Rosa Rubicondior: Malevolent Designer - How The Influenza Virus Appears To Be Intelligently Designed to Make Us Sick

Influenza virus. 3D illustration showing surface glycoprotein spikes hemagglutinin purple and neuraminidase orange.

Image Credit: Kateryna Kon / Shutterstock.

HZI | How influenza viruses communicate with cells

In their attempts to pass creationism off as legitimate science, Discovery Institute fellows William A. Dembski and Michael J. Behe have unwittingly undermined their own case. Their arguments—largely based on a classic god-of-the-gaps fallacy and a false dichotomy—can just as easily be turned against the very idea that their supposed intelligent designer is the God of the Christian Bible.

While they stop short of making that claim explicitly, the infamous Wedge Document [1.1], which outlines the political aims and strategy of the Discovery Institute, leaves no doubt: their ultimate goal is a fundamentalist Christian theocracy governed by so-called "Christian principles" and that selling the idea that 'Intelligent Design' creationism is real science, is a fundamental aspect of that strategy because it would enable them to teach creationism to children at taxpayers' expense, under the guise of real science.

And yet, even within their own paradigm, the evidence points not to a benevolent deity but to something far more disturbing.

Take, for example, recent research from the Helmholtz Centre for Infection Research, which offers a striking illustration of what Dembski might call "complex specified information" and what Behe might regard as "irreducible complexity". The study reveals how the influenza virus is 'designed'—if one accepts their terminology—with remarkable sophistication to circumvent our defences and invade human cells. Ironically, these very defences are what the same creationists insist were intelligently designed to protect us—against, among other things, intelligently designed viruses. We are left, according to this worldview, with the absurd spectacle of a designer who engineers both the pathogens and the immune system meant to defend us from them—a system that, demonstrably, does not always work.

And this is held up as evidence of a supreme intelligence!

Far from supporting creationist claims, these findings align far more convincingly with what we would expect from a blind, indifferent process of evolution—one that requires no designer at all. Once again, creationists are faced with an uncomfortable dilemma: either accept the notion of a malevolent and inept designer or acknowledge the explanatory power of natural selection and evolutionary biology.

What is currently know about how viruses enter cells? Viruses are not living organisms in the traditional sense—they lack the machinery to replicate independently. Instead, they must hijack a host cell’s systems. The process by which viruses enter cells is both intricate and highly evolved:

Attachment to the Host Cell

Viruses begin by recognizing and binding to specific receptor molecules on the surface of a susceptible host cell. For example, the influenza virus uses a protein called hemagglutinin (HA) to bind to sialic acid residues on human respiratory tract cells.

Entry via Endocytosis

Once attached, the influenza virus is internalized into the cell through a process called endocytosis, where the host cell engulfs the virus in a membrane-bound vesicle known as an endosome.

Fusion and Release of Viral Genetic Material

Inside the endosome, the acidic environment induces a conformational change in the HA protein, triggering the fusion of the viral envelope with the endosomal membrane. This fusion releases the viral RNA genome into the host cell's cytoplasm. [2.1,3.1]

Replication and Assembly

The viral RNA is transported into the nucleus, where it is replicated and transcribed into messenger RNA (mRNA) by the viral RNA-dependent RNA polymerase. The mRNA is then translated into viral proteins in the cytoplasm. New viral particles are assembled and eventually bud off from the host cell, acquiring a portion of the host's membrane as their envelope.

This process is the result of millions of years of virus-host co-evolution and illustrates how finely tuned these mechanisms are. Rather than pointing to deliberate design, this efficiency is exactly what we would expect from natural selection acting on viral populations over vast timescales.

Influenza virus infection cycle. Basic structural features of an influenza virus are diagrammed in the top left corner. Infection begins with the binding of hemagglutinin (HA) proteins to receptor molecules on the cell surface. The cycle is completed when new particles, each containing eight RNA segments, bud off from the cell membrane. Neuraminidase (NA) protein cleaves the bonds between HA and sialic acid molecules, allowing new virus to disperse.

Source: Lambert, L. C., & Fauci, A. S. (2010). Influenza Vaccines for the Future. New England Journal of Medicine, 363(21), 2039–2044.

The Helmholtz team have published their findings in two open access papers in the journal Nature Communications and explain it further in a Helmholtz Center for Infection Research news item:

Viruses under the super microscope: How influenza viruses communicate with cells
Researchers at the HZI and the Medical Center – University of Freiburg uncover new mechanisms for influenza viruses to enter cells
Influenza viruses are among the most likely triggers of future pandemics. A research team from the Helmholtz Centre for Infection Research (HZI) and the Medical Center - University of Freiburg has developed a method that can be used to study the interaction of viruses with host cells in unprecedented detail. With the help of their new development, they have also analyzed how novel influenza viruses use alternative receptors to enter target cells. The results were recently published in two papers in the journal Nature Communications.

Viruses have no metabolism of their own and must therefore infect host cells in order to replicate. Contact between the virus and the cell surface is a crucial first step, which can also prevent infections if entry into the cells is blocked. “The interaction with a host cell is dynamic and transient for influenza viruses. In addition, associated processes occur at the nanoscale, requiring super-resolution microscopes for a more precise investigation. Using conventional approaches, it has therefore not been possible to investigate this important first contact in more detail,” says Prof. Christian Sieben, head of the junior research group “Nano Infection Biology” at HZI, explaining the challenge the team has faced.

In collaboration with Prof. Mark Brönstrup's department “Chemical Biology” at HZI, his team has developed a universal protocol to investigate how viruses communicate with host cells. To do this, the scientists immobilized viruses individually on microscopy glass surfaces. Cells were then seeded on top. In conventional experiments, the viruses are added on top of pre-seeded cells.

The advantage of our ‘upside-down’ experimental setup is that the viruses interact with cells but do not enter them - the critical moment of initial cell contact is thus stabilized and can be analyzed.

Professor Christian Sieben, senior author.
Nanoscale Infection Biology Group
Helmholtz Centre for Infection Research
Braunschweig, Germany.

Using the example of a seasonal influenza A virus, the researchers used high-resolution and super-resolution microscopy to show that contact between the virus and the cell surface triggers a cascade of cellular reactions. First, the cellular receptors accumulate locally at the virus binding site. This is due to the fact that the receptors move more slowly through the cell membrane near the binding site and are therefore more abundant locally. Subsequently, specific cellular proteins are recruited and finally the actin cytoskeleton is dynamically reorganized.

However, the researchers applied their method not only to an established influenza A model, but also to a novel influenza strain of animal origin: the H18N11 virus, which is found in bats in Central and South America. Unlike most influenza viruses, which bind to glycans - i.e. carbohydrate chains on the cell surface - for infection, the H18N11 virus has a different target.

This virus binds to MHC class II complexes - protein receptors that are typically found on certain immune cells.

Dr. Peter Reuther, co-author
Institute of Virology
Medical Center - University of Freiburg
Freiburg, Germany.
[Dr. Reuther] is studying the cell entry of bat-derived H18 influenza A viruses.

Using single-molecule tracking, the researchers were able to show for the first time that MHCII molecules cluster specifically on the cell surface upon contact with the virus - a process that is essential for the virus to enter the cell. The teams from Braunschweig and Freiburg have thus characterized a new model of influenza A infection: the binding to MHCII as an alternative receptor and the associated dynamic reorganization of the cell surface.

The finding that influenza viruses do not bind exclusively to cellular glycans opens up new perspectives for research into these pathogens. Particularly in view of their zoonotic potential, it is crucial to better understand these alternative receptors.

Dr. Peter Reuther.

The virus-cell binding step is also the focus of the EU project COMBINE, which was launched at the beginning of 2025 and is coordinated by HZI researcher Sieben. In COMBINE, scientists from five European countries are investigating the virus entry process of newly emerging viruses, especially those with pandemic potential.

This process is a potential target for antiviral therapies. The methodology we have developed to investigate the virus entry process can be applied to many other viruses,.

Professor Christian Sieben.

The new results not only provide detailed insights into the biology of influenza viruses. They also provide a methodological basis for investigating the entry mechanisms of potential pandemic pathogens in a more targeted manner - and thus identifying new targets for antiviral therapies.

Publications:

Broich, L., Wullenkord, H., Osman, M.K. et al.
Single influenza A viruses induce nanoscale cellular reprogramming at the virus-cell interface.
Nat Commun 16, 3846 (2025). DOI: 10.1038/s41467-025-58935-8.
Osman, M.K., Robert, J., Broich, L. et al.
The bat influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment.
Nat Commun 16, 3847 (2025). DOI: 10.1038/s41467-025-58834-y

Abstract
During infection, individual virions trigger specific cellular signaling at the virus-cell interface, a nanoscale region of the plasma membrane in direct contact with the virus. However, virus-induced receptor recruitment and cellular activation are transient processes that occur within minutes at the nanoscale. Hence, the temporal and spatial kinetics of such early events often remain poorly understood due to technical limitations. To address this challenge, we develop a protocol to covalently immobilize labelled influenza A viruses on glass surfaces before exposing them to live epithelial cells. Our method extends the observation time for virus-plasma membrane association while minimizing viral modifications, facilitating live imaging of virus-cell interactions. Using single-molecule super-resolution microscopy, we investigate virus-receptor interaction showing that viral receptors exhibit reduced mobility at the virus-binding site, which leads to a specific local receptor accumulation and turnover. We further follow the dynamics of clathrin-mediated endocytosis at the single-virus level and demonstrate the recruitment of adaptor protein 2 (AP-2), previously thought to be uninvolved in influenza A virus infection. Finally, we examine the nanoscale organization of the actin cytoskeleton at the virus-binding site, showing a local and dynamic response of the cellular actin cortex to the infecting virus.

Introduction
Influenza A viruses (IAVs) are a major human health threat that cause annual epidemics and sporadic pandemics¹. IAVs are enveloped particles, and their membrane harbors the two major viral envelope proteins, hemagglutinin (HA) and neuraminidase (NA). To initiate viral replication and ensure the production of progeny virions, IAVs need to infect susceptible host cells. The infection process begins with the binding of the viral HA to sialylated glycan receptors on the host cell plasma membrane². While this initial interaction is critical for IAV host tropism¹, it is of inherently low affinity³. We could recently show that IAVs overcome this limitation by forming multivalent contacts through the binding of receptor nanoclusters within the plasma membrane⁴. However, subsequent steps of the infection process remained elusive at the single-virus level.

Following receptor binding, IAVs enter cells by clathrin-mediated endocytosis (CME) or macropinocytosis^5,6. For CME-based cell entry, IAVs were shown to use pre-existing clathrin-coated pits or induce the de novo formation of new endocytosis sites, suggesting a specific signaling function into the cell⁷. Since sialylated receptors do not possess any signaling capacity, glycoproteins were hypothesized early on, and more recently a number of candidates have been proposed to be involved in IAV cell entry^8,9,10,11,12. Among them are tyrosine kinases such as the epidermal growth factor receptor (EGFR) or c-Met11. siRNA-mediated knock-down of EGFR in susceptible cell lines could reduce the infection rate of human H1N1 IAV strain A/Puerto Rico/8/34 (PR8) by about 60%¹¹. Co-localization on the plasma membrane could also be shown, suggesting a direct interaction between IAV and EGFR^4,11. We have recently performed single-virus tracking experiments to better understand how IAVs engage with functional EGFR nanodomains. Our results suggested that IAVs explore the plasma membrane in a receptor-dependent way, thereby eventually reaching plasma membrane nanodomains that harbor both sialylated receptors and EGFRs, which then become activated, leading to downstream signal transduction and induction of CME⁴. However, the spatial and temporal visualization of this process at the single-virus level remained difficult due to the transient nature of the cell entry process and the small size of the IAV-cell interface.

In this work, we present a method to stabilize the interaction between viruses and cells, allowing for a comprehensive examination of the dynamics at the virus-cell interface, including receptor recruitment and the subsequent induction of clathrin-mediated endocytosis (CME). We developed a protocol to modify microscopy glass substrates for the immobilization of unmodified IAVs, thereby generating a stable viral interface that can then be brought in contact with live cells for microscopic investigation. With our method, we were able to prolong the plasma membrane contact between virus and cells to investigate the interaction between IAVs and individual EGFR molecules, using advanced single-molecule localization microscopy (SMLM) and single-particle tracking. By determining the mobility of individual receptors, we could identify a significant decrease of receptor diffusion in proximity to IAV, indicating a direct interaction between receptor and virus. In subsequent experiments, we show the induction of CME as well as the dynamics and nanoscale response of the actin cytoskeleton at the virus binding site. Taken together, our approach enables a nanoscale view of IAV-induced cellular reprogramming at the virus-cell interface.

Broich, L., Wullenkord, H., Osman, M.K. et al.
Single influenza A viruses induce nanoscale cellular reprogramming at the virus-cell interface.
Nat Commun 16, 3846 (2025). DOI: 10.1038/s41467-025-58935-8.

Copyright: © 2025 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Abstract
Prior to the discovery of bat influenza A virus (IAV) subtypes H17N10 and H18N11, all IAVs were thought to bind sialic acid residues via hemagglutinin (HA) to mediate attachment and subsequent viral entry. However, H17 and H18 engage a proteinaceous receptor: the major histocompatibility complex class II (MHCII). The mechanistic details of this hitherto unknown protein-mediated entry are not understood. Given that conventional IAVs rely on multivalent binding to sialylated glycans, we hypothesized that bat HA similarly interacts with multiple MHCII molecules. Using photoactivated localization microscopy (PALM) on fixed and live cells, we demonstrate that bat IAV particles attach to pre-existing MHCII clusters and induce a further increase in cluster size upon binding. To measure the impact of viral attachment on the dynamics of MHCII, we employ an “inverse attachment” approach, immobilizing viral particles on coverslips before seeding live MHCII-expressing cells on top. Single-molecule tracking reveals that the mobility of MHCII is indeed slowed down in viral proximity leading to a local enrichment of MHCII molecules beneath the viral particle. These findings suggest that viral attachment induces MHCII clustering, a process similar to the MHCII dynamics observed during the formation of an immunological synapse. Introduction
Influenza A viruses (IAV) have a major impact on global health causing annual epidemics and sporadic pandemics. Until 2012, aquatic birds were believed to represent the sole reservoir of IAV maintaining all previously known hemagglutinin (HA) (H1-16) and neuraminidase (NA) (N1-9) subtypes^1.2,2.2,3.2. This notion changed with the discovery of two novel IAV subtypes, designated H17N10 and H18N11, in bats from Central and South America^4.2,5.2,6.2. While these bat IAVs structurally resemble conventional IAVs of avian origin, their HA and NA surface glycoproteins are functionally distinct. In contrast to conventional HAs, the bat IAV HAs (H17 and H18) do not bind sialic acids for cell entry and the correspondent NAs (N10 and N11) lack sialidase activity^{5.2,7.2,8.2,9.2}. Previous studies using recombinant vesicular stomatitis virus (VSV) expressing either H18 or N11, have shown that H18 but not N11 is sufficient to mediate cell entry and allow viral spread^10.2. Consistent with these observations, we demonstrated that a mutant H18N11 lacking the N11 ectodomain (designated rP11) not only replicates efficiently in cell culture but also in its natural host the Jamaican fruit bat (Artibeus jamaicensis)^11.2. Even though N11 is still required for efficient transmission among bats, H18 thus seems to be the key determinant of effective infection at the cellular level. However, the receptor(s) involved in H18-mediated entry remained unknown until recently.

We and others showed that bat IAVs rely on a proteinaceous receptor for cell entry: the major histocompatibility complex class II (MHCII)^12.2,13.2. MHCII is a heterodimeric transmembrane protein complex consisting of an α and β chain, each comprising two extracellular domains: α1, α2 and β1, β2^14.2. MHCII is mainly expressed on professional antigen-presenting cells (APC) such as macrophages, dendritic cells and B cells^15.2. Here, MHCII has an essential role in adaptive immunity by presenting peptides from endocytic compartments to CD4+ T cells. Interestingly, MHCII from various vertebrate species including the human leukocyte antigen DR (HLA-DR), support H17 and H18-mediated infection and the highly conserved amino acid residues within the α2 domain of MHCII are required for cell entry^12.2,16.2. However, the initial steps of bat IAV infection, including receptor engagement, endocytosis and endosomal release, remain elusive. In-depth analysis of receptor engagement by classical biochemical approaches has been unsuccessful likely due to a low affinity between bat HA and MHCII, a feature reminiscent of the HAs of conventional IAVs, which bind sialic acids very weakly^{17.2,18.2,19.2}. So far, an MHCII-H18 interaction could only be confirmed by chemical crosslinking on the cell surface^12.2.

Conventional IAV particles interact with sialylated cell surface glycoproteins^20.2, which are organized in submicrometer nanoclusters^21.2,22.2. These clusters represent multivalent virus binding platforms that provide the avidity necessary for attachment of multiple low-affinity HAs and subsequent endocytosis of the viral particle. Based on a previous observation that MHCII is enriched in membrane clusters of APCs, we hypothesized that these MHCII clusters also serve as multivalent attachment sites^{23.2,24.2,25.2}. As our recent in silico model suggests that one H18 homotrimer can bind three MHCIIs, we speculate that upon attachment of bat IAV particles, additional MHCII complexes are recruited^16.2.

Super-resolution microscopy represents a powerful tool to study interactions of IAV proteins and associated host factors^{21.2,26.2,27.2,28.2,29.2}. Here, we use photoactivated localization microscopy (PALM) to visualize the nanoscale organization of MHCII and the interaction dynamics of bat IAV and MHCII in live cells at the single-molecule level^30.2,31.2. We show that individual bat IAV particles interact with clusters of MHCII, resulting in decreased mobility of the viral particle at the cell surface. Using an “inverse attachment” approach, which allows to study virus-receptor interactions on live cells by PALM, we show that additional MHCII molecules are trapped at the virus-cell interface. This results in increased MHCII cluster size, suggesting that viral particles induce nanoscale MHCII clustering upon host cell attachment.

Osman, M.K., Robert, J., Broich, L. et al.
The bat influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment.
Nat Commun 16, 3847 (2025). DOI: 10.1038/s41467-025-58834-y

Copyright: © 2025 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

For those ID proponents who genuinely understand both their own arguments and the biology involved, findings like this present a serious and inescapable problem. If the influenza virus is to be considered an example of "complex specified information" or "irreducible complexity", then so too must be our immune system. But this immediately raises a paradox: why would an intelligent designer create an exquisitely complex immune system only to pit it against equally sophisticated pathogens it also designed?

This is not simply a theological conundrum—it undermines the scientific credibility of Intelligent Design itself. ID posits that complexity is evidence of foresight and benevolence; yet here we have complexity with devastating consequences. If one accepts the ID argument as valid, then the designer must also be held responsible for the suffering, death, and evolutionary arms race that define the host-pathogen relationship.

In contrast, evolutionary biology provides a coherent, testable, and predictive framework for understanding these dynamics. Natural selection, operating without foresight or intent, explains both the development of viral mechanisms for cell entry and the counter-adaptations of host immunity. It accounts for inefficiencies, vulnerabilities, and the messy, contingent nature of biological systems.

In short, the very mechanisms that ID proponents attempt to co-opt as evidence for design are far better explained by evolution. The influenza virus does not bear witness to divine engineering—it is a textbook example of evolutionary adaptation. For those willing to follow the evidence wherever it leads, the conclusion is clear: the explanatory power of evolution continues to outmatch that of Intelligent Design, especially when the evidence is at its most intricate and unforgiving.

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