Unmasking Influenza A’s Strategy: How PA-X Hijacks Host Cells for Replication

Scientists at the University of Wisconsin-Madison uncover the secrets of PA-X, a crucial protein used by influenza A to take over host cells.

According to a recent study, researchers have uncovered how a key viral protein produced by influenza A devastates the genetic material of host cells. Influenza A, one of the two influenza viruses responsible for costly annual flu seasons, poses a constant threat to humans and various animals. Additionally, it has caused devastating pandemics, such as the one in 1918, resulting in millions of casualties and wreaking havoc on healthcare systems and society at large.

Although influenza A was identified as a health concern nearly a century ago, it is only in the past decade that scientists have successfully identified one of the virus’s crucial proteins responsible for infiltrating host cells and sabotaging their defense mechanisms.

A team of researchers at the University of Wisconsin–Madison has made significant progress in understanding the workings of this protein, challenging previous assumptions. Their findings suggest that viruses like influenza A take control of host cells using a strategic strike rather than brute force.

The protein in question, PA-X, disrupts host cells by degrading their RNA—the genetic material necessary for protein synthesis and mounting defenses against invading viruses. PA-X slashes host cell RNA in multiple locations, effectively disarraying the cell’s genetic instructions.

However, viruses need to employ this protein while ensuring the functionality of their own RNA. Scientists have been striving to understand how the influenza A virus seizes control of host cells while minimizing self-inflicted damage. These conflicting priorities present a fundamental dilemma that lies at the heart of influenza A’s persistent threat over time.

Marta Gaglia, an associate professor of medical microbiology and immunology who led the study, describes the process by which the virus commandeers host cells for self-replication as mounting “a surgical strike for the host without messing up its own replication.” Gaglia joined the faculty at UW–Madison’s Institute for Molecular Virology in 2022.

By employing high-throughput sequencing and advanced statistical modeling, Gaglia and her colleagues have made significant progress in unraveling the secret behind PA-X’s ability to degrade host cell RNA without causing excessive harm.

Gaglia explains, “It turns out that PA-X has a strong preference for a very specific sequence of RNA.”

Importantly, Gaglia and colleagues discovered that the RNA sequence frequently targeted by PA-X is abundant in the genetic material of humans and animals infected by influenza A viruses but rarely occurs in the virus’s own RNA. While the protein’s precision is not flawless—it occasionally cuts through non-target RNA sequences—it appears to be effective enough to disrupt host cell functions. These findings are detailed in a new paper published on June 22 in the journal Nature Microbiology.

In addition to identifying the specific RNA sequences targeted by PA-X, the study suggests that the influenza A virus possesses a mechanism to distinguish between RNA sequences in the genetic material of hosts and its own RNA. While self/non-self recognition is a well-known aspect of hosts’ immune response to pathogens, this phenomenon has not been previously observed in viruses.

Gaglia remarks, “It’s interesting to see the virus also has found a way to do that, flipping the script.”

Many aspects regarding the precise function of PA-X remain unknown. Gaglia and her colleagues are investigating whether their current methods adequately capture the location and number of sites in the RNA sequences where PA-X induces cuts. This research involves refining the statistical models developed in collaboration with Gaglia’s husband, Christopher Rycroft, a mathematics professor at UW–Madison.

Marta Gaglia, Associate Professor of Medical Microbiology and Immunology at the University of Wisconsin-Madison, emphasizes the team’s goals, stating, “We’ve collected some more datasets that we hope to use to refine the methods so we can make this a really robust program that other people can use to analyze their data as well.”

Another unresolved matter concerning PA-X pertains to its impact on the severity of an influenza infection. Previous studies have indicated a correlation between influenza A strains with a less active PA-X protein and more severe symptoms. However, researchers have yet to identify specific genetic indicators or hallmarks of an active PA-X protein, which would shed light on its level of activity.

“An ideal world that we would like to get to is: If you give me a sequence, I could take a look and say, ‘This is a really active version,’ or, ‘This is a less active version,'” adds Gaglia. “And in simplistic terms, that could indicate whether it could be a more dangerous strain.”

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