Containing the invader. Malaria vaccine is based on antibody that locks the Plasmodium parasite (dark, rodlike shapes) inside red blood cells.

Containing the invader. A malaria parasite, filling this red blood cell, separates into smaller components (four round shapes bordered by whitish walls) before bursting out and infecting other cells. A new vaccine is based on an antibody that keeps

J. Kurtis

Weak Immune System? Malaria Doesn't Care

SNOWBIRD, UTAH—Parasites have to walk a fine line. Be too weak, and they can't replicate or feed off you. Be too aggressive, and they risk killing you—their only home. That's what makes a new study, presented here last week at Evolution 2013, so surprising. Researchers have found that in mice with weak immune systems the malaria parasite becomes more aggressive, further compromising the health of an already compromised host. If the finding holds true in humans, it will help doctors understand why parasites might get more deadly over time.

Just like animals in the wild, parasites in your body have to adapt or die. Take antibiotics, and a few microbes may evolve resistance, allowing them to continue causing problems. Vaccines work the same way. If your immune system is already primed to fight an invader, that invader better evolve tough defenses or it's toast. That's indeed what researchers have found: vaccinate mice against malaria, and the worm-like plasmodium parasite that attacks red blood cells becomes even more virulent.

The same should hold true for our immune system. A stronger immune system should cause parasites to evolve to become tougher. But would the opposite hold true? That is, would a weakened immune system lead to more benign parasites? Andrew Read, an evolutionary biologist at Pennsylvania State University (Penn State), University Park, decided to find out. He and Victoria Barclay set up a 21-week experiment at Penn State in which mice were given antibodies that disabled a key immune molecule, the CD4 receptor. Once the rodents were immuno-compromised, the researchers injected the animals with the mouse malaria parasite Plasmodium chabaudi (in the wild, it's transferred by a mosquito bite). A week later, they transferred the pathogen in those mice to another set of antibody-treated mice. They repeated this step throughout the course of the experiment, freezing samples of the pathogen biweekly. After the experiment was over, they tested how aggressive the pathogens from weeks 10 and 21 were in mice with intact immune systems. "The study was heroic," because of the number of steps involved over an extended time, says Curtis Lively, an evolutionary biologist from Indiana University in Bloomington who was not involved in the work. (As a control, the experiment was also done in unvaccinated healthy mice.)

With a weaker immune system to contend with, the plasmodium parasite should have little reason to evolve and indeed might get more benign to keep from killing its host prematurely. But as Read reported at the meeting, the microbe behaved the same way in the immune-compromised mice as in the vaccinated ones. "The parasites had gotten more virulent," he said. In mice with intact immune systems, the parasites from week 21 grew faster and caused more anemia and weight loss than parasites from week 10. They even did more damage than parasites that had evolved in vaccinated mice.

Read thinks that with no immune system to keep them in check, parasites multiply to extremely high densities, so much so that there's tremendous competition for red blood cells and other resources, and thus selection to mature fast. At the same time, those larger numbers of parasites increase the pool of mutants, upping the chances of some having greater virulence potential. Past studies have shown that virulent parasites tend to outcompete less aggressive counterparts.

Read's mouse experiment "is a very elegant and sobering study," says Daniel Bolnick, an evolutionary biologist at the University of Texas at Austin. Yet "we certainly can't take it for granted that biological patterns in mice can be extrapolated to humans." Indeed shutting down the CD4 receptor is just a rough approximation of compromising the immune system, Read notes, and transferring the parasite from mouse to mouse bypasses the mosquito stage of the parasite.

Still, if the results do hold in humans, they suggest that society could be at risk. AIDS patients, for example, are living longer, yet they still have compromised immune systems—and many live in Africa where malaria is rampant. One study in Africa has already estimated that HIV infection has resulted in a 20% increase in the number of malarial parasites. What's more, organ transplant recipients and individuals taking immune-suppressing drugs to treat autoimmune diseases such as Crohn's disease are on the rise. "We should ask, 'is this what is happening where there are lots of immune-suppressed people?'" Read tells ScienceNOW. Answering that question could be very difficult, however, because virulence "is really hard to estimate in a human disease," he notes.

*Correction, 8 July, 5:30 p.m.: A previous version of this article stated that Andrew Read is located at Pennsylvania State University in Philadelphia. Read is actually located at Penn State's main campus, University Park. This has been corrected.