There are four types of influenza viruses: A, B, C, and D. Among them, influenza A virus (IAV) is the most dangerous as it can lead to pneumonia and even death.
The primary target for the influenza virus is the respiratory epithelium, which is responsible for the innate immune response and serves as the body’s first line of defense against viral infection. The immune system recognizes the influenza virus using RIG-I and MDA5 receptors, initiating a cascade of reactions that produce interferons (IFNs) and other molecules that suppress infection spread.
The body must finely regulate IFN production. IFN deficiency can lead to chronic infection, while excess can cause excessive inflammation and autoimmune reactions. Precise IFN production tuning allows effective virus combat while minimizing inflammatory reactions.
Influenza viruses have learned to evade the immune response. Researchers at the University of Illinois at Chicago have found that influenza A virus affects the level of Miz1 protein, which suppresses IFN production.
Miz1 Suppresses Type I IFN Production and Promotes Viral Replication During Influenza
An experiment on mouse lung epithelial cells with the Miz1 gene deactivated showed that after infection with the H1N1 influenza virus, the production of type I interferon mRNA: IFN-α and IFN-β increased. These interferons suppressed influenza replication, confirming a decrease in viral particles in the cell culture. Conversely, exogenous Miz1 reduced IFN-β production and restored viral replication.
Miz1 activity depends on its structural part – the POZ domain, which is necessary for interacting with other proteins to regulate gene activity. Removing the POZ domain increases IFN production and reduces virus replication.
Phosphorylation of Miz1 on Ser178 is Responsible for Suppressing IFN Production
The Ser178 site influences miz1 activity – serine, one of the amino acids that compose the protein. For Ser178 to regulate gene activity, its chemical modification, which a phosphate group attaches to, is essential. This chemical modification is called phosphorylation. Phosphorylation of Ser178 affects the body’s response to influenza. Researchers experimented on two types of cells: one producing normal Miz1 and the other producing mutant Miz1, where Ser178 was replaced with alanine, which does not undergo phosphorylation. Cells with mutant Miz1 showed increased interferon gene activity and low levels of viral particles after influenza infection compared to cells with normal Miz1.
Conclusion: Phosphorylation of Miz1 at Ser178 plays a crucial role in suppressing interferon production and helps the influenza virus evade the immune response.
Removing The POZ Domain in Miz1 Enhances Type I IFN Production And Increases Survival
Researchers investigated how the Miz1 protein affects the immune response to the influenza virus. They used mice in which the POZ domain of the Miz1 protein in the lungs was removed through genetic engineering. After influenza infection, mice without the POZ domain in Miz1 showed significantly better survival and faster recovery than control mice. While all control mice died within 10 days after infection, only 30% of genetically modified mice died within 14 days.
Removing the POZ domain in Miz1 stimulated the immune response and helped suppress virus replication, improving survival. Mice without the POZ domain showed significantly increased type I interferon production in the lungs, accompanied by a decreased virus titer.
Influenza A Infection Contributes to Miz1 Accumulation
An experiment on mouse lung epithelial cells showed that Miz1 cell levels increase during influenza infection. Moreover, the amount of mRNA encoding Miz1 did not change, which means that changes in Miz1 levels occur after it is synthesized. The increase in Miz1 level is because during influenza infection, the level of another protein, Mule, which participates in Miz1 degradation, decreases. This decrease may contribute to Miz1 accumulation during influenza. Experiments with artificially suppressing Mule activity confirmed its effect on Miz1 level and its ability to control interferon production in response to infection.
Conclusion: Influenza virus reduces the level of Mule protein, leading to an increase in Miz1 level, which diminishes interferon production and promotes virus replication.
Conclusion
Influenza virus A influences the immune response by manipulating Miz1 protein levels in lung cells. Experiments have shown that deactivation of Miz1 increases the production of interferons, which suppress influenza replication. However, when Miz1 is active, it suppresses interferon production, facilitating virus replication.
The influenza virus reduces the level of Mule protein, which is involved in Miz1 degradation, leading to an increase in Miz1 levels. As a result, interferon production decreases, allowing the influenza virus to replicate unhindered.
Current methods of combating influenza include annual vaccination and antiviral drugs. However, vaccines may prove ineffective due to the high variability of the influenza virus, and some individuals may not respond to antiviral treatment. Therefore, an alternative strategy targeting the body’s response to the influenza virus may prove helpful.
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