p53 Could Have Role in Controlling Malaria Fever

Immunological signatures can predict whether malaria-infected children will develop fever or other symptoms, according to a study published today in Immunity. Surprisingly, activation of the well-known tumor-suppressor protein p53 is associated with enhanced protection against malaria fever—and increasing p53 in human immune cells and in mice results in a decrease in malaria-induced inflammation.

"Malaria is caused by the Plasmodium falciparum parasite and remains a major killer of children in Africa," says senior study author Peter Crompton of the NIAID. "Our limited understanding of how the human immune system controls malaria-induced inflammation and parasite growth impedes the development of vaccines and adjunctive therapies for this devastating disease."

To gain insights into host factors that might protect against malaria disease, Crompton and first author Tuan Tran applied a systems biology approach to study children who differed in their ability to control parasite growth and fever following P. falciparum infection. They collected and analyzed blood samples from healthy, uninfected Malian children at enrollment before the malaria season, during bi-weekly scheduled visits, and at their first malaria episode of the ensuing season. They focused on children aged 6-11 years, the age during which malaria immunity begins to be acquired in this region.

During the first malaria season, the researchers identified three distinct outcomes of P. falciparum infection. Twenty children were immune and showed no symptoms, 26 children showed early fever at the time of infection, and 34 children experienced delayed fever two days to two weeks later. Protection from malaria symptoms was associated with a pre-infection signature of B cell enrichment, platelet and monocyte activity, T helper cell responses, including interferon-driven pro-inflammatory responses, and p53 activation. In addition, control of parasite growth was associated with increased immunoglobulin G and Fc receptor activation prior to infection.

After this analysis, the researchers next set out to specifically investigate the role of p53 in malaria. Using multiple approaches in the laboratory, they found that increased p53 attenuates malaria-induced inflammation in human monocytes and in a mouse model of malaria, providing evidence that p53 activation contributes to the control of malaria fever.

"There has been extensive research on p53 in the context of cancer, but much less is known about its role in the immune response to infections, particularly in humans," Crompton says. "It may be that low expression of p53 in blood could serve as a marker for individuals or populations at greater risk of harmful inflammation when infected by malaria or other pathogens. Or perhaps increasing p53 pathways relevant to controlling inflammation could potentially reduce the severity of late-stage malaria."