Murine Model System for Human Cytomegalovirus Latency and Pathogenesis
OHSU # 1224
- Jay Nelson, VG.Vaccine & Gene Therapy Institute
- J. Victor Garcia-Martinez
- William Fleming, SM.Pediatrics
- Florence Othieno
- Alexis Bailey, SM.Medicine
- Felicia Goodrum
Human cytomegalovirus (HCMV) is an important ubiquitous pathogen that is a leading viral cause of birth defects and a significant problem in bone marrow transplant patients as well as individuals receiving cancer therapy. Approximately 1 in 750 children born with or develops permanent disabilities due to HCMV. Approximately 8,000 children each year suffer permanent disabilities caused by HCMV. Infection with HCMV is a major cause of disease and death in immunocompromised patients, including organ and bone marrow transplant recipients, hemodialysis patients, cancer patients, patients receiving immunosuppressive drugs and HIV-infected patients. Primary (or the first) CMV infection in the immunocompromised person can cause serious disease. However, the more common problem is when the virus becomes active again in the body after being inactive in the body. This is called reactivation.
Central to the ability of HCMV to survive within the host is the ability to establish a lifelong latency within host bone marrow. Although a number of in vitro and histological studies have addressed aspects of HCMV persistence and latency, investigations into mechanisms involved in HCMV latency and reactivation have been hampered by the lack of an animal model due to the species specificity of the virus. One of the first humanized mouse models to support HCMV replication was the severe combined immunodeficiency (SCID) mouse into which human (hu) fetal thymus, liver, lung and colon were implanted into mice, thereby termed SCID-human mice. While this model was useful to examine aspects of HCMV acute infection, these mice did not support latent infection nor could virus be reactivated in these animals. These investigators have created a novel mouse model engrafted with human hematopoietic cells infected with HCMV. In this unique model, the virus is able to spread to organ tissue and bone marrow, which is the site of HCMV latency, and replicate within organ tissue in human cells.
This is the first in vivo model to study the entire life cycle of HCMV.
The systemic infection in this mouse model is ideal for testing novel antiviral drugs to HCMV. Furthermore, the investigators have been able to recapitulate a clinically relevant scenario of bone marrow transplantation. Additional clinically relevant applications of this model could include the transplantation of allogeneic mouse organs into engrafted mice to mimic allogeneic reactivation of HCMV, which frequently occurs during organ transplantation. Finally, this mouse model allows a number of basic HCMV biological questions to be addressed, including the identification of the earliest site of HCMV latency in the bone marrow.
HCMV animal models that recapitulate the viral life cycle, specifically viral latency and spread to organ tissue, have not previously been developed due to HCMV species specificity. This current HCMV mouse model overcomes the barrier of species specificity by the transplantation of human stem cells that reconstitute the mouse with a human hematopoietic cell population throughout the animal. Systemic infection of these mice mimics the viral life cycle rather than providing a limited microenvironment.
This mouse model is available for non-exclusive licensing and collaborative studies.
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