Deconstructing our natural defences

26 February 2020

Dr W K Eddie Ip (Croucher Fellowship 2003) is an assistant professor and consultant with the Mayo Clinic’s Departments of Immunology and Internal Medicine in Minnesota in the United States, and a man with a significant mission.

The scientist is seeking to decode how human bodies defend themselves against viruses, bacteria, and other pathogens, a quest stretching back nearly two decades.

“My long-term goal is to understand the biology of macrophage cells and how they sense microbes and control their inflammatory responses in the innate immune system,” Ip said.

After graduating from Hong Kong University of Science and Technology with a bachelor’s degree in biochemistry, Ip went on to complete his master’s and PhD in immunology at the University of Hong Kong. He moved to the United States in 2003 to undertake post-doctoral research at Harvard Medical School. He later joined the Department of Immunobiology at Yale University School of Medicine as an associate research scientist before moving to the Mayo Clinic to continue his work.

The body’s immune system has two branches: adaptive and innate. The latter is the most evolutionarily conserved arm of the immune system.

“The innate system reacts to foreign particles and pathogens, such as viruses and bacteria,” he said. “We should be able to react to them immediately, within minutes or hours, and generate rapid and non-specific immune responses.”

This is the first line of our body’s defence against microbes and provides vital protection against unknown pathogens, for example, the novel coronavirus SAR-CoV-2 that causes COVID-19. It includes innate immune cells and physical barriers such as skin, the mouth’s mucous membrane, and the lining of our stomachs and GI tract – areas of the body that encounter outside substances as well as trillions of commensal microbes, which live in these areas without either helping or hurting them.

“We are interested in macrophages, which are key innate immune cells,” Ip said. “These cells are essential for triggering a protective inflammatory response in the host body against pathogens.”

Macrophages are a type of cell found in all vertebrates. They can reside in tissues or derive from monocytes that are recruited to sites of infection as a host defence mechanism.

Ip explained that macrophages can be found in most of our tissues. “Other than host defence against pathogens, they are also found to promote chronic inflammation,” he said, noting that this occurs in conditions such as inflammatory bowel disease (IBD).

Working in the United States, Ip is well positioned to study the immunological mechanism of inflammatory issues. “IBD, including ulcerative colitis and Crohn’s disease, has the highest rate of incidence in developed countries,” he said.

The concentration of such diseases in such countries is also a telling sign of what may be responsible. “There are many contributing factors,” Ip said. “Genetics is one of them, but I also think lifestyle and diet are important.”

Inflammatory disease does not discriminate between ages. “The genetic model we are looking at is essential, even critical, in the earlier stages of life,” Ip pointed out.

Nor does it apply only to humans. In fact, the scientist works primarily with mice. “The mouse is a very malleable model for us because robust tools to modify its genomes are already available,” Ip said. “We can easily delete genes to understand the defect, something we can’t do in humans.”

Ip and his research team have been using genetic mouse models that can develop very-early-onset IBD to study the role of intestinal macrophages in the pathogenesis of the disease.

“Mice’s immune system is highly conserved with that of humans,” he added. “So, what we learn with mice, we can generally apply to humans.”

Immunometabolism is now emerging as a new discipline in the field

While pathogen sensing has always been a key focus of Ip’s research, his recent interest has been shaped over the years by advances in the field. “Ten years ago, not many people were interested in the link between inflammation and metabolism,” Ip said. “We are now starting to realise the importance of metabolism in our body’s immune system.”

A growing interest in the relationship between metabolism and inflammatory response encouraged Ip to take a closer look at its effect on macrophages.

“When many cell types are activated, including macrophages, they undergo what we call metabolic reprogramming,” he explained. “If we understand metabolism, then we may be able to identify metabolic targets to control inflammatory response.”

Ip previously led research to investigate how interleukin-10 (IL-10), a gene already known to be associated with IBD, controls inflammatory response by regulating metabolic reprogramming in macrophages. The findings were published in Science in 2017.

The metabolic control of inflammation could have direct implications for sufferers of inflammatory diseases, from allergies and asthma to diabetes and autoimmune diseases.

Currently, Ip is leading a group at Mayo Clinic to further dissect the metabolic regulation of macrophage functions, which will help uncover new molecular targets for treating infectious diseases and diseases involving aberrant tissue inflammation, including IBD. “Immunometabolism is now emerging as a new discipline in the field,” he said.

Dr W K Eddie Ip is an assistant professor in the Department of Immunology at the Mayo Clinic. He received his BSc in Biochemistry from the Hong Kong University of Science and Technology, and MPhil and PhD from the University of Hong Kong. Ip began his postdoctoral research at Harvard Medical School. He then joined the Department of Immunobiology at Yale University School of Medicine as an associate research scientist. His current research interests focus on host-pathogen interaction, innate immunity and inflammatory diseases, such as inflammatory bowel disease (IBD). He received a Croucher Fellowship in 2003.

To view Dr Ip’s Croucher profile, please click here