A University of Washington study is the first to provide visualizations of tuberculosis infections in an intact living organism and reveals how tuberculous granulomas, the tight aggregates of macrophages that are the hallmarks of this infection, are formed within infected organisms (Macrophages are a specialized class of white blood cells that patrol tissues and ingest foreign particles, such as bacteria and viruses, as well as dead and dying cells. Macrophages provide the backbone of the immune system.).
TB bacteria exploit the behavior of macrophages to efficiently infect other macrophages and spread through the organism, according to the study published as the cover article in the December 2002 edition of Immunity by Dr. Lalita Ramakrishnan, UW assistant professor of microbiology and medicine and her colleagues. The study was conducted through direct imaging of labeled bacteria within developing zebra fish embryos. Ramakrishnan said the study has important implications for understanding how TB granulomas form in humans.
“This is the first time that an infection has been followed visually in an intact organism like this,” Ramakrishnan said. “Zebra fish have become a favorite organism of developmental biologists because they are optically transparent, allowing researchers to visualize processes in living animals. We’ve exploited this transparency to study an important infectious disease.”
This novel approach helps explain a very old problem and perhaps point the way to a cure for a disease that kills millions of people each year.
Tuberculosis and some other bacteria have evolved strategies to evade the body’s immune system by exploiting the macrophages’ appetite. After being ingested, the TB bacteria are able to multiply. Then, through the use of a still-unknown signaling pathway, the TB bacteria begin to alter the social behavior of infected macrophages, causing them to congregate into tightly packed assemblies or granulomas. Researchers have long suspected that granulomas, which can form in many organs of the human body, provide a reservoir for recurring bouts of TB infection.
Ramakrishnan and her colleagues filmed for the first time the dynamics of TB-infected macrophages within living granulomas. Using Mycobacterium marinum, a close relative of the TB bacteria and a natural pathogen of zebrafish, the researchers discovered at least two separate routes by which TB bacteria can move from infected to uninfected macrophages. Either a dying macrophage containing TB bacteria can be engulfed by an uninfected macrophage, or direct transfer of TB bacteria can take place between macrophages via intercellular protrusions.