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The MVMp P4 promoter is a host cell-type range determinant in vivo
Chen Meir1, Michal Mincberg1, Irina Rostovsky1
1Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Abstract:
The protoparvovirus early promoters, e.g. P4 of Minute Virus of Mice (MVM), play a critical role during infection. Initial P4 activity depends on the host transcription machinery only. Since this is cell-type dependent, it is hypothesized that P4 is a host cell-type range determinant. Yet host range determinants have mapped mostly to capsid, never P4. Here we test the hypothesis using the mouse embryo as a model system. Disruption of the CRE element of P4 drastically decreased infection levels without altering range. However, when we swapped promoter elements of MVM P4 with those from equivalent regions of the closely related H1 virus, we observed elimination of infection in fibroblasts and chondrocytes and the acquisition of infection in skeletal muscle. We conclude that P4 is a host range determinant and a target for modifying the productive infection potential of the virus - an important consideration in adapting these viruses for oncotherapy.
Insights
The P4 promoter of protoparvovirus is a host cell-type range determinant, not just the capsid. Modifying P4 can alter viral infection potential for applications like oncotherapy.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Protoparvovirus early promoters, like Minute Virus of Mice (MVM) P4, are crucial for viral infection.
- P4 activity relies on host transcription machinery, suggesting a role in host cell-type specificity.
- Host range determinants in parvoviruses have historically been linked to the capsid, not the promoter.
Purpose of the Study:
- To investigate whether the P4 promoter acts as a host cell-type range determinant for protoparvoviruses.
- To explore the potential of P4 as a target for modifying viral host range and infection potential.
Main Methods:
- Utilizing a mouse embryo model system to study protoparvovirus infection.
- Disrupting the CRE element within the MVM P4 promoter.
- Swapping promoter elements between MVM P4 and the related H1 virus.
Main Results:
- Disruption of the P4 CRE element reduced infection levels but did not change the host range.
- Exchanging MVM P4 elements with H1 virus promoter regions resulted in altered tropism.
- Specifically, infection was eliminated in fibroblasts and chondrocytes, while skeletal muscle infection was acquired.
Conclusions:
- The P4 promoter is confirmed as a host range determinant for protoparvoviruses.
- P4 represents a viable target for engineering viral tropism, with implications for oncotherapy applications.