Nav: Home

Tuberculosis bacteria build 'edible' havens in immune cells

April 18, 2016

Bacteria that cause tuberculosis trick immune cells meant to destroy them into hiding and feeding them instead. This is the result of a study led by researchers from NYU Langone Medical Center and published online April 18 in Nature Immunology.

The study results revolve around the ancient battle between the human immune system and bacterial invaders, where immune cells strive to recognize bacteria as the microbes work to evade them. Mycobacterium tuberculosis remains the leading bacterial cause of death globally because, like other successful pathogens (e.g. HIV), it goes beyond evasion to take over functions of immune cells.

The newly published study describes how tuberculosis bacteria cause mammalian immune cells, called macrophages, to make more of a key snippet of genetic material. Higher levels of this snippet, called microRNA-33 (miRNA-33), change the action of many genes to strip macrophages of their ability to package TB bacteria for destruction. At the same time, these genetic regulatory changes force the cells to build up fat for the TB bacteria to feed on. Although this study was done in mice, the same mechanisms were found in human macrophages infected with TB.

"Our study results describe precise mechanisms that enable tuberculosis bacteria to persist in the body, which is central to the infection's deadliness," says senior study author Kathryn Moore, PhD, the Jean and David Blechman Professor of Cardiology at NYU Langone. "While anti-cholesterol medications like statins are currently under investigation for the treatment of tuberculosis, our study points to other ways in which we might reverse TB-driven fat build-up in immune cells to better clear the disease."

Upon entering macrophages, most bacteria are enfolded into vesicles called phagosomes. These pockets then fuse with lysosomes, a second set of compartments filled with bacteria-destroying chemicals. TB bacteria can evade capture by phagolysomes, getting free in the cell's cytosol where a back-up mechanism, autophagy, seeks again to deliver them to lysosomes.

While the first role of autophagy is to enfold aging cell parts into vesicles where they can be broken down and recycled, evolution has also put this mechanism to work in controlling fat (lipid) levels and as a back-up system for removing harmful bacteria. TB bacteria take advantage of this convergence of cell functions to change conditions in their favor.

Specifically, the new study found that TB bacterial proteins trigger an immune signaling pathway inside macrophages, where a protein complex called NFKappaB triggers a key gene to make more of microRNA-33. This dramatically dials down the signal delivered by several autophagy genes that would otherwise keep fat levels down.

Future Treatment Design

With the emergence of the idea that TB might need fat build-up to thrive, there had been excitement around the idea of using statins against TB. Could these inhibitors of cholesterol synthesis counter some lipid build-up in macrophages? In 2010, Moore's team published a paper in Science that found miR-33 to be encoded in the same gene that statins turn up, so statins would cause macrophages to make more miR-33 even as they lowered cholesterol levels.

Given the better understanding of the role of miR-33 and fat build-up in TB infection, the study authors argue that the bacterial lipid effect may be countered using antisense oligonucleotides, another set of molecular chains that are the right shape to grab miR-33 and remove it from action. An example of this kind of medication is mipomersen, an antisense molecule already available for the treatment of inherited conditions that cause high cholesterol levels.

"Like many diseases that are now rare in the United States, but still common causes of death in developing countries, the economics of engaging industry to help develop new treatments will be challenging," says Moore. Any treatment would have to be very inexpensive to be viable in the developing world, and antisense oligonucleotide injectable drugs are costly.

Moving forward, the team will be looking for other drugs to test in mouse models of TB infection that can lower levels of miR-33 to boost the pathways suppressed by TB through this tiny RNA.
Along with Moore, NYU Langone authors were lead author Mireille Ouimet, Bhama Ramkhelawon, Coen van Solingen, Scott Oldebeken, and Tathagat Dutta in the Ray Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine; along with Stefan Koster, Erik Sakowski, Cynthia Portal Celhay, and Jennifer Philips in Division of Infectious Diseases and Immunology. Also leading the study were Denuja Karunakaran, Katey Rayner, and Yves Marcel at the University of Ottawa Heart Institute and departments of Biochemistry, Microbiology and Immunology; Frederick Sheedy in the Department of Clinical Medicine, School of Medicine, Trinity College Dublin; as well as Katharine Cecchini and Philip Zamore of the RNA Therapeutics Institute, Howard Hughes Medical Institute and the University of Massachusetts Medical School.

Support for this work came through grants from the National Institutes of Health (R01 HL108182, HL119047; R01 AI087682, R21 AI105298), the American Heart Association (13POST14490016, 14POST20180018), the NYU Physician-Scientist Training Program, Potts Memorial Foundation, Edward J. Mallinckrodt, Jr. Foundation, Science Foundation Ireland (13/SIRG/2136), and Canadian Institutes of Health Research (MOP130365, MSH130157).

New York University

Related Bacteria Articles:

Bacteria might help other bacteria to tolerate antibiotics better
A new paper by the Dynamical Systems Biology lab at UPF shows that the response by bacteria to antibiotics may depend on other species of bacteria they live with, in such a way that some bacteria may make others more tolerant to antibiotics.
Two-faced bacteria
The gut microbiome, which is a collection of numerous beneficial bacteria species, is key to our overall well-being and good health.
Microcensus in bacteria
Bacillus subtilis can determine proportions of different groups within a mixed population.
Right beneath the skin we all have the same bacteria
In the dermis skin layer, the same bacteria are found across age and gender.
Bacteria must be 'stressed out' to divide
Bacterial cell division is controlled by both enzymatic activity and mechanical forces, which work together to control its timing and location, a new study from EPFL finds.
How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.
The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?
Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.
Bacteria uses viral weapon against other bacteria
Bacterial cells use both a virus -- traditionally thought to be an enemy -- and a prehistoric viral protein to kill other bacteria that competes with it for food according to an international team of researchers who believe this has potential implications for future infectious disease treatment.
Drug diversity in bacteria
Bacteria produce a cocktail of various bioactive natural products in order to survive in hostile environments with competing (micro)organisms.
More Bacteria News and Bacteria Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 3: Shared Immunity
More than a million people have caught Covid-19, and tens of thousands have died. But thousands more have survived and recovered. A week or so ago (aka, what feels like ten years in corona time) producer Molly Webster learned that many of those survivors possess a kind of superpower: antibodies trained to fight the virus. Not only that, they might be able to pass this power on to the people who are sick with corona, and still in the fight. Today we have the story of an experimental treatment that's popping up all over the country: convalescent plasma transfusion, a century-old procedure that some say may become one of our best weapons against this devastating, new disease.   If you have recovered from Covid-19 and want to donate plasma, national and local donation registries are gearing up to collect blood.  To sign up with the American Red Cross, a national organization that works in local communities, head here.  To find out more about the The National COVID-19 Convalescent Plasma Project, which we spoke about in our episode, including information on clinical trials or plasma donation projects in your community, go here.  And if you are in the greater New York City area, and want to donate convalescent plasma, head over to the New York Blood Center to sign up. Or, register with specific NYC hospitals here.   If you are sick with Covid-19, and are interested in participating in a clinical trial, or are looking for a plasma donor match, check in with your local hospital, university, or blood center for more; you can also find more information on trials at The National COVID-19 Convalescent Plasma Project. And lastly, Tatiana Prowell's tweet that tipped us off is here. This episode was reported by Molly Webster and produced by Pat Walters. Special thanks to Drs. Evan Bloch and Tim Byun, as well as the Albert Einstein College of Medicine.  Support Radiolab today at