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Virology

The department faculty in this area of research focus on mechanisms underlying virus-host interactions, virus assembly, gene regulation, oncogenesis and neurovirology. Work from our virology laboratories has provided novel insights into neuroinvasion, epithelial transformation, gene delivery and subversion of host cell function.

Labs in This Research Area

 Eva Gottwein Lab

Targets and functions of miRNAs encoded by the human herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV)

Research Description

Viruses commonly modify their cellular environment to optimize viral replication and persistence. Much has been learned about the intervention of viral proteins with cellular pathways. More recently, it has become clear that herpesviruses also encode large numbers of microRNAs (miRNAs). The modest amount of space miRNA precursors occupy in the viral genome, their lack of immunogenicity and their potential as regulators of gene expression make miRNAs ideal candidates for viral effectors.

The lab’s research focuses on identifying targets and functions of miRNAs encoded by the human herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV causes cancer in immuno-compromised individuals. The clinically most relevant KSHV-induced disease is Kaposi’s sarcoma (KS), a complex tumor driven by KSHV-infected endothelial cells. Due to the AIDS epidemic, KS has become the most common cancer in parts of Africa. KSHV also infects B lymphocytes and can consequently cause B cell lymphomas, including primary effusion lymphoma (PEL). KSHV constitutively expresses viral miRNAs from 12 precursors, suggesting a role of these miRNAs in viral replication and pathogenesis.

My lab is currently pursuing the comprehensive identification of mRNA targets of these miRNAs in primary effusion lymphoma cell lines and KSHV-infected endothelial cells. Our data suggest that, together, the KSHV miRNAs directly target hundreds of cellular mRNAs encoding proteins with roles in several different biological pathways. Our goal is to use this knowledge to characterize the most important functions of the KSHV miRNAs.

For lab information and more, see Dr. Gottwein's faculty profile and lab website.

Publications

See Dr. Gottwein's publications on PubMed.

Contact

Contact Dr. Gottwein at 312-503-3075 or the lab at 312-503-3076.

Lab Staff

Postdoctoral Fellows

Mark Manzano, Kylee Morrison

Graduate Students

Neil Kuehnle

Technical Staff

Kevin Chung, Ajinkya Patil

 Laimonis Laimins Lab

Molecular biology of human papillomaviruses (HPV) and their association with cervical cancer

Research Description

Our efforts are divided into two main categories:

  • An examination of how the viral oncoproteins E6 and E7 contribute to the development of malignancy
  • Studies on the mechanisms controlling the viral life cycle in differentiating epithelia

More than 100 distinct types of human papillomavirus have been identified and approximately one-third specifically target squamous epithelial cells in the genital tract. Of these genital papillomaviruses, a subset including types 16,18 and 31 have been shown to be the etiological agents of most cervical cancers.

One of our goals is to understand why infection by specific HPV types contributes to the development of malignancy. For these studies we have examined the interaction of the oncoproteins E6 and E7 with cellular proteins. In particular, E6 binds the p53 protein and facilitates its degradation by a ubiquitin-mediated pathway. It also activates telomerase as well as associates with PDZ-domain containing proteins. The interactions of the E6 and E7 proteins with these cellular proteins are being examined at both the biochemical and genetic level.

In examining the papillomavirus life cycle, we have used organotypic tissue culture systems to faithfully reproduce the differentiation program of epithelial cells in the laboratory. Using this system, the viral life cycle has been duplicated.  We are studying the mechanisms that regulate viral DNA replication, cell entry, immune evasion and gene expression. These studies should provide insight into viral pathogenesis as well as the mechanisms regulating epithelial differentiation.

For lab information and more, see Dr. Laimins' faculty profile and lab website.

Publications

See Dr. Laimins' publications on PubMed.

Contact

Contact Dr. Laimins at 312-503-0648 or the lab at 312-503-0650.

Lab Staff

Postdoctoral Fellows

Ekaterina Albert, Elona Gusho, Takeyuki Kono, Sreedhar Pujari

Technical Staff

Archit Ghosh, Paul Hoover, Paul Kaminski, Brian Studnicka

 Jonathan Leis Lab

Mechanisms of retrovirus replication

Research Description

Multidisciplinary molecular genetics and biochemical approaches are being used to study replication of avian and human retroviruses.  Areas of particular interest are in reverse transcription, viral DNA integration, and virion assembly.      

Specific projects include studying:

  • The role of viral RNA secondary structures in initiation of reverse transcription
  • The mechanism of concerted integration of viral DNA into the host chromosome by integrase (IN) using an in vitro reconstituted system and identification of the amino acids of tIN responsible for specificity for the LTR ends
  • The mechanism of processing of Gag and Pol polyproteins into mature viral proteins by the virus-specific protease (PR)
  • The role of a Gag polyprotein assembly domain in budding of virus particles from cells

In many of these studies, amino acid substitutions have been placed at biochemically or structurally important residues and the effect these changes have on viral replication and on the properties of the mutant proteins have been defined.

For lab information and more, see Dr. Leis's faculty profile.

Publications

See Dr. Leis's publications on PubMed.

Contact

Contact Dr. Leis at 312-503-1166 or the lab at 312-503-1195.

 Richard Longnecker Lab

Epstein-Barr virus (EBV) and herpes simplex virus (HSV) entry, replication and pathogenesis.

Research Description

Research in the Longnecker laboratory focuses on herpes simplex virus (HSV) and Epstein-Barr virus (EBV). These viruses typically cause self-limiting disease within the human population but both can be associated with serious complications. EBV is associated with variety of hematopoietic cancers such as African Burkitt lymphoma, Hodgkin Lymphoma and adult T-cell leukemia. EBV-associated lymphoproliferative disease occurs in individuals with congenital or acquired cellular immune deficiencies. The two notable epithelial diseases associated with EBV infection are nasopharyngeal cancer and oral hairy leukoplakia. Similar to EBV, HSV latent infections are very common in humans. HSV typically does not cause severe disease but is associated with localized mucocutaneous lesions, but in some cases can cause meningitis and encephalitis. The Longnecker laboratory focuses on several aspects of EBV and HSV replication and pathogenesis. First, the molecular basis EBV transformation and how it relates to cancer is being investigated. The laboratory is currently screening selective inhibitors that may be beneficial in EBV-associated cancers such as Hodgkin lymphoma, Burkitt lymphoma and proliferative disorders that occur in HIV/AIDS and transplant patients. Second, the laboratory is investigating herpesvirus latency in the human host and pathogenesis associated with infections in humans. In this regard, the laboratory is developing animal models for EBV and HSV infections. Finally, the laboratory is investigating the function of herpesvirus encoded proteins and the cellular receptors that are important for infection both using in vivo culture models as well as animal models. Ultimately, studies by the Longnecker laboratory may provide insight for the development of novel therapeutics for the treatment of herpesvirus infections in humans and better understanding of the herpesvirus life cycle in the human host

For lab information and more, see Dr. Longnecker's faculty profile.

Publications

See Dr. Longnecker's publications on PubMed.

Contact

Contact Dr. Longnecker at 312-503-0467 or the lab at 312-503-0468 or 312-503-9783.

Lab Staff

Research Faculty

Jia Chen, Qing Fan, Kamonwan "Pear" Fish, Masato Ikeda

Adjunct Faculty

Sarah Connolly, Michelle Swanson-Mungerson

Graduate Students

Cooper Hayes, Daniel Giraldo Perez, Seo Jin Park

Technical Staff

Sarah Kopp, Rachel Riccio, Samantha Schaller, Nanette Susmarski

 Mojgan Naghavi Lab

Microtubule regulation and function during infection by Human Immunodeficiency Virus (HIV)

Research Description

Our research focuses on infection by Human Immunodeficiency Virus type 1 (HIV-1), a retrovirus and causative agent of acquired immunodeficiency syndrome (AIDS). In addition to suppressing the immune system, rendering victims susceptible to opportunistic infections, HIV-1 can cross the blood-brain barrier and cause serious damage to the central nervous system, ultimately leading to HIV-associated dementia.

We are interested in how HIV-1 particles move within infected cells, including brain cell types such as microglia. Our work focuses on how the virus exploits host microtubules, the intracellular filaments that mediate cargo trafficking to different subcellular sites within the cell.

Our earlier work, employing a variety of screening approaches, identified a number of host proteins involved in cytoskeletal regulation and motor function as playing key roles in the early stages of HIV-1 infection. This includes Ezrin-Radixin-Moesin (ERM) proteins, which cross-link the actin and microtubule cytoskeletons. In exploring their role in HIV-1 infection, we identified the first biological function for the host protein, PDZD8, demonstrating that it binds ERMs to control microtubule stability. Furthermore, we uncovered that PDZD8 is a direct target for the HIV-1 protein, Gag.

Other work in our laboratory has shown that HIV-1 can induce the formation of highly stable microtubule subsets to facilitate early HIV-1 trafficking to the nucleus. We are interested in the role played in this process by proteins such as PDZD8, as well as a family of specialized microtubule regulatory proteins called +TIPs, which accumulate at the ends of dynamically growing microtubule filaments to control their growth and stability. We are also interested in the function of microtubule motors and cargo adaptor proteins in HIV-1 infection. In particular, we are exploring how Fasciculation and Elongation factor Zeta-1 (FEZ-1), a kinesin-1 adaptor protein that is highly expressed in neurons, functions to control HIV-1 infection. Our work employs a range of approaches, including biochemical characterization of protein-protein interactions as well as live imaging of fluorescently-labeled HIV-1 particles as they move within infected cells.

The ultimate goal of our work is to understand the molecular basis behind how microtubules, regulators of microtubule dynamics and microtubule motor proteins function to enable HIV-1 movement to and from the nucleus.

For lab information and more, see Dr. Naghavi's faculty profile and lab website.

Publications

See Dr. Naghavi's publications at PubMed.

Contact

Contact Dr. Naghavi at 312-503-4294.

Lab Staff

Postdoctoral Fellows

Qingqing Chai, Feng Gu, Viacheslav Malikov, Sahana Mitra, Gina Pisano, Eveline Santos da Silva, Shanmugapriya Swamy

Technical Staff

Marie-Philipe Boisjoli, Kayla Schipper

 Pablo Penaloza-MacMaster Lab

Immune regulation and vaccines

Research Description

The immune system can mount a robust adaptive response following encounter with a pathogen or during the emergence of cancer. However, if an infectious microorganism  or a cancer disseminates rapidly, adaptive immune response exhaust, resulting in antigen persistence and the onset of disease. Our laboratory has demonstrated various key aspects of the exhausted immune response, including the concerted role of inhibitory pathways and T regulatory cells. In addition, we have shown the fine line between immune protection and immunopathology and our data highlight the importance of regulating helper CD4 T cell function during antigen persistence.

Overall, our main interests are vaccines and immune regulation during antigen persistence. We utilize various systems to assess immune responses (LCMV, Listeria, vaccinia, adenovirus, tumor challenge models, as well as the humanized mouse model of HIV infection and the SIV infection model in macaques). We hope that our basic immunological research can one day translate into effective treatments against cancers and chronic infections (such as HIV), which affect millions of people worldwide.

For lab information and more, see Dr. Penaloza-MacMaster's faculty profile.

Publications

See Dr. Penaloza-MacMaster's publications on PubMed.

Contact

Contact Dr. Penaloza-MacMaster at 312-503-0357.

Lab Staff

Postdoctoral Fellow

Tanushree Dangi, Juan Loredo Varela

Graduate Student

Young Rock Chung, Nicole Palacio

 Greg Smith Lab

Cell and molecular biology of herpesvirus invasion of the nervous system

Research Description

We investigate the relationship between infection of the nervous system by herpesviruses and disease outcome. Some of the most traumatic diseases – including polio, rabies and encephalitis – result from infections of the nervous system.  In contrast, herpesviruses are highly proficient at infecting the nervous system, yet normally do not cause neurological disease.  This is achieved in part by self-imposed restrictions encoded within the viruses that limit viral reproduction and prevent dissemination into the brain.  For the individual, this results in a relatively benign infection, yet the virus becomes a life-long occupant of the nervous system that will periodically reemerge at body surfaces to infect others. Unfortunately, this infectious cycle can go awry resulting in several forms of severe disease (i.e. keratitis and encephalitis).

We have pioneered methods to genetically manipulate herpesviruses and visualize individual viruses in living neurons. Using these methods, we are studying the mechanisms by which the virus achieves its stringently controlled infectious cycle. Current genetic manipulations are based on a full-length infectious clone of the herpesvirus genome. The clone was made as a bacterial artificial chromosome (BAC) in E. coli. Transfection of purified E. coli BAC plasmid into permissive eukaryotic cells is sufficient to initiate viral infection, allowing for immediate examination of viral mutant phenotypes in a variety of biological assays.  For example, by fusing the green fluorescent protein (GFP) to a structural component of the viral capsid, individual viral particles can be tracked within the axons of living neurons during both entry and egress phases of the infectious cycle. Studies in culture can be complemented by examining the pathogenesis of mutant viruses in rodent models of infection.

Using these methods, we have discovered key aspects of cellular infection, viral assembly and intracellular transport. Looking forward, we are continuing to pursue our multidisciplinary approach of combining neuroscience, cell biology, bacterial genetics and virology to better understand these important pathogens.

For lab information and more, see Dr. Smith's faculty profile.

Publications

See Dr. Smith's publications on PubMed.

Contact

Contact Dr. Smith at 312-503-3745 or the lab at 312-503-3744.

Lab Staff

Research Faculty

Sarah Antinone 

Postdoctoral Fellows

Oana Maier

Graduate Students

Kennen Hutchison, Caitlin Pegg, Jen Ai Quan

Technical Staff

Austin Stults 

 Bayar Thimmapaya Lab

Cell cycle deregulation by DNA tumor virus oncogenes

Research Description

Studies of viral oncogenes such as adenovirus (Ad) E1A, simian virus 40 large T and human papilloma virus (HPV) E6 and E7 have led to the discovery of tumor suppressor proteins including retinoblastoma family proteins, p53 and transcriptional coactivators p300/CBP. These proteins are key regulators of cell cycle progression. Interaction of the viral oncoproteins with these cell cycle regulators results in growth transformation of cultured cells, or in the case of HPV, results in human cancer.

We study the role of Ad E1A and HPV E7 in cell cycle deregulation and the mechanisms by which these oncoproteins induce S phase in cells. In particular, we are studying the cellular proteins targeted by Ad E1A and HPV E7 in relation to cell cycle deregulation, and the mechanisms by which these oncoproteins induce changes in the dynamics of cellular DNA replication. Studies include role of viral oncogene induced c-Myc in cell cycle progression, the mechanisms by which E1A and E7 transcriptionally induce c-Myc, how c-Myc cooperates with E2F family proteins in inducing cellular DNA replication, changes in the activity of the proteins involved in initiation of cellular DNA replication (Cdt1, for example), and the changes in cellular replication origin activity (re-replication in the case of E1A). We also study the viral oncogene induced replication stress when viral oncoproteins are expressed in normal cells.

In a separate study, in collaboration with Dr. Janardan Reddy (Professor, Pathology Department), we are investigating the role of transcriptional coactivators PIMT and Med1 in liver functions. The liver plays a vital role in energy homeostasis by controlling metabolic pathways of protein, fat and carbohydrates. PIMT (also known as NCoA6IP) is an RNA methylase that is involved in methylating cap structures of RNAs and PIMT may also have a chromatin role. Med1 is a major component of the Mediator complex that is critical for transcription. Both of these proteins interact with several nuclear receptors in transcriptional regulation of liver specific genes.

For lab information and more, see Dr. Thimmapaya's faculty profile.

Publications

See Dr. Thimmapaya's publications on PubMed.

Contact

Contact Dr. Thimmapaya at 312-503-5224 or the lab at 312-503-5176.

Lab Staff

Temporary Staff

Heba Kamel

Volunteer

Varsha Shete

 Derek Walsh Lab

Mechanisms of poxvirus and herpesvirus infection; translational control of gene expression; virus trafficking

Research Description

Research in our laboratory focuses on two aspects of DNA virus biology:

1) The role of the host translation system during infection by poxviruses. Members of the poxvirus family include Variola Virus (VarV), the causative agent of smallpox, and Vaccinia Virus (VacV), a close relative that was used as a vaccine against smallpox and which has become the laboratory prototype for poxvirus research. These large double-stranded DNA viruses exhibit an impressive level of self-sufficiency and encode many of the proteins required for transcription and replication of their DNA genomes. Indeed, unlike many other DNA viruses, poxviruses do not require access to the host nucleus and replicate exclusively in the cytoplasm of infected cells within compartments termed “viral factories”. However, like all viruses, they remain dependent on gaining access to host ribosomes in order to translate their mRNAs into proteins and must also counteract host antiviral responses aimed at crippling the translation system to prevent virus replication.

Our work focuses on the function of two eukaryotic translation initiation factor (eIF) complexes, eIF3 and eIF4F, that regulate ribosome recruitment to capped mRNAs and their role in VacV infection. We have found that VacV stimulates the assembly of eIF4F complexes and that this is important for both viral protein synthesis and control of host immune responses. Furthermore, we have found that eIF3 functionally communicates with eIF4F during translation initiation and that this plays an important role in VacV replication. We have also found that VacV redistributes key eIF4F subunits to specific regions within viral factories, a process that appears to involve the viral I3 protein.

We are currently exploring the compartmentalized replication of VacV as a means to better understand fundamental mechanisms of localized translational control and how this functions to regulate viral protein synthesis and host antiviral responses. We are also studying how the virus controls eIF4F activity by targeting upstream signaling pathways, with a particular emphasis on the metabolic sensor mammalian target of rapamycin (mTOR).

2) Microtubule regulation and function during herpes simplex virus infection. We are also interested in how herpes simplex virus type 1 (HSV-1) exploits host signaling pathways and specialized microtubule regulatory proteins, called +TIPs, to facilitate virus movement within the cell at various stages of the viral lifecycle.

For lab information and more, see Dr. Walsh's faculty profile and the lab website.

Publications

See publications on PubMed.

Contact

Contact Dr. Walsh at 312-503-4292

Lab Staff

Postdoctoral Fellows

Stephen DiGiuseppe, Charles Hesser, Nathan Meade, Dean Procter

Graduate Students

Colleen Furey, Madeline Rollins

Technical Staff

Helen Astar