Researchers at the Francis Crick Institute have discovered that
the bacterium responsible for tuberculosis (TB) can hide and live
on inside the very immune cells that are sent to hunt and kill
it.
Daniel Greenwood, working in Maximiliano Gutierrez's lab at the
Crick, explains his team's findings: "Macrophages are one of our
immune system's main defences. These cells actively hunt down
microbes, eating them and then killing them. But Mycobacterium
tuberculosis - the bacterium that causes TB - subverts this
killing process.
"Like Jonah after being swallowed by the whale, M.
tuberculosis can survive and even thrive inside macrophages
before bursting back out into the body. But unlike Jonah, these
ungrateful houseguests kill their host macrophage in the
process.
Thomas Lerner, a lead author of this work, explained: "People
had assumed that this macrophage death is simply a by-product of
the bacteria rupturing the cell on the way out, but instead our
research finds that bacteria can live for days inside the dead
cell, feasting on the remnants of their former host. In discovering
this, we have found a previously unknown niche for bacterial
replication in the body - with important consequences for
understanding how TB persists and causes disease."
To carry out their research, the team performed very high
resolution microscopy of samples of live M. tuberculosisin human blood provided for research by donors at the NHS blood and
transplant service.
Their technique, called confocal fluorescence microscopy,
allowed them to observe the whole infection cycle from the moment
the bacteria were eaten by a macrophage to the moment they burst
out of the dead cell and infected their neighbours. It showed in
real time how the bacteria continued to replicate for days in the
dead shell of their former host macrophage before eventually
escaping.
The scientists also used special chemical inhibitors to slow the
death of the macrophages. This slowed the growth of the TB
bacteria, showing how the death of the host cells promotes
bacterial replication.
Dr Gutierrez commented on the findings: "Last year, TB killed
more people than any other infectious disease. Many other bacterial
infections cause illness rapidly but can be cured by antibiotics
within a few weeks. But for patients with TB, symptoms may not show
for years after infection - if at all, and treatment takes a
minimum of six months. Understanding better how these bacteria
infect us and where they live in the body is key to our efforts to
improve outcomes for people affected by this disease.
"The bacteria that cause TB can infect many tissues in our
bodies, from our lungs to our bones to our immune system.
Macrophages are one of the first cell types to encounter the
infection, and are therefore very important in determining the
future of the outcome of the infection. This research demonstrates
how M. tuberculosis kills its host cell and then lives on in the
dead macrophage, providing a niche in which the bacteria can
persist and replicate."
The paper, Mycobacterium tuberculosisreplicates within necrotic human macrophages, is published in
the Journal of Cell Biology.