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CETI scientists discover the importance of microbiota maintenance and mucosal health

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Posted: Mar 30, 2020 - 01:50pm

IgT, an antibody that does it all

New research published recently in Science Immunology by collaborators Dr. Irene Salinas at The University of New Mexico Center for Evoluationary & Theoretical Immunology and Dr. J. Oriol Sunyer at the University of Pennsylvania, Veterinary School, brings new importance of immune defenses at mucosal barriers from an antibody, IgT, which apparently does it all.                                                                 

Mucosal tissues, including those in the mouth, lungs and stomach, perform important, complex physiological roles. These jobs include nutrition or gas exchange aided by friendly microbes that live in symbiosis with every animal. These symbioses have proven very beneficial for the survival and success of every species, but also have pushed immune systems to evolve ingenious ways to allow and help “good bacteria” to do these jobs. Mucosal antibodies such as IgT in fish and IgA in mammals are responsible for this tricky balance.

The research paper, titled “Specialization of mucosal immunoglobulins in pathogen control and microbiota homeostasis occurred early in vertebrate evolution,” sheds new light onto the conundrum of why did mucosal antibodies first evolve – to allow “good bacteria” to colonize animals or to keep pathogens at check?

The team was able to answer this question using rainbow trout, a species that most immunologists do not think as their gold standard laboratory model. However, both Salinas and Sunyer have been working on rainbow trout for decades and this animal continues to illuminate a field in which only mouse genetic models had been previously applied until now.

"The beauty of our model system is that we can remove IgT in an animal with a perfectly developed mucosal immune system and a normal mature microbiome. This is critical when comparing the findings of our paper to other situations in life in which our mucosal antibody levels drop."  Irene Salinas, associate professor, Department of Biology

Trout Gills
A mucosal antibody, IgT is secreted by bony fish into the mucus that covers their skin, gills, gut, mouth and nose. IgT reduces bad microbes and promotes the presence of certain beneficial bacteria.

“IgT is a mucosal antibody that bony fish secrete into the mucus that covers their skin, gills, gut, mouth and nose,” said Salinas. “It is remarkably similar to IgA, making the findings of this paper translational in many ways. The question about the primordial function of IgA has been chased for a while using mice. Mouse models in which IgA was genetically absent from mucosal secretions are obviously valuable and interesting, yet not perfect to answer all questions.

“The beauty of our model system is that we can remove IgT in an animal with a perfectly developed mucosal immune system and a normal mature microbiome. This is critical when comparing the findings of our paper to other situations in life in which our mucosal antibody levels drop. For instance, stress, drugs, depression or even perhaps toxins, decrease IgA levels in our bodies. If so, what then happens to our ability to fight pathogens? And how do “good bacteria” respond to those changes?”

The results presented in this research paper clearly show that IgT can do it all, say the scientists.

“We found that IgT is playing two paradoxical roles, on the one hand reducing bad microbes and on the other hand promoting the presence of certain beneficial bacteria,” said Sunyer. “Fish are the earliest bony vertebrates to possess a mucosal immune system, and so the fact that fish possess an specialized immunoglobulin that does both jobs suggests that these two processes are so fundamentally important for vertebrate survival that they arose concurrently, early on in evolution”.

“When trout were depleted from IgT, and then challenge to a pathogen, they did not survive well. When trout were depleted from IgT, the ‘good bacteria’ did not like it either. Some were lost, indicating that they could no longer colonize the host,” said Salinas. “Importantly, some other bacteria were able to expand and even cross the tissue barriers of the trout. This meant that the gills of IgT depleted animals were not healthy and bacteria travelled inside the animal.”

Among the bacteria that expanded in the absence of IgT, researchers identified Flavobacterium sp., a well- known foe in fish farms causing serious economic losses. "Given the global impact of aquaculture towards market fish supply and how damaging mucosal pathogens can be in this industry, we are excited about applying these findings to problems that threaten fish farms," Salinas said.

This work culminates years of work to develop and bring a non-model species such as rainbow trout to the attention of all the Immunology research community.

“The bold image on the cover of the journal Science Immunology with two swimming trout certainly helps our mission,” Salinas said. “We are committed to unravel immunological solutions used by species that most people do not use in their laboratories. And we certainly believe it is worth it.”

In addition to Salinas and Sunyer, other co-first authors of the study were Zhen Xu and Fumio Takizawa. Additional authors included from UPenn vet were Yasuhiro Shibasaki, Yang Ding, and Yongyao Yu; Elisa Casadei and Thomas J. C. Sauters from The University of New Mexico Biology Department are also co-authors on the paper.

The study was supported by the National Science Foundation (Grant 1457282), the U.S. Department of Agriculture (Grant USDA-NIFA-2016-09400), the National Institutes of Health (grants GM085207-09 and GM103452), the National Natural Science Foundation of China, the Japan Society for the Promotion of Science, JSPS Overseas Fellowships, and The University of New Mexico’s Initiative for Maximizing Student Development Program.