Human Cytomegalovirus (CMV) is a ubiquitous, opportunistic pathogen with a seroprevalance of approximately 80% in the United States. For most, a CMV infection shows few if any disease manifestations. However, for the immunologically immature or compromised, such as neonates, transplant recipients, AIDS and cancer patients, CMV infection can cause a range of symptoms, from no overt signs of disease to mental impairment, leucopenia, blindness and death. Although the cause for the range of symptoms is unclear, we hypothesize that it is related to the known genetic variability of CMV. In many studies, various loci of the CMV genome are found to be hypervariable. Additionally, there is evidence that infections with multiple CMV genotypes lead to more severe disease. Investigation of this potential link requires the monitoring of CMV genomic variability during CMV infection and disease. I propose to deep sequence the CMV genomic population during the course of solid organ renal transplant from CMV+ kidney donors to CMV- recipients over three timepoints. This experimental design creates a defined pathogenesis model and represents three genomic populations that have been shaped by clinically relevant selective pressures after known perturbations. Additionally, I will use the lllumina(R) Genome Analyzer deep sequencing technology, a massively parallel deep sequencing platform that yields greater than a gigabase of sequence information per run. The vast sequence information will cover a large section of the viral genomic population, allowing the study to focus on whole genome trends as well as providing information about individual genes. In a collaboration with Laura Gibson, M.D., we will combine the data from the deep sequencing experiments with immunological data collected from the same patients. This will allow us to analyze the host-pathogen interaction with a high level of detail.
This study will provide unprecedented insight on the genomic variability and pathology of a human pathogen in a clinical setting. Hence, it will have direct impact on disease management of CMV and other viral diseases, while also creating technology useful for a new phase of molecular pathogenesis.
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|Renzette, Nicholas; Kowalik, Timothy F; Jensen, Jeffrey D (2016) On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity. Mol Ecol 25:403-13|
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|Renzette, Nicholas; Bhattacharjee, Bornali; Jensen, Jeffrey D et al. (2011) Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants. PLoS Pathog 7:e1001344|