Hemagglutinin and fusion proteins precede measles virus ribonucleoproteins and marshal cell-to-cell spread in airway epithelium
- 1Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, lowa, USA
- 2Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, lowa, USA
- 3Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Abstract
Measles virus (MeV) is the most contagious human respiratory pathogen. To understand how it spreads in the airways, we infected well-differentiated primary cultures of human airway epithelial cells (HAE). We discovered that the MeV attachment protein (hemagglutinin, H), the fusion (F) protein, and the assembly organizer protein (matrix, M) reach newly infected cells ahead of, and independently from, the replicative complex proteins. To characterize the mechanisms of MeV spread, we generated a replication-deficient adenoviral vector expressing the MeV M, F, and H proteins in a doxycycline-inducible manner. This viral vector formed infectious centers that preserved epithelial function like those from MeV infection. To further dissect this process, we generated Ad vectors expressing individual MeV proteins, termed Ad-M, Ad-F, and Ad-H. Transduction of HAE with single, double, and triple Ad vector combinations revealed that Ad-F and Ad-H are necessary and sufficient to form MeV-like infectious centers. MeV enters and spreads within airway epithelia via H protein binding to adherens junction protein, nectin-4. To disrupt spread, we introduced the point mutation HY543A, a mutation previously described to inhibit nectin-4 binding, in the Ad-H vector. Co-transduction of Ad-F and Ad-HY543A did not result in MeV-like infectious center formation. Finally, we assessed whether the MeV-related paramyxovirus Nipah (NiV) attachment and fusion proteins (G and F, respectively) support cell-to-cell spread. Co-transduction of HAE with Ad-NiV-G and Ad-NiV-F did not result in infectious center formation, suggesting that decoupling of the membrane fusion apparatus function from replication is a unique feature of the MeV envelope glycoproteins.
IMPORTANCE: Measles virus is a highly contagious pathogen. We characterized a mechanism by which measles virus spreads rapidly through the cells that line the human airway in an ex vivo model. We show that the proteins of the viral membrane fusion apparatus, hemagglutinin (H) and fusion (F), move independently from and reach newly infected cells before the proteins of the replicative complex. Thus, viral protein spread is assembled and arranged in order (i.e., marshaled). Using adenovirus-based vectors, we show that co-expression of H and F proteins promotes rapid sequential spread to multiple cells and the formation of infectious centers. Further elucidation of the mechanism of measles virus amplification and cell-to-cell spread within the lung may help explain its highly contagious nature.
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BibTeX
@article{clark2026hemagglutinin,
title = {{Hemagglutinin and fusion proteins precede measles virus ribonucleoproteins and marshal cell-to-cell spread in airway epithelium}},
author = {Stephanie E. Clark and Justin W. Kaufman and Kalpana Yadav and Roberto Cattaneo and Brajesh K. Singh and Patrick L. Sinn},
journal = {Microbiology Spectrum},
year = {2026},
month = oct,
doi = {10.1128/spectrum.02297-26},
url = {https://doi.org/10.1128/spectrum.02297-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hemagglutinin and fusion proteins precede measles virus ribonucleoproteins and marshal cell-to-cell spread in airway epithelium
AU - Stephanie E. Clark
AU - Justin W. Kaufman
AU - Kalpana Yadav
AU - Roberto Cattaneo
AU - Brajesh K. Singh
AU - Patrick L. Sinn
PY - 2026
DA - 2026/10/14
JO - Microbiology Spectrum
DO - 10.1128/spectrum.02297-26
UR - https://doi.org/10.1128/spectrum.02297-26
AB - Measles virus (MeV) is the most contagious human respiratory pathogen. To understand how it spreads in the airways, we infected well-differentiated primary cultures of human airway epithelial cells (HAE). We discovered that the MeV attachment protein (hemagglutinin, H), the fusion (F) protein, and the assembly organizer protein (matrix, M) reach newly infected cells ahead of, and independently from, the replicative complex proteins. To characterize the mechanisms of MeV spread, we generated a replication-deficient adenoviral vector expressing the MeV M, F, and H proteins in a doxycycline-inducible manner. This viral vector formed infectious centers that preserved epithelial function like those from MeV infection. To further dissect this process, we generated Ad vectors expressing individual MeV proteins, termed Ad-M, Ad-F, and Ad-H. Transduction of HAE with single, double, and triple Ad vector combinations revealed that Ad-F and Ad-H are necessary and sufficient to form MeV-like infectious centers. MeV enters and spreads within airway epithelia via H protein binding to adherens junction protein, nectin-4. To disrupt spread, we introduced the point mutation HY543A, a mutation previously described to inhibit nectin-4 binding, in the Ad-H vector. Co-transduction of Ad-F and Ad-HY543A did not result in MeV-like infectious center formation. Finally, we assessed whether the MeV-related paramyxovirus Nipah (NiV) attachment and fusion proteins (G and F, respectively) support cell-to-cell spread. Co-transduction of HAE with Ad-NiV-G and Ad-NiV-F did not result in infectious center formation, suggesting that decoupling of the membrane fusion apparatus function from replication is a unique feature of the MeV envelope glycoproteins. IMPORTANCE: Measles virus is a highly contagious pathogen. We characterized a mechanism by which measles virus spreads rapidly through the cells that line the human airway in an ex vivo model. We show that the proteins of the viral membrane fusion apparatus, hemagglutinin (H) and fusion (F), move independently from and reach newly infected cells before the proteins of the replicative complex. Thus, viral protein spread is assembled and arranged in order (i.e., marshaled). Using adenovirus-based vectors, we show that co-expression of H and F proteins promotes rapid sequential spread to multiple cells and the formation of infectious centers. Further elucidation of the mechanism of measles virus amplification and cell-to-cell spread within the lung may help explain its highly contagious nature.
SN - 2165-0497
ER -