Blood cues sex choice for parasites.

For a man, four gals for every guy sounds like a dream night at a singles bar. For the parasites that cause malaria in people and other vertebrates, such sex ratios were thought standard. "You generally find in all species of malaria parasites that there are many more females than males," notes Richard E.L. Paul of the Pasteur Institute in Paris.

Paul and his colleagues, however, wondered whether that sex ratio varies during the course of an infection. The investigators now report in the Jan. 7 SCIENCE that in chickens, as malaria infections progress, the sex ratio usually changes so that male and female forms of the parasite become almost equally represented. Paul's team also describes evidence that a protein that stimulates red blood cell production may trigger this sex-ratio shift.

The new findings provide a welcome insight into the puzzle of sex determination among malaria parasites. In theory, such knowledge could lead to a malaria treatment. A drug designed to completely masculinize or feminize the parasites would halt their sexual reproduction.

"This is very important work. It is the first demonstration of a mechanism that would drive sex ratio in a malaria parasite. That has been a great mystery for over a century," says Joseph J. Schall of the University of Vermont in Burlington.

As part of its complex life cycle, a malaria parasite produces gametocytes while in the blood of a vertebrate host. The gametocytes come in male and female versions. When a mosquito draws the gametocytes into its gut, males develop as many as eight spermlike structures, each of which can fertilize a female. According to one theory, the ability of a single male to fertilize multiple females leads to the female-biased sex ratio that had been recognized.

The newly discovered shift toward a more equal ratio likely occurs, says Paul, because an infected host mounts an immune response that hinders the male gametocytes' swimming ability. Since this mobility is crucial to finding a female gametocyte, the presence of a greater number of males at this stage of the infection counters their reduced reproductive chances, he concludes.

How does a parasite know to make more males? Unexpectedly, the signal may come from the host's decision to create more red blood cells. In parallel with its growing immune response, a host makes red blood cells to replace the ones incapacitated by the parasites.

Paul and his colleagues found that they could trigger the parasites' shift to the balanced sex ratio early in an infection if they stimulated a chicken's red blood cell production by bleeding the animal or depriving it of oxygen. Simply injecting erythropoietin, a protein that naturally stimulates red blood cell synthesis, into infected mice also induced malaria parasites to make more males.

Paul has begun to examine whether the parasite sex ratio changes in human malaria and if so, whether such shifts occur in the acute or chronic stages of infections. Moreover, he and his colleagues plan to continue studying how different sex ratios alter the malaria parasite's chances of reproductive success.