Within the primate family, relatives are not treated equally by disease. While AIDS, malaria, and cancer kill millions of humans each year around the world, non-human primates largely shrug these diseases off. For example, chimpanzees can be infected with a form of HIV (called Simian Immunodeficiency Virus, or SIV, in their case), but the disease rarely progresses to AIDS. What is different about the immune system of humans and their primate peers to create this startling difference in disease susceptibility?
The obvious answer, as always, is evolution. When humans and chimpanzees went their separate genetic ways from their common ancestor and started living in different environments with different diseases, their immune systems also diverged. Fortunately, the story of that divergence can still be read in the genes, provided you have the right equipment to do so. Luis Barreiro, a postdoctoral researcher in the human genetics laboratory of Yoav Gilad, has started looking for that story by comparing the immune pathways of different primate species.
The first such comparison, published last week in PLoS Genetics, focused on the innate immune system of humans, chimpanzees, and rhesus monkeys. Unlike the better-known adaptive immune system, which produces antibodies to fight specific viruses and bacteria, the innate immune system is a less specific system, the first line of defense against infection. Pattern recognition receptors, such as the toll-like receptor (TLR) family, recognize common features of pathogens and activate genes to begin the fightback.
“Each time you have a pathogen that invades your body, you have this first alert, the first genes that are going to fight the infection,” Barreiro said. “It’s probably the most ancient mechanism of immune defense; it’s present in all species, whereas adaptive immune response is much more recent.”
Barreiro, with John Marioni, Ran Blekhman, and Matthew Stephens, isolated blood cells from the three species and stimulated them with lipopolysaccharide, a molecule found in the membrane of gram-negative bacteria that stimulates TLRs. The researchers then measured gene expression – genes activated or deactivated by the stimulus – across the three species, looking for differences in immune system responses.
The experiment showed that the “core” general response of the innate immune system was very similar between the three primates, with the majority of affected genes shared across the species – evolution has not changed this process very much. But when researchers dialed in on the specific response to viruses, more species differences in patterns of gene expression appeared, suggesting rapid evolution of the immune defenses to these pathogens.
“That is interesting, because we know that viruses are evolving very, very quickly,” Barreiro said. “So we can imagine that the immune response to fight these viruses also has to evolve quickly to adapt to these changes.” [an example of the Red Queen Hypothesis]
As humans and their non-human cousins adapted to different environments, evolution selected for different immune strengths that may have left weaknesses in other areas. The immune response of chimpanzees to TLR stimulation is enriched in genes known to interact with HIV, suggesting the species developed a heightened defense against similar viruses millions of years ago that is once again protective, by chance, against one of today’s deadliest diseases. Humans, by contrast, show a gene response enriched for genes related to cancer – an adaptation that may have made sense when the human lifespan was much shorter than it is in the 21st century.
“There’s always this trade-off, especially in terms of immune defenses and response to pathogens. It’s always fluctuating,” Barreiro said. “With the environment and the pathogens changing all the time, what’s good today is bad tomorrow, and then it can be good again.”
Subsequent experiments will use more specific infectious agents to focus on the biological ramifications of these divergent responses in the three primates. For instance, just because a pathogen influences a bunch of HIV-related genes in chimpanzees, that doesn’t mean that all of those genes are involved in a chimp’s resistance to developing AIDS. A handful of critical genes may alone be responsible for that protection, and once discovered, those genes could offer new clues for preventing or fighting AIDS infections in humans, Barreiro said.
“If you definitely show these genes are the reason why chimpanzees will be more resistant to AIDS, they would definitely represent good targets for therapy,” Barreiro said. “I think it’s a good way to prioritize candidate genes for susceptibility to disease.”
Barreiro, L., Marioni, J., Blekhman, R., Stephens, M., & Gilad, Y. (2010). Functional Comparison of Innate Immune Signaling Pathways in Primates PLoS Genetics, 6 (12) DOI: 10.1371/journal.pgen.1001249