Tuberculosis bacteria can commandeer the body's defenses in the early stages of infection and redirect them for their own offensive strategies, according to results reported today in the scientific journal Cell.
The dense granulomas characteristic of TB were originally thought to thwart infection by walling-off newly invading tuberculosis bacteria and preventing their spread. Today's published findings suggest that these structures do just the opposite, at least in the early stages of infection.
"Tubercles or granulomas have long been considered host-protective. What we observed completely overturns the fundamental dogma on their role, at least early in infection," said Dr. Lalita Ramakrishnan, University of Washington (UW) associate professor of microbiology, medicine, and immunology, who conducted the study with Dr. J. Muse Davis of the Immunology and Molecular Pathogenesis Graduate Program at EmoryUniversity and a visiting scholar at the UW.
Granolomas are dense, complex clusters of immune cells, some of which are infected with TB bacteria. The outer edges are granulomas are surrounded by tightly interlocked white blood cells. Evidence from Ramakrishnan's and Davis' latest research suggests they might be created when newly arrived TB bacteria grow and emit signals to recruit c -- the body's germ-eating and clean-up cells -- to the initial infection site, then pirate the macrophages to truck fresh bacteria to other spots and replicate themselves there to establish more granulomas.
The granulomas form within days of infection. This occurs during the period when the body is trying to launch its first, generalized response to infection, called innate immunity. Later, when the body targets its fight, called adaptive immunity, Ramakrishnan says that the host and the bacteria usually reach a stalemate.
"One of the reasons we are studying the mechanisms of early TB infection," Ramakrishnan said, "is to see where medical science might be able to intervene to stop the disease with new treatments without the problem of creating antibiotic resistance." For example, she said, if scientists can figure out how TB bacteria signal to recruit and exploit macrophages and usurp the body's immune processes to gain a foothold, perhaps researchers could then find a way to block this takeover.
By comparing fully virulent wild strains of bacteria that have a secretion system called ESX-1/RD1 with less virulent, mutant strains without this system, Ramakrishnan and Davis found that RD1 appears to encourage macrophages to arrive quickly at the site of infection. These macrophages moved five times faster than macrophages heading to the mutant bacteria, and covered greater areas with their haphazard movements.
The researchers saw that the fast macrophages took on the striking appearance of white cells racing to the scene after a chemical alarm: they had elongated centers, a ruffled front edge, and a trailing rear extension. The roundness of the slower macrophages going to the mutant bacteria indicated that they weren't getting the same "hurry up" chemical signal.
