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. Her recent work has defined the epidermal growth factor receptor (EGFR) as primary pathway targeted by these viral determinants to switch between latent and replicative states of infection. The goal of their research program is to define the mechanistic underpinnings of HCMV latency and 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 viruses 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, including transplant, AIDS and cancer patients. CMV infection is also the leading cause of infectious disease-related birth defects, affecting ~1% of live births in the US. The health cost of the latent coexistence of CMV is just beginning to emerge in an association to age-related pathologies including atherosclerosis, immune senescence and frailty. The key to eradicating CMV lies in understanding latency in order to ultimately develop novel antiviral strategies targeting latently infected cells. 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

Cheng, S., Caviness, K., Buehler, J., Smithey, M., Nikolich-Žugich, J., & Goodrum, F. (2017). Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency. Proceedings of the National Academy of Sciences of the United States of America, 114(49), E10586-E10595.

The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a nonreactivating, latent-like or a replicative infection in CD34+ hematopoietic progenitor cells, we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides insight into the HCMV transcriptome associated with latency in the host and a resource for investigating virus-host interactions underlying persistence.

Leng, S. X., Kamil, J., Purdy, J. G., Lemmermann, N. A., Reddehase, M. J., & Goodrum, F. D. (2017). Recent advances in CMV tropism, latency, and diagnosis during aging. GeroScience, 39(3), 251-259.

Human cytomegalovirus (CMV) is one of the largest viruses known to cause human diseases. Chronic CMV infection, as defined by anti-CMV IgG serology, increases with age and is highly prevalent in older adults. It has complex biology with significant immunologic and health consequences. This article aims to summarize research findings presented at the 6th International Workshop on CMV and Immunosenescence that relate to advances in the areas of CMV tropism, latency, CMV manipulation of cell metabolism, and T cell memory inflation, as well as novel diagnostic evaluation and translational research of chronic CMV infection in older adults. Information summarized here represents the current state of knowledge in these important fields. Investigators have also identified a number of areas that deserve further and more in-depth investigation, including building more precise parallels between mouse CMV (mCMV) and human CMV (HCMV) research. It is hoped that this article will also stimulate engaging discussion on strategies and direction to advance the science to the next level.

Goodrum, F. D., & Ornelles, D. A. (1999). Roles for the E4 orf6, orf3, and E1B 55-kilodalton proteins in cell cycle-independent adenovirus replication. Journal of virology, 73(9), 7474-88.

Adenoviruses bearing lesions in the E1B 55-kDa protein (E1B 55-kDa) gene are restricted by the cell cycle such that mutant virus growth is most impaired in cells infected during G(1) and least restricted in cells infected during S phase (F. D. Goodrum and D. A. Ornelles, J. Virol. 71:548-561, 1997). A similar defect is reported here for E4 orf6-mutant viruses. An E4 orf3-mutant virus was not restricted for growth by the cell cycle. However, orf3 was required for enhanced growth of an E4 orf6-mutant virus in cells infected during S phase. The cell cycle restriction may be linked to virus-mediated mRNA transport because both E1B 55-kDa- and E4 orf6-mutant viruses are defective at regulating mRNA transport at late times of infection. Accordingly, the cytoplasmic-to-nuclear ratio of late viral mRNA was reduced in G(1) cells infected with the mutant viruses compared to that in G(1) cells infected with the wild-type virus. By contrast, this ratio was equivalent among cells infected during S phase with the wild-type or mutant viruses. Furthermore, cells infected during S phase with the E1B 55-kDa- or E4 orf6-mutant viruses synthesized more late viral protein than did cells infected during G(1). However, the total amount of cytoplasmic late viral mRNA was greater in cells infected during G(1) than in cells infected during S phase with either the wild-type or mutant viruses, indicating that enhanced transport of viral mRNA in cells infected during S phase cannot account for the difference in yields in cells infected during S phase and in cells infected during G(1). Thus, additional factors affect the cell cycle restriction. These results indicate that the E4 orf6 and orf3 proteins, in addition to the E1B 55-kDa protein, may cooperate to promote cell cycle-independent adenovirus growth.

Bughio, F., Umashankar, M., Wilson, J., & Goodrum, F. (2015). Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells. Journal of virology, 89(13), 6536-50.

Endothelial cells (ECs) are a critical target of viruses, and infection of the endothelium represents a defining point in viral pathogenesis. Human cytomegalovirus (HCMV), the prototypical betaherpesvirus, encodes proteins specialized for entry into ECs and delivery of the genome to the nuclei of ECs. Virus strains competent to enter ECs replicate with differing efficiencies, suggesting that the virus encodes genes for postentry tropism in ECs. We previously reported a specific requirement for the UL133/8 locus of HCMV for replication in ECs. The UL133/8 locus harbors four genes: UL133, UL135, UL136, and UL138. In this study, we find that while UL133 and UL138 are dispensable for replication in ECs, both UL135 and UL136 are important. These genes are not required for virus entry or the expression of viral genes. The phenotypes associated with disruption of either gene reflect phenotypes observed for the UL133/8NULL virus, which lacks the entire UL133/8 locus, but are largely distinct from one another. Viruses lacking UL135 fail to properly envelop capsids in the cytoplasm, produce fewer dense bodies (DB) than the wild-type (WT) virus, and are unable to incorporate viral products into multivesicular bodies (MVB). Viruses lacking UL136 also fail to properly envelop virions and produce larger dense bodies than the WT virus. Our results indicate roles for the UL135 and UL136 proteins in commandeering host membrane-trafficking pathways for virus maturation. UL135 and UL136 represent the first HCMV genes crucial for early- to late-stage tropism in ECs.

Goodrum, F., & Bughio, F. (2015). Viral infection at the endothelium. Oncotarget, 6(29), 26541-2.