Johns Hopkins. US: The cascade of events leading to bacterial infection and the immune
response is mostly understood. However, the molecular mechanisms
underlying the immune response to the bacteria that causes tuberculosis
have remained a mystery — until now. Researchers at the Johns Hopkins
University School of Medicine have now uncovered how a bacterial
molecule controls the body’s response to TB infection and suggest that
adjusting the level of this of this molecule may be a new way to treat
the disease. The report appears this week as an advance online
publication of Nature Medicine.
“We unraveled part of the cat-and-mouse game that plays out when TB
bacteria infect human cells. The microbes release a small piece of DNA
that resembles viral DNA, and this tricks the human cells to react as if
they were responding to a virus instead of a bacterium; this may
explain in part why the human immune response is often unable to combat
TB,” says William Bishai, M.D., Ph.D.,
co-director of the Johns Hopkins Center for Tuberculosis Research
Laboratory and corresponding author on the paper. “The exciting part is
that with the knowledge of this molecular trickery, we may be able to
come up with better drugs and vaccines for TB — tools that are sorely
needed.”
After tuberculosis bacteria infect a host, the bacteria release a
molecule called c-di-AMP into the host’s cells. Those cells have
built-in early detection systems that recognize these foreign molecules
and start an inflammatory response, which then leads to a complex
reaction to combat the infection. The research team first measured
c-di-AMP levels in the bacteria and found that its levels increase when
the bacteria are actively multiplying.
To determine if c-di-AMP is indeed altering the host immune response,
the researchers infected mouse immune cells with TB bacteria engineered
to make different levels of c-di-AMP and compared how much of an immune
response the cells mounted by measuring levels of INF-beta protein. They
found that the more c-di-AMP released into the mouse cell, the higher
the INF-beta levels.
But, according to Bishai, INF-beta levels may not reveal the whole
picture of what transpires during infection. So they then looked at how
well the bacteria themselves grow when releasing different amounts of
c-di-AMP into the cells they’ve infected. The bacteria making the
highest levels of c-di-AMP, it turns out, showed the slowest growth
rates.
“Others had suggested that molecules of the same class as c-di-AMP can
trigger autophagy, when a cell chews up and disposes of its insides,”
says Bishai. “So we set out to see if overproducing c-di-AMP was causing
the infected host to eat the TB bacteria. Using cells marked with
glowing proteins, the researchers saw under microscopes that cells
infected with TB bacteria making high levels of c-di-AMP indeed
underwent more autophagy than those with lower levels of c-di-AMP.
The team then examined whether differences in c-di-AMP could alter the
severity of the disease in mice. Infection with normal bacteria causes
death at about 150 days, whereas infection with bacteria engineered to
overproduce c-di-AMP led to longer survival times — 321 days.
“We still don’t know if altering c-di-AMP levels can be linked to
different outcomes in humans with TB, but this study does suggest that
it would be well worth looking into,” says Bishai.
The study was funded by the National Institute of Allergy and
Infectious Diseases (grant numbers AI037856, AI097138 and AI036973), and
Bishai is supported by the Howard Hughes Medical Institute.
Other authors on the paper include Bappaditya Dey, Ruchi Jain Dey,
Laurene S. Cheung, Supriya Pokkali, Ph. D., Haidan Guo and Jong-Hee Lee,
Ph.D.