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Determinants of organ tropism of Sendai virus
1Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan. mtashiro@nih.go.jp
Abstract:
Wild-type Sendai virus is exclusively pneumotropic in mice. Protease activation mutants, ts-f1 and F1-R, were isolated from persistently infected tissue culture cells. Additional mutants were isolated from wild-type Sendai virus with phenotypes similar to the pantropic mutant, F1-R. The genome of the mutants was sequenced and mutations were revealed in several proteins encoded by the genes. Three of the six mutations in the fusion (F) proteins were considered prime candidates for the determinant of pantropism. Characterization of the mutants led to the finding that the exchange (Ser to Pro) residue 115 next to the cleavage site of the F protein was the primary determinant that resulted in the enhanced cleavability of the F protein. Another important finding was bipolar budding of F1-R in polarized epithelial cells and mouse bronchial epithelium. This has been attributed to two mutations in the matrix (M) protein, at residues 128 (Asp to Gly) and 210 (Ile to Thr). Thus, the determinants of pantropism of F1-R are protease activation of the F protein and biopolar budding attributed to the mutated M protein.
Insights
Sendai virus pantropism is determined by mutations in fusion (F) and matrix (M) proteins. Enhanced F protein cleavability and M protein bipolar budding drive viral spread.
Area of Science:
- Virology
- Molecular Biology
Background:
- Wild-type Sendai virus exhibits limited tropism, primarily affecting the lungs in mice.
- Persistent Sendai virus infections can lead to the emergence of mutants with altered host range.
Purpose of the Study:
- To identify the genetic determinants responsible for the pantropic (widespread) nature of certain Sendai virus mutants.
- To elucidate the molecular mechanisms underlying enhanced viral spread and tissue tropism.
Main Methods:
- Isolation and characterization of Sendai virus mutants (ts-f1, F1-R) from infected cells.
- Genome sequencing of isolated mutants to identify genetic alterations.
- Analysis of viral protein mutations, focusing on the fusion (F) and matrix (M) proteins.
Main Results:
- Mutations in the fusion (F) protein, particularly Ser115Pro, enhance its cleavage and contribute to pantropism.
- Two mutations in the matrix (M) protein (Asp128Gly and Ile210Thr) were linked to bipolar budding in polarized epithelial cells.
- The F1-R mutant displayed pantropic behavior attributed to both F protein activation and M protein-mediated bipolar budding.
Conclusions:
- Protease activation of the F protein is a key determinant of Sendai virus pantropism.
- Mutations in the M protein leading to bipolar budding further contribute to the virus's ability to spread widely.
- Understanding these determinants provides insights into viral pathogenesis and host-pathogen interactions.