How does a bird virus infect a person? Surprising findings from B.C.’s human case of H5N1 avian flu

How do we know when an animal virus might pose a risk to humans? Canada confirmed a human case of H5N1 avian influenza (often called “bird flu”) in 2024, the first ever known to have been acquired in Canada. The patient, a thirteen-year-old British Columbian, suffered severe symptoms including respiratory failure but recovered with intensive care in hospital.

Uncovering insights into how pathogens can switch from animals to humans — as in this human case of bird flu — can help researchers and public health agencies prepare for future outbreaks. In a recent study, our lab examined viral mutations in this case and uncovered an unexpected result: the effects of these mutations were inconsistent with the usual warning signs we expect to see in a virus adapted to infect humans.

How we usually monitor influenza

Public health agencies and collaborating groups use complementary approaches to monitor infectious disease outbreaks and risk. Human outbreak data comes from many places, including care settings and associated surveillance labs, volunteers reporting disease status, and wastewater monitoring. Current routine virological tests in public health labs include sequencing viral genes, testing for antiviral resistance and assessing immunity against strains of interest.

Read more:
Sewage surveillance: How scientists track and identify diseases like COVID-19 before they spread

From wildlife and agricultural monitoring, Canadian agencies have tracked the arrival of the currently dominant H5N1 lineage of avian influenza, of which the B.C. case is a member. In this case of a human H5N1 patient in B.C., sequencing efforts found three mutations of interest. One is already a well-studied sign of adaptation from birds to mammals.

Immunity and Society is a new series from The Conversation Canada that presents new vaccine discoveries and immune-based innovations that are changing how we understand and protect human health. Through a partnership with the Bridge Research Consortium, these articles — written by experts in Canada at the forefront of immunology, biomanufacturing, social science and humanities — explore the latest developments and their impacts.

The other two mutations caught our attention since they are less understood. Both were in hemagglutinin, the viral surface protein that binds to cells and initiates infection by fusing the virus and cell membranes. These mutations, E190D and Q226H (representing 28 per cent and 35 per cent, respectively, of hemagglutinin genetic material sequenced), were at the part of hemagglutinin known to interact with receptors on host cells.

Bird and human cells tend to display different types of receptors, which is why scientists use receptor binding as a common test for species adaptation. These hemagglutinin mutations had not previously been observed to switch binding to human-type receptors in H5N1 influenza.

What this case revealed

Our lab investigated the role of these two mutations in what types of receptors these viruses bind to more favourably. Receptor binding can influence which cells, and which species, a virus is more likely to infect. Therefore, we made versions of the hemagglutinin protein with and without each mutation and measured how they bound to different receptors.

The results were unexpected. When we produced hemagglutinin protein with either of these mutations, not only did we not observe the expected binding to human-type receptors that would support human infection, but the binding to avian receptors was severely diminished. Using standard approaches, binding to any receptor was essentially undetectable.

Yet the virus in the B.C. patient clearly replicated in human tissue. So, our team tested the ability of the hemagglutinin variant carrying both mutations to fuse cells derived from human lung cells. After binding to host cells, fusion is the second major step mediated by hemagglutinin. The result of fusion is that viral genetic material and proteins required for replication are released from inside the viral particle into the host cell where they can function.

Just as we saw when we looked at the receptor binding, we saw a substantial reduction in the virus’s hemagglutinin protein’s ability to fuse membranes of the lung-derived cells, likely a consequence of the reduced binding. However, we did detect a low level of fusion, which suggests that we might see both receptor binding and membrane fusion activity under conditions that better mimic actual human lungs.

In a human case of infection with a virus that usually affects birds, we would normally expect to see the surface protein (hemagglutinin) binding with human receptors. That would be typical in a virus that was adapting from birds to humans.

But what we saw in the B.C. case of human infection with H5N1 was a reduced ability not only to bind to human receptors, but also to bird cell receptors, resulting in a low ability to fuse with cell membranes. However, the combination of lots of hemagglutinin proteins on the virus’s surface, and many receptors on the cell’s surface, may have compensated for the poor ability to bind to individual receptors.

What we can learn from this case

This case demonstrates that there is much to learn about the complex factors that may result in a virus developing the ability to infect humans. From decades of investigation, we had reason to believe these hemagglutinin mutations were interesting, so it’s a success for our existing knowledge base.

Our lab depended on successes in the public health system leading up to the B.C. Centre for Disease Control Public Health Laboratory being able to sequence viruses in the patient, and releasing its data to the influenza research community, as well as generous support of our research from the federal and provincial sources.

The unexpected findings suggest that we need greater functional understanding of human disease risk. Our existing set of mutational warning signs does not capture all threats as we monitor animal outbreaks. Functional laboratory studies are slower and more expensive, but they can tell us more directly how viruses behave.

Public health agencies already run certain on-the-fly functional tests such as assessing vaccine match to seasonal influenza. This data continues to inform our response to outbreaks. Greater monitoring of other influenza functions would further enhance public health efforts.

The stronger our basic knowledge of how these viruses work, the better we can interpret surveillance data, prepare for outbreaks and design interventions.