Why Some Flu Viruses Are More Dangerous Than Others — The Cause Is the Launch of an Interferon "Storm"

Influenza remains one of the most significant respiratory infections, but the severity of the disease varies greatly: from a “cold on the legs” to fulminant pneumonia and respiratory failure. Scientists from the Paul Ehrlich Institute (Germany) compared 11 strains of the influenza A virus - from the usual seasonal to highly pathogenic avian strains - and showed that the decisive difference lies in which innate immune cells the virus can productively infect. If the virus “enters” certain myeloid cells and multiplies in them, it triggers a powerful production of type I interferon (IFN-α) and a subsequent “cytokine storm” - the very same hyperinflammation that often kills more than the virus itself. The results are published in the journal Emerging Microbes & Infections.

Background of the study

Why do some flu strains cause "normal" illness while others cause an overreaction? Plasmacytoid dendritic cells (pDCs) were once thought to be the key to the mystery: They are factories of type I interferon and capture viral RNA even when cells are not fully infected. New work confirms that pDCs do indeed "boil" IFN-α during virtually all flu infections. But that's not the only explanation.

The authors showed that in really severe flu, other cells of the innate immune system come into play - myeloid dendritic cells and different types of macrophages. And here the principle is different: for them to start churning out IFN-α, the virus must productively infect them, that is, actually reproduce inside them.

It turns out that highly pathogenic avian viruses (like H5N1) are better at “hijacking” these human myeloid cells and triggering an IFN-α storm. This helps explain why zoonotic strains that jump from birds to humans carry a disproportionately high risk of severe pneumonia and death.

Thus, the severity of influenza is not only a question of “which virus” and “which tissues” it infects, but also which immune cells it is able to infect. Differences at this level change the architecture of the early response - from modest antiviral protection to destructive hyperinflammation (“cytokine storm”).

This logic fits in well with the observations of clinicians: in severe cases, we see an avalanche-like release of inflammatory mediators, in which the immune system itself “fires.” New data suggest where exactly the “trigger” is located - in the productive infection of myeloid cells in “evil” strains.

Why is this important?

Understanding the cellular "address" of the virus is an opportunity to more accurately predict the danger of new flu variants and to intervene in the immune cascade: to restrain the excessive IFN response exactly where it is triggered incorrectly, without depriving the body of basic protection. This is relevant both for sanitary surveillance (assessment of the threat of zoonotic strains) and for the development of anti-inflammatory adjuvants to therapy.

Purpose of the study

To compare how seasonal and highly pathogenic avian influenza A viruses interact with different types of human innate immune cells and what conditions are required for IFN-α production: is contact with the virus sufficient (as in pDCs) or does productive infection require (as in myeloid dendritic cells and macrophages).

Materials and methods

The authors examined 11 influenza A virus strains, including common seasonal variants and highly pathogenic avian viruses (such as H5N1), and tested them in panels of human immune cells: plasmacytoid and myeloid dendritic cells, as well as different macrophage populations. They measured infectivity, cell viability, and IFN-α production to separate “alarm bells” from full-blown viral replication in the cell.

What exactly was compared:

• Seasonal strains against highly pathogenic avian viruses based on their ability to productively infect myeloid cells and induce IFN-α.
• The response of different innate immune cells: pDC (interferon without productive infection) vs myeloid DC/macrophages (interferon with productive infection).

How was the effect assessed:

• Markers of viral replication and IFN-α secretion; comparison of cell viability during infection with different strains; integration of results to explain the risk of "cytokine storm".

Results and interpretation

The picture formed into a clear two-stage model. pDC consistently produced high IFN-α upon contact with a virus of any nature - they do not require full replication of the virus to "sound the siren". Against this background, differences between strains became noticeable precisely in myeloid dendritic cells and macrophages: interferon appeared only during a productive infection, and highly pathogenic avian viruses are best "trained" in it.

It is this combination of “universal pDCs + infected myeloid cells” that explains why some strains lead to a deafening interferon storm and hyperinflammation, while others remain within the bounds of controlled defense. It also points to cellular targets where it makes sense to inhibit the excessive response without completely nullifying the antiviral defense.

Discussion

Commenting on the results, Acting Vice President of the Paul-Ehrlich-Institute Professor Zoe Weibler summed up: “ Our results show that not only those immune cells that have traditionally been considered the main sources of type I interferon, but also other cells of the innate immune system can play a decisive role in triggering an excessive response. This knowledge is important in order to more accurately assess the risk of dangerous viral variants.” This idea moves the conversation from the abstract “bad strain” to the specific cellular ecology of the infection.

Practical significance

- For clinicians and surveillance systems:

• When assessing the severity of emerging zoonotic strains, focus on the ability of the virus to replicate in human myeloid cells and induce IFN-α; such characteristics can be included in risk laboratory test panels.

- For the development of therapies and vaccines:

• Consider selective early response immunomodulators targeting myeloid cells (or their signaling pathways) as an adjuvant to antiviral agents to dampen the “storm” without depriving pDC-mediated protection.

Restrictions

The publication relies on ex vivo/cellular models and a panel of 11 strains; the generalizability of the findings to the full spectrum of circulating and future viruses requires confirmation. The contribution of other innate populations and tissue niches (e.g., lung cells in situ) remains a subject of further research, as do the optimal points of immunomodulation that do not impair antiviral control.

Conclusions

The danger of "bird" flu is explained not only by a set of mutations, but also by their ability to enter certain human myeloid cells and multiply inside them. Then the pDC signal, paired with the "connected" myeloid cells, spins up an interferon storm - a harbinger of a severe course. This knowledge helps to more accurately assess the risks of new strains and design combined strategies: the virus - to beat with antivirals, the immune "overheating" - to cool down specifically.

Source: Niles MA, Kronhart S., Decker KE, Gogesch P., Sawatsky B., Stock S., Kochs G., Waibler Z., Anzaghe M. Influenza A virus induced interferon-alpha production by myeloid dendritic cells and macrophages requires productive infection. Emerging Microbes & Infections. Online ahead of print, September 3, 2025. DOI: 10.1080/22221751.2025.2556718.