Underhill Awarded Grant for Fever Research

David Underhill, PhD, associate director of the Division of Immunology Research in the Cedars-Sinai Department of Biomedical Sciences, has received a $380,160 grant from the National Institutes of Health to study the role of body temperature in fighting infection.

While high temperature, or fever, is known to be an important defense mechanism, the processes by which it promotes resistance to infection and helps clear infections are not completely understood.

Underhill, principal investigator on the study and professor of biomedical sciences and medicine, plans to focus on white blood cells, such as macrophages and dendritic cells, that kill bacteria and yeast by "eating" them within intracellular compartments called phagosomes. He hypothesizes that high temperatures promote the body's defenses by enhancing this cellular activity.

To test this theory, Underhill and his colleagues will use novel microscopic imaging techniques and molecular reporter systems to monitor the temperatures experienced by microbes during phagocytosis — the process by which white blood cells "eat" them. Genetically engineered bacteria will be used to sense and report the temperature of their environment. The experiments will be conducted in mice cells in a laboratory dish.

The researchers hope to discover how temperature directly affects the molecular mechanisms of defense against infection and how disease-causing microbes respond to this threat. What they learn may help develop future therapies to combat infections.

"We suspect that if temperature is a key regulator of killing potentially disease-causing bacteria and fungi, certain microbes will have developed mechanisms to resist or manipulate these processes. This could provide a novel process to target in treatment," said Underhill.

In a wider sense, the advanced microscopy methods and molecular reporters being developed in this project potentially may help other investigators explore this critical field of study.

"It's important to understand as thoroughly as possible how the body fights infection," Underhill said.

Photo: Immune cells internalize and kill pathogens in a process that involves the degradation of proteins, or proteolysis, and the generation of a chemical known as reactive oxygen species (ROS). Cedars-Sinai researchers hypothesize that high temperatures promote the body's defenses by enhancing this process, which occurs within intracellular compartments called phagosomes.