Gut bacteria links to immune responses in the brain

  • January 14, 2021
Gut bacteria links to immune responses in the brain

Zachary Fitzpatrick on the background to his research investigating immune responses in the brain

Gates Cambridge has been like a second home to me and has taught me that it is important to be a human first.

Zachary Fitzpatrick

Bugs in the gut may hold the key to protective immune measures in the brain which could have implications for diseases such as Parkinson’s and multiple sclerosis, according to a new study led by Gates Cambridge Scholar Zachary Fitzpatrick.

A paper based on his PhD research has recently been published in Nature and it highlights interactions between the adaptive immune system and the central nervous system – and how these interactions are influenced by the gut microbiome. Zach’s background in studying immune responses to viruses used as gene therapy vectors aided his work in investigating immune responses in the brain.

For Zach [2015] the path to his research at Cambridge began after he finished high school in a rural part of Louisiana and started working at a chronic pain management centre. He continued this work throughout his Biochemistry degree at Louisiana State University. Prior to starting he had been thinking about a career in medicine, but it made him want to pursue scientific research to expand the treatment options for patients. “I realised there must be other options for pain treatment as the ones we were using were either ineffective or plagued with serious side effects,” he said.

It was not easy to find chronic pain research labs to work in so Zach started working in other labs. One of his first major research experiences was at an extended summer internship with Katherine High at the Children’s Hospital of Philadelphia in 2012.

Her research was focused on gene therapy for haemophilia B patients and involved using adeno-associated virus (AAV) vectors for therapeutic gene transfer. This research, however, highlighted immune system barriers to the therapy’s effectiveness; for instance, patients who have pre-existing antibodies to this virus due to natural exposure are often ineligible to receive this gene-based treatment as the virus would be neutralised before therapeutic transgene expression is achieved. That experience has driven Zach’s interest in immunology ever since.

During his research stint in Philadelphia, Zach came across a paper from investigators at Harvard Medical School describing a novel AAV vector platform whereby virions, entire virus particles, are enclosed by cell membrane-derived vesicles – or exosomes. Zach hypothesised that this vector could be used to resist pre-existing antibodies and that, ultimately, this which could make it possible to extend AAV-based treatment options to patients who had already been exposed to the virus.

Pathway to a PhD

Zach wrote a research proposal to carry out this work with Casey Maguire at Harvard Medical School. He started working there in 2013 and then won a Fulbright Scholarship to go to Paris to continue this line of investigation with Federico Mingozzi at Genethon, a company committed to the development of gene-based products to treat rare genetic diseases. Zach ended up spending a year and a half in France, researching this platform and studying immune-related barriers to the effective application of AAV-based drugs, while completing his master’s at the Pasteur Institute of Paris.

Zach had applied to do a master’s at Cambridge before going to Paris and won the Gates Cambridge Scholarship, but had deferred. Having already got a master’s in France he was able to proceed straight to a PhD in Medicine at Cambridge in 2016.

Zach had also applied to the National Institutes of Health (NIH) Oxford-Cambridge Scholars Programme, intending to study rare genetic diseases and continue his work on gene therapy. However, he was having trouble finding a lab and mentor that fit with his work when Professor Menna Clatworthy invited him to join her immunology laboratory to study adaptive immune responses in the brain. This meant Zach could continue studying the immune system but in the brain, a place that has been historically considered immune-privileged or lacking the ability to mount local immune responses.

Professor Clatworthy became his mentor and Zach describes her as “a change agent”. “It was a unique experience,” he says. Under the NIH OxCam programme, he had another mentor – Dorian McGavern, who provided a good balance to Professor Clatworthy’s out of the box way of approaching scientific investigation.

From the gut to the brain

Zach’s first paper on his PhD research was recently published by Nature. It describes how plasma cells, or antibody-secreting cells, can be found in the human and mouse meninges [the membranous coverings of the brain and spinal cord] in health. Through creating a technique to image mouse meninges, the researchers found there were a number of plasma cells present around the brain which preferentially localised around the meningeal venous sinuses, large veins responsible for draining the brain’s blood supply. They were then able to work out the type of antibodies these cells were expressing and found they were predominately expressing IgA, an isotope which is normally found in the gut, and other mucosal barriers.

From there, they were interested to see if IgA-secreting plasma cells played a role in the outcome of a brain infection so they used a neurotropic yeast pathogen to study this. When animals were depleted of meningeal IgA plasma cells, they had enhanced infection in the brain and were more likely to succumb to this fungal challenge. “We were able to show that these plasma cells have a protective function in the context of a brain infection,” says Zach.

The researchers then wanted to know where the IgA cells were coming from. Working with germ-free mice from the Sanger Institute they found no evidence of IgA cells around their brains, but these cells could be restored when mice were colonised with gut commensals, such as bacteria, suggesting that the presence of these cells is dependent on the gut microbiota.

Using B cell receptor sequencing techniques, they deduced that the cells were coming from the gut. They also found that the number of peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. “It was a huge finding to see such a similarity between IgA clones in the gut and the brain,” says Zach, adding that it could unlock new routes for understanding neuroinflammatory pathways and their role in diseases like multiple sclerosis and Parkinson’s where research has already shown a link to the gut.

Zach, who is now looking to continue his research in industry with the aim of developing immunomodulatory and gene-based therapies to counter neurodegenerative diseases, adds that he has really enjoyed his experience at Cambridge as a Gates Cambridge Scholar. “Gates Cambridge Scholars really care about making a difference in the world,” he says. “The Trust supported me when I switched labs because they invest in the scientist as a person rather than in an idea. Gates Cambridge has been like a second home to me and has taught me that it is important to be a human first.”

Image: Confocal micrograph showing the superior saggital sinus in the mouse. Immune cells are shown in green lining this tube, and blood vessels in red. Credit: Zach Fitzpatrick

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