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Foal pneumonia is one of the leading causes of disease and death in foals, with severe cases being most commonly caused by the bacterium Rhodococcus equi (R. equi).

Studies by researchers at Texas A&M University and at other universities have shown that foals are not only exposed to but can get infected by R. equi soon after birth.

"The younger the foal, the more susceptible to R. equi it is," said Dr. Angela Bordin, an assistant professor in the College of Veterinary Medicine and Biomedical Sciences' Department of Large Animal Clinical Sciences. "Once symptoms begin, it might be too late to save the foal."

As part of their ongoing efforts to protect foals from pneumonia, researchers at the Texas A&M Equine Infectious Disease Laboratory (EIDL) have uncovered new, complex interactions between the gut, lungs and immune system.

Their new study, in Scientific Reports, may pave the way for a future vaccine for foals and disease treatments for other species.

A stomach for research

In the study, EIDL researchers sought to uncover why bacteria introduced in the stomach generate an immune response in the lungs through a communication between the gut and the lungs referred to as the "gut-lung axis."

"Decades ago, researchers discovered that administering live R. equi directly into the stomachs of foals via a feeding tube protected them against development of pneumonia by R. equi," Bordin said.

"While this method of inoculation isn't practical on a large scale at farms, we believe that understanding the mechanisms and pathways behind this induced protection may help us make progress toward a vaccine for foals."

To do this, the researchers used the feeding tube method to give a group of foals live R. equi bacteria and then, weeks later, analyzed their blood cells.

"We found that certain types of white blood cells had undergone subtle changes, called epigenetic modifications, which alter the way genes are turned on or off, without altering their DNA. This was unexpected because these particular cells are part of the innate immune system and are short-lived, so the cells demonstrating this change were not the same ones exposed to R. equi in the gut," Bordin said.

The innate immune system is the body's first line of defense against intruders; certain cells within the innate system quickly respond and try to destroy "intruding" microbes.

Conversely, the adaptive immune system—including antibodies and white blood cells known as T and B lymphocytes—develops an immune response over time as an individual encounters specific antigens or pathogens, such as viruses.

"Normally, we don't expect cells in the innate immune system to sustain changes weeks after exposure to pathogens because that's the job of the adaptive immune system," Bordin said.

"This sustained change is called immune memory. This is how, for example, B lymphocytes from a vaccinated individual 'remember' the pathogen and make antibodies quicker and more efficiently when exposed to that same pathogen later on."

Getting to the marrow of disease immunity

That the foals' innate immune system responded when the Texas A&M researchers gave them the live R. equi bacteria was unexpected, but it is a situation that scientists sometimes encounter, involving what is called trained immunity.

"We suspect that the changes we observed in the innate immune cells start in the bone marrow, which is home to the stem cells that make white blood cells," Bordin said.

"While the innate immune system doesn't produce the long-lived memory cells that respond to specific pathogens, it appears that it can be 'trained' through epigenetic modifications."

But how a pathogen in the gut manages to stimulate a trained response in the bone marrow is still a mystery that the researchers are studying.

"Overall, our goal is still to develop a vaccine for foal pneumonia that will stimulate both the innate and adaptive immune systems," Bordin said.

"But we now believe that the innate immune system—and specifically, trained immunity—plays an important part in protecting foals, especially in the early stages of exposure. And better innate immune responses also help generate stronger adaptive immune responses, which, together, protect the foals from developing pneumonia."

In addition to helping protect foals from pneumonia, Bordin is also hopeful that exploring the "black box" of the gut-lung axis and its relationship to trained immunity will advance medical treatments for many species, not just horses.

"This communication between the gut and the lungs happens in all species," she said. "Understanding it will help improve care and treatment options for vulnerable neonates and infants in general."