I’ve diffused it through my colleagues at work (Mol. Inform. dep. of a big pharma) – was expecting to stir much more noise, though…

The authors of the new study set out to find the difference between these parasitic cousins. They focused on how each species of Plasmodium gets into red blood cells. Every Plasmodium species uses special molecular hooks on its surface to latch onto receptors on the cell, and then noses its way through the membrane to get inside. The parasite has a number of hooks, each of which is adapted to latch onto particular kinds of receptors. One of the most important groups of receptors that Plasmodium needs to latch onto are sugars known as sialic acids, which are found on all mammal cells.

These sugars play a crucial but mysterious role in human evolution. As I’ve written here (and here), almost all mammals carry a form of the sugar called Neu5Ac on their cells, as well as a modified version of it, known as Neu5Gc. In most mammals, this modified form, Neu5Gc is very common. In humans, it’s nowhere to be found. That’s because the enzyme that converts the precursor Neu5Ac into Neu5Gc doesn’t work. We still carry the gene for the enzyme, but it became mutated about three million years ago and stopped working.

Since chimpanzees make Neu5Gc and we don’t, the researchers hypothesized that the two Plasmodium species must use different strategies to latch onto red blood cells. To test their hypothesis, they genetically engineered cells to produce the molecular hooks used by human Plasmodium falciparum, and other cells to produce the chimp parasite hooks. The researchers then mixed the engineered cells with red blood cells from humans and chimpanzees to see how well they attached. In another set of experiments, they made human blood cells more chimpanzee-like by adding Neu5Gc sugars to them, to see if the change helped the chimpanzee parasites attack them, or if it impaired the attacks of human parasites.

Their results show that humans are uniquely vulnerable to Plasmodium falciparum because our ancestors lost the Neu5Gc sugar. Plasmodium falciparum prefers to bind to Neu5Ac, the sugar we still carry. At the same time, the sugar we lost somehow blocks Plasmodium falciparum’s hooks from latching onto Neu5Ac. That’s why chimpanzees don’t get sick with Plasmodium falciparum, despite carrying both kinds of sugars. On the other hand, we don’t get sick with chimpanzee malaria, because Plasmodium reichenowi prefers attaching to Neu5Gc, the sugar we lost.

The scientists argue that some seven million years ago the common ancestor of chimpanzees and humans carried both kinds of sugars on their cells. This ancient ape would sometimes get sick with malaria, caused by the common ancestor of today’s P. rechnowi and P. falciparum. This ancient parasite preferred to latch onto Neu5Gc to get into its host’s blood cells.

Looks to me like maybe hominids have been running from malaria over the last few million years and this has thrown some other things out of whack. Immunologically speaking, of course.

Normally, T-cell activiation depends on two molecular signals. One through the T-cell receptor, which recognizes a specific antigen processesed and displayed by an antigen presenting cell, and another through a molecule delivered by the same cell that recognizes CD28. There are some ways of getting around this in the lab, so I wonder what they did to get T-cells to proliferate just through CD28.

Part of TGN1412′s problem, I had thought, was that it can activate T-cells via CD28 alone, independent of T cell receptor recognition, cutting antigen presenting cells out of the loop. This seemed to work in mice and primates because TGN1412 appeared to favor T regulatory cells, which keep autoreactive T-cells in check. In humans, TGN1412 likely recongized other T-cells, resulting in out of control inflammation.

I wonder if the promiscuous activity of TGN1412 in humans was due to a lack of Siglics?