Felicia D Goodrum Sterling
Director, Graduate Program in Immunobiology
Professor, BIO5 Institute
Professor, Cancer Biology - GIDP
Professor, Cellular and Molecular Medicine
Professor, Genetics - GIDP
Professor, Immunobiology
Professor, Molecular and Cellular Biology
Primary Department
Department Affiliations
(520) 626-7468
Work Summary
Dr. Goodrum's long-standing research focus is to understand the molecular virus-host interactions important to human cytomegalovirus (CMV) latency and persistence in the host. She has focused on identifying viral and host determinants mediating the switch between latent and replicative states. The goal of her research program is to define the mechanistic underpinnings of HCMV latency and reactivation to lay the foundation for clinical interventions to control CMV disease in all settings.
Research Interest
Felicia Goodrum earned her Ph.D. from Wake Forest University School of Medicine studying cell cycle restrictions to adenovirus replication. She trained as a postdoctoral fellow at Princeton University in the laboratory of Dr. Thomas Shenk studying human cytomegalovirus latency. Dr. Goodrum joined the faculty at the University of Arizona in 2006. Dr. Goodrum is the recipient of the Howard Temin Award from the National Cancer Institute, the Pew Scholar in Biomedical Sciences Award, and the Presidential Award for Early Career Scientists and Engineers.Dr. Goodrum's research focuses on the complex host-virus interactions that result in viral persistence. Progress in understanding latent programs of persistence have been impeded by the inherent complexity of the herpesviruses and that paucity of adequate model systems. Herpesviruses are extraordinary for their ability to coexist with their host by establishing life-long latent infections. Latency is defined as a reversibly quiescent state during which viral gene expression and replication is highly restricted. Her laboratory studies cytomegalovirus or CMV, one of eight human herpesviruses. CMV is remarkable in that it persists latently in 60-99% of the population, generally in the absence of disease in the immunocompetent host. Reactivation of CMV from latency poses life-threatening disease risks in immunocompromised individuals, particularly transplant patients. CMV infection is also the leading cause of infectious disease-related birth defects, affecting ~1% of live births in the US. Further, the health cost of the latent coexistence of CMV is just beginning to emerge in an association to age-related pathologies including vascular disease, immune dysfunction and frailty. The key to eradicating CMV lies in understanding latency in order to ultimately develop novel antiviral strategies targeting latently infected cells or to prevent reactivation. Our studies aim to define the molecular basis of persistence by defining viral and cellular determinants important to viral persistence and the mechanisms by which these determinants function in relevant cell models. In turn, our work will provide critical insights into how CMV assimilates into and impacts human biology.

Publications

Zalckvar, E., Paulus, C., Tillo, D., Asbach-Nitzsche, A., Lubling, Y., Winterling, C., Strieder, N., Mücke, K., Goodrum, F., Segal, E., & Nevels, M. (2013). Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein. Proceedings of the National Academy of Sciences of the United States of America, 110(32), 13126-31.

Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-deficient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.

Goodrum, F., Jordan, C. T., Terhune, S. S., High, K., & Shenk, T. (2004). Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations. Blood, 104(3), 687-95.

The cellular reservoir for latent human cytomegalovirus (HCMV) in the hematopoietic compartment, and the mechanisms governing a latent infection and reactivation from latency are unknown. Previous work has demonstrated that HCMV infects CD34+ progenitors and expresses a limited subset of viral genes. The outcome of HCMV infection may depend on the cell subpopulations infected within the heterogeneous CD34+ compartment. We compared HCMV infection in well-defined CD34+ cell subpopulations. HCMV infection inhibited hematopoietic colony formation from CD34+/CD38- but not CD34+/c-kit+ cells. CD34+/CD38- cells transiently expressed a large subset of HCMV genes that were not expressed in CD34+/c-kit+ cells or cells expressing more mature cell surface phenotypes. Although viral genomes were present in infected cells, viral gene expression was undetectable by 10 days after infection. Importantly, viral replication could be reactivated by coculture with permissive fibroblasts only from the CD34+/CD38- population. Strikingly, a subpopulation of CD34+/CD38- cells expressing a stem cell phenotype (lineage-/Thy-1+) supported a productive HCMV infection. These studies demonstrate that the outcome of HCMV infection in the hematopoietic compartment is dependent on the nature of the cell subpopulations infected and that CD34+/CD38- cells support an HCMV infection with the hallmarks of latency.

Ornelles, D. A., Broughton-Shepard, R. N., & Goodrum, F. D. (2007). Analysis of adenovirus infections in synchronized cells. Methods in molecular medicine, 131, 83-101.

Adenoviruses (Ads) are small DNA tumor viruses that have played a pivotal role in understanding eukaryotic cell biology and viral oncogenesis. Among other cellular pathways, Ad usurps cell cycle progression following infection. Likewise, progression of the viral infection is influenced by the host cell cycle. We describe here methods developed for synchronizing dividing cell populations and for analysis of cell cycle synchrony by flow cytometry. Furthermore, three methods used to evaluate the outcome of Ad infection in synchronized cell populations are described. These include two assays for infectious centers and an assay for analyzing production of progeny virus by transmission electron microscopy. These methods have been used to demonstrate that Ads that fail to direct synthesis of the E1B 55-kDa or E4orf6 proteins replicate most effectively upon infecting cells in S phase.

Collins-McMillen, D., & Goodrum, F. D. (2017). The loss of binary: Pushing the herpesvirus latency paradigm. Current clinical microbiology reports, 4(3), 124-131.

Herpesvirus latency has been viewed as a binary state where replication is either on or off. During latency, gene expression is thought to be restricted to non-coding RNAs or very few proteins so that the virus avoids detection by the immune system. However, a number of recent studies across herpesvirus families call into question the existence of a binary switch for latency, and suggest that latency is far more dynamic than originally presumed. These studies are the focus of this review.

Goodrum, F. D., Shenk, T., & Ornelles, D. A. (1996). Adenovirus early region 4 34-kilodalton protein directs the nuclear localization of the early region 1B 55-kilodalton protein in primate cells. Journal of virology, 70(9), 6323-35.

The localization of the adenovirus type 5 34-kDa E4 and 55-kDa E1B proteins was determined in the absence of other adenovirus proteins. When expressed by transfection in human, monkey, hamster, rat, and mouse cell lines, the E1B protein was predominantly cytoplasmic and typically was excluded from the nucleus. When expressed by transfection, the E4 protein accumulated in the nucleus. Strikingly, when coexpressed by transfection in human, monkey, or baby hamster kidney cells, the E1B protein colocalized in the nucleus with the E4 protein. A complex of the E4 and E1B proteins was identified by coimmunoprecipitation in transfected HeLa cells. By contrast to the interaction observed in primate and baby hamster kidney cells, the E4 protein failed to direct the E1B protein to the nucleus in rat and mouse cell lines as well as CHO and V79 hamster cell lines. This failure of the E4 protein to direct the nuclear localization of the E1B protein in REF-52 rat cells was overcome by fusion with HeLa cells. Within 4 h of heterokaryon formation and with protein synthesis inhibited, a portion of the E4 protein present in the REF-52 nuclei migrated to the HeLa nuclei. Simultaneously, the previously cytoplasmic E1B protein colocalized with the E4 protein in both human and rat cell nuclei. These results suggest that a primate cell-specific factor mediates the functional interaction of the E1B and E4 proteins of adenovirus.