Cracking the Case

For the veterinary detectives in the Auburn University College of Veterinary Medicine’s Animal Health and Agro-/Bio-Defense, (AHAD), program, it is the classic case of  “whodunnit?”.

A string of sudden deaths. Unexpected — and unsuspecting — victims. A dangerous killer that is a master of disguise and identity change. The plot has all the twists and turns of the most intricate crime novel.

But it won’t take Sherlock Holmes to solve this mystery. The Auburn AHAD team is already well acquainted with their chief suspect. In fact, the killer is an old foe that appears in many forms. In this particular case, the villain is avian influenza virus (AIV).

The Auburn AHAD program has been hot on the trail of AIV since it was established in 2021 as a new element in the national network of U.S. government agencies and land-grant universities focusing primarily on diseases affecting economically important domestic animals. These include illnesses that can be transmitted from animals to humans, or zoonotic diseases. Such diseases pose a significant threat to public health and can impact security and economic stability locally, nationally and globally.

To advance their avian flu research, AHAD team member and Assistant Professor of Pathobiology Dr. Miria F. Criado recently received a grant from the U.S. Department of Agriculture’s (USDA) U.S. National Poultry Research Center for approximately $644,000 per year. The grant — renewable for up to four years and $2.5 million — is a collaboration between the USDA and Auburn University.

Criado, the lead principal investigator, and co-investigator Dr. Constantinos Kyriakis, associate professor of pathobiology, are collaborating through the grant with Dr. Erica Spackman, acting research lead within the USDA’s Exotic and Emerging Avian Viral Diseases Research Program, and Dr. David Suarez, acting USDA laboratory director.

Poultry are susceptible to two different kinds of avian influenza: low pathogenicity (LPAI) and highly pathogenic (HPAI) viruses. LPAI viruses can cause mild symptoms — or none at all. But HPAI strains typically lead to the death of infected birds within two days. Criado’s team works only with LPAI strains. It is the best way to study avian flu in a safer environment.

“Our work is focused on understanding how avian influenza circulates between species, how the virus evolves to continue circulating and how the bird’s immune system responds to the virus,” Criado said. “We are especially interested in how we can use some currently available tools or vaccines to help control these outbreaks.”

“Monitoring the ecology and emergence of influenza viruses in animal populations, including swine and birds, is of critical importance for pandemic preparedness,” added Kyriakis. “Influenza viruses can jump from one animal species to another or exchange gene segments with other flu viruses in a phenomenon known as antigenic shift, or reassortment, resulting in the emergence of novel viruses capable of infecting and transmitting to new animal species.”

In the case of AIV, that’s exactly what has occurred. Since 2020, a disease-causing strain of bird flu, known as HPAI virus H5N1 clade 2.3.4.4b, has spread from wild bird populations to affect millions of commercial poultry flocks across the U.S. and world as well as the associated industries that depend on them.

In Alabama alone, poultry generates more than 80,000 jobs and $15 billion in annual revenue. Since infected birds usually die quickly, and entire flocks must be culled to control further spread, outbreaks of avian flu can be absolutely devastating to the poultry industry.

While H5N1 has affected wild bird populations in the past, Criado said they usually had no sign of illness. But in this most recent outbreak, there have been several differences from previous cycles that have led to the deaths of thousands of wild birds as well as some cross-species spread, including severe disease and death in some cases.

“The influenza virus strains that have circulated before have required a really high dose of virus in order to infect a bird,” Criado explained. “With the current strain, that’s not the case. Now a much smaller viral load is required. In addition, this circulating virus strain shows the ability to bind to both human and avian cellular receptors. That has caused global outbreaks in avian species as well as some infection in mammals, including humans.”

The transmission from wild bird populations to poultry was not an unprecedented event. But the number of infected flocks, and the failure of the virus to decline over time, led to a further spread to dairy cattle. In cattle, the disease is not fatal, but it does lead to a decline in milk production and feed intake, along with respiratory distress.

The virus was also detected in cats and other domesticated animals that died on affected premises. There have even been several cases of human infection of workers who were in close contact with infected flocks or dairy herds. There are still questions about how the transmission between species occurred.

But while the current avian flu outbreak has garnered a lot of publicity and alarmed comparisons to the recent Covid pandemic, Criado is quick to point out there are major differences between the two diseases.

“For now, H5N1 is not at the same threat level as Covid,” she said. “First, the H5N1 strain from the current outbreak still does not spread easily between people. Ferret models are used to understand influenza transmission, disease severity and risk assessments for pandemic potential in humans. Studies with this model showed that transmission of the current strain requires direct contact for infection and that it does not spread efficiently via respiratory droplets.”

“Second,” she added, “flu viruses have been around a long time and — unlike with Covid — humans already have antibodies that provide some degree of protection against them thanks to previous infections and vaccinations against other strains of influenza.”

Finally, Criado noted, whereas Covid vaccines had to be developed from a standing start, there are already flu vaccines available that can be adapted to help protect against new strains. Even so, she cautions, this virus is still a big threat. The longer H5N1 continues to circulate, the more opportunities it has to become adept at spreading easily between people and causing serious illness, especially in susceptible populations.

With that in mind, studying the effectiveness of different vaccines and other weapons that can be utilized in the fight against avian influenza is yet another part of the AHAD mission. “In the CVM, we are constantly studying both new and proven vaccine technologies.” Kyriakis said. “Once a virus mutates, the effectiveness of any vaccine is reduced — even a third-generation product like mRNA vaccines. Even so, most are still effective at preventing severe disease.”

In the meantime, Criado says there are other measures that remain just as important in the long battle against avian flu and other flu strains. “Constant surveillance is critical,” she noted. “We need to know which strains are circulating and to have professionals who can rapidly identify and study them. We need to understand what we are up against so proper countermeasures can be taken, from vaccines to biodefense.”

“At AHAD,” she concluded, “We also seek to answer basic questions. How does the virus spread to different species? How is it transmitted? Can animals and human be infected more than once? How effective are vaccines? The answers to those questions can benefit both animals and people, and that’s the very essence of what One Health is all about.”