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Stringent requirement for the C protein of wild-type measles virus for growth both in vitro and in macaques
Kaoru Takeuchi1, Makoto Takeda, Naoko Miyajima
1Department of Infection Biology, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. ktakeuch@md.tsukuba.ac.jp
Abstract:
The P gene of measles virus (MV) encodes the P protein and three accessory proteins (C, V, and R). However, the role of these accessory proteins in the natural course of MV infection remains unclear. For this study, we generated a recombinant wild-type MV lacking the C protein, called wtMV(C-), by using a reverse genetics system (M. Takeda, K. Takeuchi, N. Miyajima, F. Kobune, Y. Ami, N. Nagata, Y. Suzaki, Y. Nagai, and M. Tashiro, J. Virol. 74:6643-6647). When 293 cells expressing the MV receptor SLAM (293/hSLAM) were infected with wtMV(C-) or parental wild-type MV (wtMV), the growth of wtMV(C-) was restricted, particularly during late stages. Enhanced green fluorescent protein-expressing wtMV(C-) consistently induced late-stage cell rounding and cell death in the presence of a fusion-inhibiting peptide, suggesting that the C protein can prevent cell death and is required for long-term MV infection. Neutralizing antibodies against alpha/beta interferon did not restore the growth restriction of wtMV(C-) in 293/hSLAM cells. When cynomolgus monkeys were infected with wtMV(C-) or wtMV, the number of MV-infected cells in the thymus was >1,000-fold smaller for wtMV(C-) than for wtMV. Immunohistochemical analyses showed strong expression of an MV antigen in the spleen, lymph nodes, tonsils, and larynx of a cynomolgus monkey infected with wtMV but dramatically reduced expression in the same tissues in a cynomolgus monkey infected with wtMV(C-). These data indicate that the MV C protein is necessary for efficient MV replication both in vitro and in cynomolgus monkeys.
Insights
The measles virus (MV) C protein is essential for efficient viral replication and preventing cell death during infection. Its absence significantly restricts MV growth in cell cultures and animal models.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- The measles virus (MV) P gene encodes multiple proteins, including accessory proteins C, V, and R.
- The specific roles of these accessory proteins in MV pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the role of the MV C protein in viral replication and pathogenesis.
- To determine if the C protein is essential for efficient MV infection in vitro and in vivo.
Main Methods:
- Generation of a recombinant wild-type MV lacking the C protein (wtMV(C-)) using reverse genetics.
- Infection of human embryonic kidney cells expressing the MV receptor SLAM (293/hSLAM) with wtMV(C-) and wild-type MV (wtMV).
- Infection of cynomolgus monkeys with wtMV(C-) and wtMV, followed by analysis of viral load and tissue distribution.
Main Results:
- Recombinant MV lacking the C protein (wtMV(C-)) exhibited restricted growth in 293/hSLAM cells, particularly at late stages.
- wtMV(C-) induced late-stage cell death, suggesting the C protein prevents apoptosis and is crucial for long-term infection.
- Viral load in the thymus of cynomolgus monkeys infected with wtMV(C-) was over 1,000-fold lower than in those infected with wtMV.
- Immunohistochemical analysis revealed significantly reduced MV antigen expression in spleen, lymph nodes, tonsils, and larynx of monkeys infected with wtMV(C-) compared to wtMV.
Conclusions:
- The MV C protein is indispensable for efficient viral replication both in vitro and in vivo.
- The C protein plays a critical role in preventing host cell death during measles virus infection.
- These findings highlight the importance of the C protein in measles virus pathogenesis and viral spread.
