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Expanded protocadherin-1 usage reveals a broader hantavirus entry landscape
Cierra Word1, Nahomi Guerra-Pilaquinga1, Ezgi Kasikci2
1Department of Microbiology and Immunology, Center for Applied Immunology and Pathological Processes, Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
Mammalian hantaviruses can infect human endothelial cells via their glycoproteins, with some using protocadherin-1 (PCDH1) for entry. This research expands understanding of hantavirus tropism and potential therapeutic targets.
Area of Science:
- Virology
- Cellular Biology
- Immunology
Background:
- Mammalian hantaviruses cause severe diseases like hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome.
- Cellular entry mechanisms for many hantaviruses are not well understood.
- Protocadherin-1 (PCDH1) has been identified as a receptor for some hantaviruses.
Purpose of the Study:
- To investigate the ability of diverse hantavirus glycoproteins to mediate cellular entry into human endothelial cells.
- To determine the role of PCDH1 in the entry of various hantaviruses.
- To evaluate the efficacy of a broadly reactive anti-Gn/Gc antibody against different hantaviruses.
Main Methods:
- Generation of replication-competent recombinant vesicular stomatitis viruses (rVSVs) expressing Gn/Gc glycoproteins from multiple hantavirus species.
- Infection assays using primary human endothelial cells and human cells lacking PCDH1.
- Binding assays with soluble PCDH1 and neutralization assays using a PCDH1-targeting monoclonal antibody and the anti-Gn/Gc antibody ADI-42898.
- Infection studies with authentic Tula virus in PCDH1 knockout endothelial cells.
Main Results:
- Gn/Gc proteins from Necoclí, Sangassou, Thottapalayam, Nova, and Tula viruses supported infection of human endothelial cells, broadening the known range of permissive hantaviruses.
- Necoclí, Tula, and Nova viruses utilize PCDH1 for efficient entry, demonstrating broader but heterogeneous receptor usage.
- The anti-Gn/Gc antibody ADI-42898 showed differential neutralization activity against the tested rVSVs, with potent activity against some but not others.
- Authentic Tula virus infection was confirmed to be PCDH1-dependent.
Conclusions:
- Endothelial cell entry is permissive for a wider array of hantaviruses than previously recognized.
- PCDH1 serves as an entry receptor for several divergent hantaviruses, expanding its known phylogenetic scope.
- Targeted strategies against viral glycoproteins and host cell receptors show differential efficacy, highlighting the complexity of hantavirus countermeasures.
