How Bioelectronics is Profiling Viral Variants
For an enveloped virus like SARS-CoV-2, infection is a multi-stage breaking and entering process, all orchestrated by the now-infamous Spike protein that protrudes from its surface 1 9 .
When the host cell has TMPRSS2 on its surface, the virus fuses directly with the cell's outer membrane after Spike protein binds to ACE2 1 3 .
When TMPRSS2 is absent, the virus is swallowed whole via endocytosis and fuses inside the endosome with help from Cathepsin L (CatL) 1 3 .
Taking inspiration from biology, scientists built a simplified, controllable model of viral entry with four key design pillars 1 :
The heart of the device is a Supported Lipid Bilayer (SLB) - an artificial cell membrane containing ACE2 receptors and TMPRSS2 proteases 1 3 .
To model the virus, researchers use Viral Pseudoparticles (VPPs) - non-infectious particles with authentic Spike proteins 1 .
The sensor uses a transparent, conductive PEDOT:PSS polymer that acts as both support and electrode, detecting changes via electrochemical impedance spectroscopy (EIS) 1 9 .
To test the platform, scientists compared the fusogenicity of Omicron subvariants BA.1 and BA.4 1 3 .
The platform successfully generated distinct electrical signals and revealed markedly different fusion signatures between variants 1 .
Relative fusion efficiency in the late pathway compared to WH1 1
| Variant | Fusion Efficiency (Late Pathway) | Fusion Characteristics (vs. WH1) |
|---|---|---|
| WH1 (Original) | Baseline | Used both early and late pathways effectively 1 |
| Omicron BA.1 | Reduced | Showed a preference for the late entry pathway, with less efficient fusion 1 |
| Omicron BA.4 | Further Reduced | Exhibited even lower fusion efficiency compared to BA.1 in the late pathway 1 |
| Measurement Type | What It Reveals | Application in Variant Profiling |
|---|---|---|
| Binding Signal | Strength of initial virus attachment to ACE2 receptor 1 | Indicates how readily a variant can latch onto host cells |
| Fusion Signal | Success and efficiency of membrane merger post-binding 1 | Reveals the variant's core ability to complete the infection process |
| Signal Kinetics | The speed and progression of the entry process 1 | Can identify if a variant has a slower or faster entry mechanism |
Building and using this bioelectronic platform requires a suite of specialized research reagents and materials.
| Research Reagent / Material | Function in the Experiment |
|---|---|
| Viral Pseudoparticles (VPPs) | Non-infectious virus mimics decorated with specific Spike proteins, used to safely model viral entry 1 |
| Supported Lipid Bilayer (SLB) | An artificial cell membrane assembled on a sensor surface, serving as the host cell mimic 1 3 |
| Cell Membrane Blebs | Vesicles containing native host cell proteins (ACE2, TMPRSS2), integrated into SLBs to provide authentic receptors 1 |
| PEDOT:PSS Electrode | A conductive, biocompatible polymer support that hosts the SLB and transduces biological events into electrical signals 1 |
| Proteases (TMPRSS2, CatL) | Enzymes that cleave the Spike protein, acting as the molecular triggers for membrane fusion in their respective pathways 1 |
| Electrochemical Impedance Spectroscopy (EIS) | The analytical technique that measures changes in electrical impedance at the electrode surface to monitor binding and fusion in real-time 1 9 |
The infection-on-a-chip platform marks a significant leap forward from simply detecting a pathogen to functionally understanding its infectivity potential.
While SARS-CoV-2 served as the prototype, the platform is designed to be adaptable. In the future, this same approach could be extended to other enveloped viruses—from influenza to potential pandemic pathogens yet unknown—ensuring that we are better equipped, faster, and smarter when the next viral threat emerges 1 .