Alison McBride, Ph.D.

Alison McBride, Ph.D.

Credit: NIAID
Chief, DNA Tumor Virus Section

Major Areas of Research

  • Mechanisms by which extrachromosomal human papillomavirus (HPV) genomes are established, partitioned, and amplified during persistent infection. 
  • The role of host intrinsic immunity, and DNA damage response and repair pathways in HPV DNA replication
  • Analysis of the mechanism and consequences of viral genome integration in HPV-associated cancers
  • Keratinocyte biology: Reprogramming Keratinocytes by Rho Kinase inhibition

Program Description

HPV Replication Mechanisms

Papillomaviruses are small DNA viruses that persistently infect and replicate in stratified cutaneous and mucosal epithelia. Each papillomavirus type is species-specific and has a tropism for certain types of epithelia. In most cases, the resulting papillomas are benign, but infection with certain papillomavirus types can lead to the development of carcinomas. In fact, HPV is the cause of about 5% of human cancers. 

The papillomavirus lifecycle.

The papillomavirus lifecycle.

Credit
NIAID

The basal cells of stratified epithelia constantly divide to replenish the overlying differentiated cell layers. The viral DNA replicates and is maintained in these dividing basal cells as low copy, extrachromosomal circular DNA molecules. Viral genome amplification and synthesis of capsid proteins occurs only in the upper layers of the epithelium. Papillomavirus infections are usually long-lived, and the dividing basal cells provide a reservoir of infected cells for the overlying virus producing tissue. This strategy requires that the papillomaviruses have a faithful and robust mechanism to replicate and retain their extrachromosomal genomes in the nuclei of dividing cells.

BPV-1 E2-mediated viral genome partitioning

BPV-1 E2-mediated viral genome partitioning by attachment to host chromatin.

Credit
NIAID

 

Papillomaviruses have exploited interactions between virus and host chromatin at many stages of the viral life cycle. Viral DNA is targeted to beneficial regions of the host nucleus to ensure that the genomes are transcriptionally active and are not eliminated from the cell or repressed in heterochromatin. Viral genomes are tethered to specific regions of host mitotic chromosomes by the E2 protein to efficiently partition the viral genomes to daughter cells. Viral DNA replication also initiates at regions of host chromatin undergoing replication stress. Here the viral E1 and E2 proteins initiate a DNA damage response that recruits cellular DNA repair proteins to viral replication foci for efficient viral DNA synthesis. 

This may explain why in HPV-associated cancers, viral genomes are often found integrated next to fragile sites in the host genome.

Keratinocyte Biology: Reprogramming Keratinocytes by Rho Kinase Inhibition

HPVs will only replicate in host keratinocytes and our studies are mostly carried out in primary human keratinocytes. In the course of these studies, we discovered that primary keratinocytes could be sustained in a conditionally proliferative state by culture in the presence of Rho kinase inhibitors. This discovery (Patent US8637310) has revolutionized the procurement and culture of primary cells.  See a detailed protocol (p623).  

A movie showing rapid increase in keratinocyte proliferation after the addition of Y-27632. Credit: NIAID

Biography

Dr. McBride received a B.Sc. Hons in molecular biology from the University of Glasgow, Scotland, and a Ph.D. in biochemistry from the Imperial Cancer Research Fund and Imperial College, England, studying Epstein-Barr virus. She began working on human and other papillomaviruses as a postdoctoral fellow in the National Cancer Institute and joined NIAID in 1994. She became a senior investigator in the Laboratory of Viral Diseases in 2000, and a section chief in 2001. Dr. McBride is also adjunct faculty, a member of the Virology Graduate Program at the University of Maryland, and co-director of the NIH-Georgetown University Partnership Program. She is a fellow, American Academy of Microbiology; section editor, PLOS Pathogens; editor, Current Protocols in Microbiology, and a member of the editorial board of Journal of Virology.

Research Group

Lab Members

Postdoctoral Fellow

Tami Coursey, Ph.D.

Predoctoral Fellows

Ashley Della Fera, B.Sc.
Sam Porter, B.Sc.

Research Fellow

Simran Khurana, Ph.D.

Visiting Fellow

Alix Warburton Ph.D.

Research Staff

Dan Chen, Bachelor of Preventive Medicine - Biologist

Alison McBride (DNA Tumor Virus Section) Research Group

Standing, left to right: Tami, Warda Arman (currently a PhD student at Tufts University), Alison, Sam, and Simran. Sitting: Ashley, Alix, and Dan.

Credit
NIAID

Selected Publications

Warburton A, Redmond CJ, Dooley KE, Fu H, Gillison ML, Akagi K, Symer DE, Aladjem MI, McBride AA. HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. PLoS Genet. 2018 Jan 24;14(1).

Stepp WH, Stamos JD, Khurana S, Warburton A, McBride AA. Sp100 colocalizes with HPV replication foci and restricts the productive stage of the infectious cycle. PLoS Pathog. 2017 Oct 2;13(10)

Van Doorslaer K, Li Z, Xirasagar S, Maes P, Kaminsky D, Liou D, Sun Q, Kaur R, Huyen Y, McBride AA. The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res. 2017 Jan 4;45(D1).

Jang MK, Shen K, McBride AA. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 2014 May 15;10(5).

Chapman S, McDermott DH, Shen K, Jang MK, McBride AA. The effect of Rho kinase inhibition on long-term keratinocyte proliferation is rapid and conditional. Stem Cell Res Ther. 2014 Apr 28;5(2).

Visit PubMed for a complete publication listing.

PaVE

The PapillomaVirus Episteme: An HPV Sequence Database

Image of PapillomaVirus Episteme bookmark

The PapillomaVirus Episteme: An HPV Sequence Database

Credit
NIAID

The Papillomavirus Episteme (PaVE) was developed in collaboration with the NIAID Bioinformatics and Computational Biosciences​ Branch. Episteme is derived from the Ancient Greek word for knowledge, science, or understanding, and this symbolizes the philosophy behind the PaVE resource. We provide information and bioinformatics resources to the scientific community for research on the Papillomaviridae. The goal of PaVE is to provide a curated HPV sequence database and bioinformatic tools that will accelerate scientific progress and ultimately our understanding, detection, diagnosis, and treatment of diseases caused by papillomaviruses. Find out more about the PaVE animal and human papillomavirus (HPV) sequence database, and join our PaVE Facebook page.

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