people carry MHCs that make them susceptible to pathogens (including the
AIDS virus, malaria and hepatitis B and C) and autoimmune diseases
(type I diabetes, rheumatoid arthritis, lupus, multiple sclerosis,
irritable bowel disease and ankylosing spondylitis).
Many people carry MHCs that make them susceptible to pathogens like the AIDS virus. Credit: NIH |
Scientists
have proposed three theories for why so many MHC gene variants exist in
vertebrate animal populations (invertebrates don’t have MHCs), and say
all three likely are involved in maintaining the tremendous diversity of
MHCs:
Theory one
An
organism with more MHC varieties has a better immune response than
organisms with fewer varieties, so over time, organisms with more MHCs
are more likely to survive. However, this theory cannot explain the full
extent of MHC diversity.
Theory two
Previous
research indicates that people and other animals are attracted to the
smell of potential mates with MHCs that are “foreign” rather than
“self.” Parents with different MHC variants produce children with more
MHCs and thus stronger immune systems.
Antagonistic
co-evolution between an organism and its pathogens: “we have an
organism and the microbes that infect it,” Kubinak says. “Microbes
evolve to better exploit the organism, and the organism evolves better
defenses to fight off the infection.” One theory to explain this great
diversity in MHC genes is that those competing interests over time favor
retaining more diversity.
“You
naturally keep genes that fight disease,” says Kubinak. “They help you
survive, so those MHC genes become more common in the population over
time because the people who carry them live to have offspring.”
Theory three
Pathogens—disease-causing
viruses, bacteria or parasites—infect animals, which defend themselves
with MHCs that recognize the invader and trigger an immune response to
destroy the invading pathogen.
But over time, some pathogens mutate and evolve to become less recognizable by the MHCs and thus evade an immune response.
As a result, the pathogens thrive.
MHCs
that lose the battle to germs become less common because they now
predispose people who carry them to become ill. It was thought that such
disease-susceptibility MHC genes eventually should vanish from the
population, but they usually don’t.
Why? While some of those MHCs do go extinct, others can persist, for two reasons.
First,
some of the now-rare MHCs gain an advantage because they no longer are
targeted by evolving microbes, so they regain an ability to detect and
fight the same germ that earlier defeated them–after that germ mutates
yet again.
Secondly, some of the rare MHCs can mount an effective immune response against completely different microbes.
MHCs may also make people susceptible to hepatitis C. Credit: NIH |
The
researchers studied 60 mice that were genetically identical, except
that the mice were divided into three groups, each with a different
variety of MHC genes known as b, d and k, respectively.
A
mouse leukemia virus named the Friend virus was grown in tissue culture
and used to infect two mice from each of the three MHC types.
The
fast-evolving virus grew in the mice for 12 days, attacking, enlarging
and replicating within the spleen and liver. Virus particles in the
spleen were collected, and the severity of illness was measured by
weighing the enlarged spleen.
Then,
virus taken from each of the first three pairs of mice (b, d and k) was
used to infect another three pairs of mice with the same MHC types.
The process was repeated until 10 pairs of mice in each MHC type were infected, allowing the virus time to mutate.
In
this first experiment, the biologists showed that they could get the
Friend virus to adapt to and thus evade the MHC variants (b, d or k) in
the mouse cells it attacked.
Next,
the researchers showed that the virus adapted only to specific MHC
proteins. For example, viruses that adapted to and sickened mice with
the MHC type b protein still were attacked effectively in mice that had
the type d and k MHCs.
In
the third experiment, the researchers showed that pathogen fitness
(measured by the number of virus particles in the spleen) correlated
with pathogen virulence (as measured by spleen enlargement and thus
weight). So the virus that evaded the MHC type b made mice with that MHC
sicker.
“The
experiments demonstrate the first step in the antagonistic
co-evolutionary dance between a virus and MHC genes,” Potts says.
The findings have important implications, say the scientists.
The
use of antibiotics to boost productivity in dairy herds and other
livestock is a major reason human diseases increasingly resist
antibiotics. Selective breeding for more milk and beef has reduced
genetic diversity in livestock, including their MHCs. So breeding more
MHCs back into herds could enhance their resistance to disease and thus
reduce the need for antibiotics.
Because
their populations are diminished, endangered species have less genetic
diversity, making them an easier target for germs. Potts says it would
be desirable to breed protective MHCs back into endangered species to
bolster their disease defenses.
Genetic
variation of MHCs in people and other organisms is important for
limiting the evolution and spread of emerging infectious diseases. In
effect, the researchers created emerging diseases by making a virus
evolve in mice. “It’s a model to identify what things change in viruses
to make them more virulent,” says Potts, “and thus emerging diseases.”
