USU Research Challenges the Accepted Paradigm for Pregnancy Recognition in Ruminants

New research from Utah State University has transformed biologists’ understanding of pregnancy recognition in ruminants, invalidating a key theory that had gone unchallenged for over 40 years.

A paper describing this research, Pregnancy in type I interferon receptor (IFNAR2) knockout sheep challenges the accepted paradigm for pregnancy recognition in ruminants, was published in the August 2026 issue of the Biology of Reproduction, by

• Christopher J. Davies.
• Evan K. Peterson.
• Aaron J. Thomas.
• Andrea L. Giles.
• Young-Min Lee.
• Irina A. Polejaeva.
• Heloisa M. Rutigliano.

The research team was comprised of individuals affiliated with

• The Department of Veterinary Clinical and Life Sciences in the College of Veterinary Medicine.
• The Department Animal, Dairy, and Veterinary Sciences in the Quinney College of Agriculture and Natural Resources.
• The Center for Integrated Biosystems.

In an editorial commentary, Alan D. Ealy from Virginia Polytechnic Institute and State University, wrote: “Davies and colleagues have unequivocally answered an important question and, in doing so, have opened the door to new questions, challenged prevailing assumptions, and stimulated the rigorous debate that drives scientific progress.”

The “prevailing theory” Ealy referred to had been the basis for more than 1,900 peer-reviewed publications examining the biology of ruminant reproduction.

The emergence of this theory in the 1960s and 1970s suggested that, in sheep, the conceptus (the fetus and surrounding placenta) must produce a signal during a critical window of early pregnancy to maintain progesterone levels necessary to sustain gestation.

Research pointed to a protein called interferon tau, produced by the outer cells of the placenta. Scientists believed interferon tau was the signal that “tells” the female sheep that she is pregnant, kicking off biological processes necessary to maintain a growing fetus. Decades of research established that interferon tau has important biological effects during early pregnancy; however, researchers had not been able to directly test whether interferon tau’s signaling through the classical type I interferon receptor was essential for pregnancy to be established. Although it was clear that interferon tau is released by the conceptus and has biological effects associated with early pregnancy, the question remained: is interferon tau signaling essential for maternal recognition of pregnancy?

USU researchers had previously created, through gene-editing and animal cloning technologies, a sheep model that was ideal for testing this theory. This model in which the type I interferon receptor is inactivated was originally created to study Zika virus infection. These sheep lack a subunit of the type I interferon receptor, rendering this receptor non-functional.

This receptor, when functional, binds to interferons alpha and beta, two type I interferons central to the immune response in sheep. It also binds to interferon tau. The original goal was to study how Zika virus infection progresses without a functional type I interferon receptor.

After the viral study concluded, these knockout sheep remained in USU’s herd and were used to study the receptor's impact on early pregnancy. The researchers initially hypothesized that female interferon receptor knockout sheep would be infertile. For this study, two 9-month-old knockout ewes (female sheep) were placed in a pen with a ram (a male sheep) to be bred. Davies then monitored the ewes’ levels of progesterone.

Of the experiment’s outset, Davies said: “We expected to get some interesting information about how the signaling works in early pregnancy. However, the results forced us to reject our initial hypothesis that interferon receptor knockout ewes would be infertile.”

In a non-pregnant or cycling sheep, after 17 days, or the length of a sheep's reproductive cycle, the progesterone level should drop, but in the two interferon receptor knockout ewes, the level remained elevated.

“When after 25 days the progesterone level was still elevated, I thought, Gee, it looks like these sheep could be pregnant,” Davies said.

The two sheep were pregnant, as subsequently confirmed by ultrasonography. In May 2023, the pregnant ewes gave birth to healthy, normal lambs. The experiment demonstrated that sheep lacking functional receptors for type I interferons, including interferon tau, could still establish and maintain pregnancy.

“That was shocking because it challenges the accepted paradigm of how reproduction works in ruminants,” Davies said.

In presenting these findings at international conferences, the researchers faced a barrage of questions. After all, other experts in the field had relied on the previously accepted notion of pregnancy recognition in ruminants for decades.

Ealy, who holds the position of Board of Reviewing Editors for Biology of Reproduction, noted in his editorial that the strong reaction to the findings was to be expected, and an essential part of the scientific process when a long-standing paradigm is challenged. He pointed out that Davies embraced the questions and used the feedback to strengthen the experiments and their interpretation.

The findings open new avenues for study, and more questions. The research does not rule out other biological roles for interferon tau or the possibility that it acts through alternative mechanisms.

“Interferon tau might help protect the conceptus against infections, which is a more normal function of a Type I interferon,” Davies said.

And are there other candidates for doing the job interferon tau was previously thought to do? That will require more research, too.

Revelations like these have been made possible by advances in genome sequencing and gene editing, which allow scientists to directly test biological assumptions that earlier generations could investigate only indirectly, Davies said.

“I think it’s important to point out that the people who did the original work weren’t trying to mislead anybody, they were very smart people,” he said. “It’s just that they didn’t have the tools back then to directly test the hypothesis the way we were able to do in this study.”

Dr. Heloisa Rutigliano, Davies’ co-author and colleague, says the unknowns raised by the USU team’s findings are an example of what makes science so exciting. She is currently developing further testing methods to attempt to answer some of these emerging questions.

“New technologies allow us to go back and directly test ideas that have been accepted for decades, sometimes because the evidence supporting them was very strong. When new evidence challenges those ideas, it doesn’t diminish the science that came before it, it’s just how science advances,” Rutigliano said. “That constant process of questioning, testing, and revising our understanding is what makes scientific discovery so dynamic.”

This research was supported by Agriculture and Food Research Initiative Competitive Grants no. 2021-67016-33504 and 2024-67016-42366 from the USDA National Institute of Food and Agriculture.