Marburg Virus Enters Human Cells 300 Times More Efficiently Than Ebola

University of Minnesota Medical School

Marburg virus kills, on average, nearly three out of every four people it infects. That 73% fatality rate makes it one of the deadliest pathogens known, yet despite decades of awareness, no approved vaccines or treatments exist. A study published in Nature by University of Minnesota researchers now explains part of what makes Marburg so lethal: it is extraordinarily efficient at getting inside human cells, and this efficiency can be traced to specific structural features of its entry machinery.

A controlled comparison, for the first time

Marburg and Ebola belong to the same virus family (Filoviridae) and share the same human receptor for cell entry, a protein called NPC1 (Niemann-Pick C1) found in cellular compartments called endosomes. But despite this shared receptor, the two viruses behave very differently in terms of lethality and disease progression. Until now, there has been no way to fairly compare how efficiently the two viruses exploit NPC1 for entry.

The research team, led by senior author Fang Li of the University of Minnesota Medical School's Department of Pharmacology, designed a tightly controlled system that isolates the entry proteins of each virus and measures their ability to drive cells to take in viral particles. The result was stark: Marburg's entry protein drove viral entry up to 300 times more efficiently than Ebola's.

Different angle, tighter grip

To understand this difference, the researchers used structural biology techniques to examine how each virus's entry protein interacts with the NPC1 receptor. They found that Marburg's entry protein binds NPC1 in a distinct orientation compared to Ebola's. This different binding angle allows Marburg's protein to make more productive contacts with the receptor, resulting in higher binding affinity.

After binding, the Marburg entry protein undergoes conformational changes, shifts in its three-dimensional shape, that facilitate the fusion of the viral membrane with the cell membrane, the final step that lets the virus's genetic material enter the cell. These shape changes appear to be more efficient in Marburg's protein, contributing to its overall entry advantage.

The framework the researchers developed enables fair comparison of entry efficiency across different viruses, something that was not previously possible. This methodology could be applied to other virus families to understand why closely related pathogens differ in infectivity.

A nanobody that blocks the door

The structural analysis also revealed a vulnerability. Marburg's entry protein carries a protective cap, a structural feature called the mucin-like domain, that shields the receptor-binding site from antibodies. Most conventional antibodies are too large to reach the binding site beneath this cap. But the researchers discovered a nanobody, a tiny antibody fragment originally derived from camelid immune systems, small enough to slip past the cap and bind directly to the receptor-binding site.

In laboratory tests, this nanobody prevented Marburg virus from entering cells. While far from a clinical treatment, the result identifies a specific molecular target for antiviral development and demonstrates that the target is accessible to the right kind of therapeutic molecule.

What this means for treatment development

Marburg outbreaks are sporadic but devastating. The most recent outbreaks have occurred in Rwanda (2024) and Tanzania (2025). Treatment options during outbreaks are limited to supportive care. Vaccines are in development but none are approved. The identification of a structural vulnerability in the entry protein, and proof that a nanobody can exploit it, provides what the authors describe as a roadmap for therapeutic intervention.

Nanobodies have practical advantages for development against emerging viruses: they are stable, relatively inexpensive to produce, and can potentially be administered through inhalation or injection. Several nanobody-based therapies have reached clinical trials for other diseases.

Limitations of the current work

The 300-fold efficiency difference was measured in a controlled laboratory system using pseudotyped viral particles, not live Marburg or Ebola virus. While pseudotype systems are standard tools in virology and provide reliable comparisons of entry efficiency, they do not capture every aspect of how these viruses behave during natural infection, including immune evasion, replication kinetics, and tissue tropism.

The nanobody was tested only in cell-based assays. Its effectiveness at preventing infection in a living animal, let alone a human patient, has not been demonstrated. Nanobodies can face challenges related to half-life in the body, tissue penetration, and potential immune reactions that are only revealed in animal models and clinical trials.

The study focuses exclusively on the entry step of viral infection. Marburg's high fatality rate likely reflects multiple factors beyond entry efficiency, including its ability to suppress immune responses, replicate rapidly in multiple organ systems, and cause vascular damage. Entry efficiency alone does not fully explain lethality.

Still, the entry step is where the infection begins, and blocking it is the most direct way to prevent disease entirely. Knowing precisely how Marburg's entry protein achieves its exceptional efficiency, and demonstrating that a small molecule can interfere with the process, is a concrete step toward the antiviral tools this pathogen demands.