Driving immunometabolism to control lung infection

Date:
July 23, 2020
Source:
Trinity College Dublin
Summary:
When drugs to kill microbes are ineffective, host-directed therapy
uses the body's own immune system to deal with the infection. This
approach is being tested in patients with COVID-19, and now a
team of researchers has published a study showing how it might
also work in the fight against tuberculosis (TB).



FULL STORY ==========================================================================
When drugs to kill microbes are ineffective, host-directed therapy uses
the body's own immune system to deal with the infection. This approach is
being tested in patients with COVID-19, and now a team of researchers at Trinity College Dublin has published a study showing how it might also
work in the fight against tuberculosis (TB). The findings are published
in the journal Frontiers in Immunology today (July 23, 2020).


========================================================================== Although the bacteria that causes TB (called Mtb) has scourged humankind
for millennia, we do not fully understand the complexities and interplay
of the human immune response to this ancient bug. Worryingly, there are increasing numbers of people with antibiotic resistant TB, which is hard
to treat and is becoming a global threat to public health.

Scientists at the Trinity Translational Medicine Institute (TTMI) at St.

James's Hospital are dedicated to understanding the intricacies of the
human immune response to Mtb with the aim of finding ways to target and
promote the immune response to overcome the infection. Scientists already
know that the human immune response can both under or over respond to the bacteria resulting in a difficulty to treat the disease. This complex
immune response is analogous to driving with both the accelerator and
the brakes fully engaged at the same time.

The research team led by Health Research Board Emerging Investigator,
Dr Sharee Basdeo, and Professor Joseph Keane, Clinical Medicine,
Trinity College has recently discovered a way to manipulate human immune responses to Mtb to tip the balance in favour of the patient. All changes
in immune cell responses to an infection are governed by changes in what
genes are active and 'open' for business. Because our DNA stretches out
to nearly 2 meters but needs to fit inside every tiny cell in our body,
it needs to be very tightly packed up. Its packaging, and how easy it is
to open and close, very often dictates the activity of the genes. This
is known as "epigenetics." The research team used a drug approved for
cancer treatment called suberoylanilide hydroxamic acid (SAHA for short,
also known as Vorinostat).

This drug is an epigenetic inhibitor, meaning it can block the machinery
that closes up genes. Using this drug on human immune cells that are
infected with the bacteria that causes TB, they discovered that SAHA
releases the brakes on the immune system by stopping the production
of an anti-inflammatory signal while at the same time promoting more appropriate pro-inflammatory signals that may help the patient to clear
the infection. Importantly, the team discovered that this fine-tuning
of the immune response early in the reaction to infection also benefits
later immune responses, which may also aid in the design of future
vaccine strategies.

Dr Donal Cox, Research Fellow, Clinical Medicine, Trinity College and
senior author on the paper, suggests that this may be a new and exciting addition to our arsenal of antibiotic therapies. He said: "Understanding
and being able to manipulate the immune system is a crucial component of treating infectious diseases. Having host directed therapies targeting
the human immune response will be key in addressing the likely pandemics
that will arise in the future due to increasing antibiotic resistance, particularly TB." "We would also like to thank and highlight the
important contributions that patients made in this study by providing
blood and lung cells without which this research would not be possible."
This work was funded by grants from the Irish Research Council, The
Royal City of Dublin Hospital Trust and the Health Research Board.


========================================================================== Story Source: Materials provided by Trinity_College_Dublin. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Donal J. Cox, Amy M. Coleman, Karl M. Gogan, James J. Phelan,
Cilian O'
Maoldomhnaigh, Pa'draic J. Dunne, Sharee A. Basdeo, Joseph Keane.

Inhibiting Histone Deacetylases in Human Macrophages Promotes
Glycolysis, IL-1b, and T Helper Cell Responses to Mycobacterium
tuberculosis.

Frontiers in Immunology, July 23, 2020; DOI:
10.3389/fimmu.2020.01609 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200723143704.htm

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