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Virus-Cell Interactions

Single-Cell Transcriptomics Reveals a Heterogeneous Cellular Response to BK Virus Infection

Ping An, Paul G. Cantalupo, Wenshan Zheng, Maria Teresa Sáenz-Robles, Alexis M. Duray, David Weitz, James M. Pipas
Lawrence Banks, Editor
Ping An
aDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Paul G. Cantalupo
aDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Wenshan Zheng
bJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
cDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA
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Maria Teresa Sáenz-Robles
aDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Alexis M. Duray
aDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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David Weitz
bJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
dDepartment of Physics, Harvard University, Cambridge, Massachusetts, USA
eWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
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James M. Pipas
aDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • ORCID record for James M. Pipas
Lawrence Banks
International Centre for Genetic Engineering and Biotechnology
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DOI: 10.1128/JVI.02237-20
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ABSTRACT

BK virus (BKV) is a human polyomavirus that is generally harmless but can cause devastating disease in immunosuppressed individuals. BKV infection of renal cells is a common problem for kidney transplant patients undergoing immunosuppressive therapy. In cultured primary human renal proximal tubule epithelial (RPTE) cells, BKV undergoes a productive infection. The BKV-encoded large T antigen (LT) induces cell cycle entry, resulting in the upregulation of numerous genes associated with cell proliferation. Consistently, microarray and transcriptome sequencing (RNA-seq) experiments performed on bulk infected cell populations identified several proliferation-related pathways that are upregulated by BKV. These studies revealed few genes that are downregulated. In this study, we analyzed viral and cellular transcripts in single mock- or BKV-infected cells. We found that the levels of viral mRNAs vary widely among infected cells, resulting in different levels of LT and viral capsid protein expression. Cells expressing the highest levels of viral transcripts account for approximately 20% of the culture and have a gene expression pattern that is distinct from that of cells expressing lower levels of viral mRNAs. Surprisingly, cells expressing low levels of viral mRNA do not progress with time to high expression, suggesting that the two cellular responses are determined prior to or shortly following infection. Finally, comparison of cellular gene expression patterns of cells expressing high levels of viral mRNA with those of mock-infected cells or cells expressing low levels of viral mRNA revealed previously unidentified pathways that are downregulated by BKV. Among these are pathways associated with drug metabolism and detoxification, tumor necrosis factor (TNF) signaling, energy metabolism, and translation.

IMPORTANCE The outcome of viral infection is determined by the ability of the virus to redirect cellular systems toward progeny production countered by the ability of the cell to block these viral actions. Thus, an infected culture consists of thousands of cells, each fighting its own individual battle. Bulk measurements, such as PCR or RNA-seq, measure the average of these individual responses to infection. Single-cell transcriptomics provides a window to the one-on-one battle between BKV and each cell. Our studies reveal that only a minority of infected cells are overwhelmed by the virus and produce large amounts of BKV mRNAs and proteins, while the infection appears to be restricted in the remaining cells. Correlation of viral transcript levels with cellular gene expression patterns reveals pathways manipulated by BKV that may play a role in limiting infection.

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Single-Cell Transcriptomics Reveals a Heterogeneous Cellular Response to BK Virus Infection
Ping An, Paul G. Cantalupo, Wenshan Zheng, Maria Teresa Sáenz-Robles, Alexis M. Duray, David Weitz, James M. Pipas
Journal of Virology Feb 2021, 95 (6) e02237-20; DOI: 10.1128/JVI.02237-20

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Single-Cell Transcriptomics Reveals a Heterogeneous Cellular Response to BK Virus Infection
Ping An, Paul G. Cantalupo, Wenshan Zheng, Maria Teresa Sáenz-Robles, Alexis M. Duray, David Weitz, James M. Pipas
Journal of Virology Feb 2021, 95 (6) e02237-20; DOI: 10.1128/JVI.02237-20
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KEYWORDS

polyomavirus
BKV
single-cell transcriptomics

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