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Investigating The Roles Of Nedd4.2s And Nef In The Release And Replication Of Hiv-1: A Dissertation, Eric R. Weiss Sep 2012

Investigating The Roles Of Nedd4.2s And Nef In The Release And Replication Of Hiv-1: A Dissertation, Eric R. Weiss

GSBS Dissertations and Theses

Replication of HIV-1 requires the assembly and release of mature and infectious viral particles. In order to accomplish this goal, HIV-1 has evolved multiple methods to interact with the host cell. HIV-1 recruits the host cell ESCRT machinery to facilitate the release of nascent viral particles from the host cell membrane. Recruitment of these cellular factors is dependent on the presence of short motifs in Gag referred to as Late-domains. Deletion or mutation of these domains results in substantial decrease in the release of infectious virions. However, previously published work has indicated that over-expression of the E3 ubiquitin ligase, NEDD4 ...


Hepatitis C Virus Non-Structural Protein 3/4a: A Tale Of Two Domains: A Dissertation, Cihan Aydin Aug 2012

Hepatitis C Virus Non-Structural Protein 3/4a: A Tale Of Two Domains: A Dissertation, Cihan Aydin

GSBS Dissertations and Theses

Two decades after the discovery of the Hepatitis C Virus (HCV), Hepatitis C infection still persists to be a global health problem. With the recent approval of the first set of directly acting antivirals (DAAs), the rate of sustained viral response for HCV-infected patients increased significantly. However, a complete cure has not been found yet. Drug development efforts primarily target NS3/4A protease, bifunctional serine protease-RNA helicase of HCV. HCV NS3/4A is critical in viral function; protease domain processes the viral polyprotein and helicase domain aids replication of HCV genome by unwinding double stranded RNA transcripts produced by NS5B ...


Studies On Cellular Host Factors Involved In The Hiv-1 Life Cycle: A Dissertation, Anna Kristina Serquiña Aug 2012

Studies On Cellular Host Factors Involved In The Hiv-1 Life Cycle: A Dissertation, Anna Kristina Serquiña

GSBS Dissertations and Theses

Human Immunodeficiency Virus Type 1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), currently the leading cause of death from infectious diseases. Since HIV-1 co-opts the host cellular machinery, the study of cellular factors involved is a rational approach in discovering novel therapeutic targets for AIDS drug development. In this thesis, we present studies on two such proteins. APOBEC3G is from the family of cytidine deaminases known to keep endogenous retroviruses and retrotransposons at bay to maintain stability of the human genome. APOBEC3G targets Vif-deficient HIV-1 particles and renders them noninfectious, partially through deaminase-dependent hypermutation of the provirus ...


Rna-Sensing Pattern Recognition Receptors And Their Effects On T-Cell Immune Responses: A Dissertation, Rachel F. Madera Jul 2012

Rna-Sensing Pattern Recognition Receptors And Their Effects On T-Cell Immune Responses: A Dissertation, Rachel F. Madera

GSBS Dissertations and Theses

Virus infection is sensed by the innate immune system through germline encoded pattern recognition receptors (PRRs). Toll-like receptors (TLRs), retinoic acid-inducible gene-I-like receptors (RLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) serve as PRRs that recognize different viral components. Microbial nucleic acids such as Ribonucleic acid (RNA) are important virus-derived pathogen-associated molecular patterns (PAMPs) to be recognized by PRRs. Virus recognition may occur at multiple stages of the viral life cycle. Replication intermediates such as single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) are detected by the RNA-sensing PRRs that initiate innate and adaptive immune responses. Triggering of the innate immune system ...


Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval Jun 2012

Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval

GSBS Dissertations and Theses

Long-term antiviral antibody responses provide protection from re-infection and recurrence of persistent viruses. Using a polyomavirus (PyV) mouse model, our lab has shown that MyD88-deficient mice generate low levels of virus-specific IgG after the acute phase of infection and that these IgG responses have a skewed isotype distribution with low levels of IgG2a/c. Moreover MyD88-deficient mice have reduced numbers of long-lived plasma cells in the bone marrow. These studies suggest an important role of MyD88-mediated signaling in long-term antiviral responses. Our lab has shown that T cell-deficient mice can also maintain long-term virus-specific IgG responses following PyV infection. The ...


Characterization Of Drug Resistance In Mycobacterium Tuberculosis Via Saturating Mutagenesis Of Drug Targets: A Master’S Thesis, Michelle J. Harris Jun 2012

Characterization Of Drug Resistance In Mycobacterium Tuberculosis Via Saturating Mutagenesis Of Drug Targets: A Master’S Thesis, Michelle J. Harris

GSBS Dissertations and Theses

Mycobacterium tuberculosis isolates from multiple drug resistant or extensively drug resistant patients show a particular set of mutations in drug targets conferring resistance. However, the selection of drug-resistant strains in vitro yields an alternative set of mutations, thought to result from the cost-benefit associated with drug resistance. Mutations allowing for survival under antibiotic may not be beneficial when presented with the host environment or with a drug-free environment. These fitness effects drive the natural evolution of this bacterium. Using recombineering a large cohort of mutations was generated within two drug targets, inhA and gyrA, to study in vitro the variability ...


Small Molecule Investigation Of Kcnq Potassium Channels: A Dissertation, Karen Mruk May 2012

Small Molecule Investigation Of Kcnq Potassium Channels: A Dissertation, Karen Mruk

GSBS Dissertations and Theses

Voltage-gated K+ channels associate with multiple regulatory proteins to form complexes with diverse gating properties and pharmacological sensitivities. Small molecules which activate or inhibit channel function are valuable tools for dissecting the assembly and function of these macromolecular complexes. My thesis focuses on the discovery and use of small molecules to probe the structure and function of the KCNQ family of voltage-gated K+ channels.

One protein that obligatorily assembles with KCNQ channels to mediate proper assembly, trafficking, and gating is the calcium sensor, calmodulin. Although resolution of the crystal structures of calmodulin associated with isolated peptide fragments from other ion ...


Transcriptional Regulation Of The Interleukin-8 Promoter By Multiple Dengue Viral Proteins: A Dissertation, Jacob M. Collins May 2012

Transcriptional Regulation Of The Interleukin-8 Promoter By Multiple Dengue Viral Proteins: A Dissertation, Jacob M. Collins

GSBS Dissertations and Theses

Dengue virus (DENV) causes over 500,000 infections annually with a spectrum of clinical diseases ranging from subclinical infection to dengue, a mild febrile illness, to life-threatening severe dengue. Vascular leakage without endothelial cell damage is the hallmark symptom of severe dengue illness and is proposed to be directly mediated by soluble inflammatory mediators IL-8 and TNFα. IL-8 production occurs in response to DENV infection, is elevated during severe dengue, is proposed to inhibit interferon, and could potentially recruit target cells to sites of infection. We previously showed that expression of DENV NS5 activates the IL-8 promoter, induces IL-8 transcription ...


The Role Of Adaptor Protein Complex-3 Delta-Mediated Hiv-1 Gag Trafficking In Hiv-1 Replication: A Dissertation, Adonia Lee Kim May 2012

The Role Of Adaptor Protein Complex-3 Delta-Mediated Hiv-1 Gag Trafficking In Hiv-1 Replication: A Dissertation, Adonia Lee Kim

GSBS Dissertations and Theses

The process of HIV-1 particle production is a multi-step process directed by the viral structural protein Gag. As Gag is the only viral protein required to form virus-like particles, it presents a viable target for anti-viral therapeutics of which there are currently none. Although the functions of Gag during the particle assembly process have been well characterized, one of the least known parts of the assembly process is how Gag is targeted to the site of virus assembly.

Two main virus assembly sites have been identified in cells that support HIV-1 replication: the plasma membrane or multivesicular bodies (MVBs). However ...


Hiv-1 R5 Tropism: Determinants, Macrophages, And Dendritic Cells: A Dissertation, Thomas A. Musich May 2012

Hiv-1 R5 Tropism: Determinants, Macrophages, And Dendritic Cells: A Dissertation, Thomas A. Musich

GSBS Dissertations and Theses

Around thirty years ago HIV-1 was identified, and from that point the known epidemic has grown to over 30 million infected individuals. Early on in the course of HIV-1 research, viruses were classified as either syncytia inducing, CXCR4-using, T-cell tropic or non-syncytia inducing, CCR5-using, macrophage tropic. Since that time, several groups have shown that this is an oversimplification. There is a great deal of diversity amongst CCR5-using HIV-1 variants. There remains a great deal to be discovered regarding HIV-1 CCR5-tropism and how this affects other aspects of HIV-1 infection.

The CD4 binding site (CD4bs) on the HIV-1 envelope plays a ...


Catalytic Mechanisms In Sec7 And Vps9 Domain Exchange Factors For Arf And Rab Gtpases: A Dissertation, Meng-Tse Lee May 2012

Catalytic Mechanisms In Sec7 And Vps9 Domain Exchange Factors For Arf And Rab Gtpases: A Dissertation, Meng-Tse Lee

GSBS Dissertations and Theses

Vesicle budding, membrane trafficking, and lipid metabolism depend on the switching of Arf and Rab GTPases from the inactive GDP bound state to the active GTP bound state. However, Arf and Rab GTPases have intrinsic rates of GDP to GTP exchange that are much slower (hours to days) than the time scale of the relevant trafficking processes (seconds or less). In cells, the activation of Arf and Rab GTPases is tightly regulated by guanine nucleotide exchange factors (GEFs) with Sec7 or Vps9 domains, respectively.

Full length Cytohesins, which have a domain architecture consisting of heptad repeats, a Sec7 domain, a ...


Targeting The Histone Acetyl-Transferase, Rtt109, For Novel Anti-Fungal Drug Development: A Dissertation, Jessica Lopes Da Rosa-Spiegler May 2012

Targeting The Histone Acetyl-Transferase, Rtt109, For Novel Anti-Fungal Drug Development: A Dissertation, Jessica Lopes Da Rosa-Spiegler

GSBS Dissertations and Theses

Discovery of new antifungal chemo-therapeutics for humans is limited by the large degree of conservation among eukaryotic organisms. In recent years, the histone acetyl-transferase Rtt109 was identified as the sole enzyme responsible for an abundant and important histone modification, histone H3 lysine 56 (H3K56) acetylation. In the absence of Rtt109, the lack of acetylated H3K56 renders yeast cells extremely sensitive to genotoxic agents. Consequently, the ability to sustain genotoxic stress from the host immune system is crucial for pathogens to perpetuate an infection. Because Rtt109 is conserved only within the fungal kingdom, I reasoned that Rtt109 could be a novel ...


Gene Therapy For Very Long Chain Acyl-Coa Dehydrogenase Deficiency Using Adeno-Associated Virus Vectors: A Dissertation, Allison M. Keeler Apr 2012

Gene Therapy For Very Long Chain Acyl-Coa Dehydrogenase Deficiency Using Adeno-Associated Virus Vectors: A Dissertation, Allison M. Keeler

GSBS Dissertations and Theses

Very long chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD deficient mice and patients’ clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD deficient mice were treated systemically with 1x10 12 vector genomes of rAAV9-VLCAD. Expression was detected in the liver, heart and muscle. Also substantial expression of VLCAD was noted in the brain, where it was expressed across different sections of the brain and in different cell types with different morphologies. Biochemical correction was observed in vector-treated mice beginning two weeks post-injection, as characterized by a significant ...


The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon Apr 2012

The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon

GSBS Dissertations and Theses

Human influenza is a contagious respiratory disease resulting in substantial morbidity and mortality worldwide. With the recent cases of avian influenza infections in humans and the heightened concern for an influenza pandemic arising from these infections, it is essential to understand host responses that would confer protective immunity to influenza. The cell-mediated immune responses to influenza virus play an important role during influenza infection.

To analyze the specificity and diversity of memory T-cell responses, we performed a genome-wide screening of T cell epitopes to influenza A virus in healthy adult donors. We identified a total of 83 peptides, 54 of ...


A New Murine Model For Enterohemorrhagic Escherichia Coli Infection Reveals That Actin Pedestal Formation Facilitates Mucosal Colonization And Lethal Disease: A Dissertation, Emily M. Mallick Mar 2012

A New Murine Model For Enterohemorrhagic Escherichia Coli Infection Reveals That Actin Pedestal Formation Facilitates Mucosal Colonization And Lethal Disease: A Dissertation, Emily M. Mallick

GSBS Dissertations and Theses

Enterohemorrhagic Escherichia coli (EHEC) colonizes the intestine and produces the phage-encoded Shiga toxin (Stx) which is absorbed systemically and can lead to hemolytic uremic syndrome (HUS) characterized by hemolytic anemia, thrombocytopenia, and renal failure. EHEC, and two related pathogens, Enteropathogenic E. coli (EPEC), and the murine pathogen, Citrobacter rodentium, are attaching and effacing (AE) pathogens that intimately adhere to enterocytes and form actin “pedestals” beneath bound bacteria. The actin pedestal, because it is a unique characteristic of AE pathogens, has been the subject of intense study for over 20 years. Investigations into the mechanism of pedestal formation have revealed that ...


The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin Mar 2012

The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin

GSBS Dissertations and Theses

Heterologous immunity is a mechanism by which immunological memory within an individual, developed in response to a previous infection, plays a role in the immune response to a subsequent unrelated infection. In murine studies, heterologous immunity facilitated by cross-reactive CD8 T-cell responses can mediate either beneficial (protective immunity) or detrimental effects (e.g. enhanced lung and adipose immunopathology and enhanced viral titers) (Selin et al., 1998; Chen et al., 2001; Welsh and Selin, 2002; Nie et al., 2010; Welsh et al., 2010). Protective heterologous immunity results in enhanced clearance of virus during a subsequent infection with an unrelated pathogen. Such ...


Characterization Of New Factors In The 18s Nonfunctional Ribosomal Rna Decay Pathway In S. Cerevisiae: A Dissertation, Christopher N. Merrikh Mar 2012

Characterization Of New Factors In The 18s Nonfunctional Ribosomal Rna Decay Pathway In S. Cerevisiae: A Dissertation, Christopher N. Merrikh

GSBS Dissertations and Theses

The molecular biology revolution of the 1960s has given rise to an enormous body of literature describing, in great detail, the inner workings of the cell. Over the course of the past 50 years, and countless hours at the bench, biologists have used the implications of basic research to produce vaccines, antibiotics, and other therapies that have improved both the quality and duration of our lives. Despite these incredible advances, basic questions remain unanswered. In even the simplest model organism, hundreds of essential genes have never been studied. Moreover, the central dogma of molecular biology—DNA to RNA to Protein ...


A Population-Based Epidemiological Description Of Socio-Demographic Characteristics And Predictors Of Severity Among Hospitalized 2009 H1n1 Influenza Cases In Massachusetts: A Dissertation, Hilary Placzek Feb 2012

A Population-Based Epidemiological Description Of Socio-Demographic Characteristics And Predictors Of Severity Among Hospitalized 2009 H1n1 Influenza Cases In Massachusetts: A Dissertation, Hilary Placzek

GSBS Dissertations and Theses

The spread of pandemic influenza A (2009 H1N1 influenza) virus resulted in a global influenza pandemic in 2009. During the early stages of the pandemic, population surveillance was crucial. However, officials around the world realized that many of our surveillance and reporting systems were not prepared to respond in a coordinated, integrated way, which made informed public health decision-making very difficult. More accurate estimates of the total number of hospitalized 2009 H1N1 influenza cases were required to calculate population-based 2009 H1N1 influenza-associated mortality, morbidity and hospitalization rates. For instance, how many people were hospitalized with 2009 H1N1 influenza in Massachusetts ...


Primary And Secondary Immune Responses During Sequential West Nile Virus And Japanese Encephalitis Virus Infections: A Dissertation, Derek W. Trobaugh Feb 2012

Primary And Secondary Immune Responses During Sequential West Nile Virus And Japanese Encephalitis Virus Infections: A Dissertation, Derek W. Trobaugh

GSBS Dissertations and Theses

Japanese encephalitis virus (JEV) and West Nile virus (WNV) are closely related Flaviviruses that are important arthropod-borne human pathogens. Both of these viruses can cause encephalitis with significant morbidity and mortality after infection. Flaviviruses co-circulate in many areas of the world, which raises the risk for sequential infection between heterologous viruses. Sequential infection between dengue virus serotypes can lead to cross-protection, but in some cases, it leads to a severe outcome, dengue hemorrhagic fever. Previous work in hamsters and non-human primates demonstrated that prior JEV immunity protects against a lethal WNV infection. However, the ability of prior WNV immunity to ...


Control Of Bovine Papillomavirus E2 Function By Acetylation And The Novel E2 Interacting Protein Rint1: A Dissertation, Edward J. Quinlan Jan 2012

Control Of Bovine Papillomavirus E2 Function By Acetylation And The Novel E2 Interacting Protein Rint1: A Dissertation, Edward J. Quinlan

GSBS Dissertations and Theses

Human papillomavirus infection is the cause of more than 99% of cervical cancer cases. The current vaccine is ineffective therapeutically; highlighting the need for continued papillomavirus research. One avenue that could be explored in this regard is the function of the papillomavirus E2 regulatory proteins. HPV E2 represses expression of the viral E6 and E7 oncoproteins. Reintroduction of E2 into cervical carcinoma cells results in growth arrest and cellular senescence. Understanding the mechanism of how E2 regulates the early promoter may be key to developing new therapeutic and prophylactic vaccines. Here, we describe regulation of E2 through acetylation and possibly ...


Insights Into Er Translocation Channel Gating. Structural Regulation Of The Transition Between The Closed And Open Channel Conformations: A Dissertation, Steven F. Trueman Oct 2011

Insights Into Er Translocation Channel Gating. Structural Regulation Of The Transition Between The Closed And Open Channel Conformations: A Dissertation, Steven F. Trueman

GSBS Dissertations and Theses

The transition between the closed and open conformations of the Sec61 complex permits nascent protein insertion into the translocation channel. A critical event in this structural transition is the opening of the lateral translocon gate that is formed by four transmembrane (TM) spans (TM2, TM3, TM7 and TM8 in Sec61p) to expose the signal sequence-binding (SSB) site. To gain mechanistic insight into lateral gate opening, mutations were introduced into a lumenal loop (L7) that connects TM7 and TM8. The sec61 L7 mutants were found to have defects in both the posttranslational and cotranslational translocation pathways due to a kinetic delay ...


M.Tb Killing By Macrophage Innate Immune Mechanisms: A Dissertation, Michelle L. Hartman Sep 2011

M.Tb Killing By Macrophage Innate Immune Mechanisms: A Dissertation, Michelle L. Hartman

GSBS Dissertations and Theses

Macrophages infected with a heavy burden of M.tb Erdman undergo a cell death that initially resembles apoptosis but quickly transitions to necrosis. Unlike the previously reported TNF dependent apoptosis induced by avirulent Mycobacterium [1], this form of macrophage cell death is not microbicidal [2]. Microbicidal effects are observed however, when the heavily infected macrophage encounters an uninfected naïve macrophage. My studies describe in part, the crosstalk between the uninfected and infected macrophage that results in the killing of the intracellular M.tb Cell contact between the two cell populations is not necessary for this killing of bacilli to occur ...


Intranasal Colonization By Streptococcus Pneumoniae Induces Immunological Protection From Pulmonary And Systemic Infection: A Dissertation, Nang H. Maung Aug 2011

Intranasal Colonization By Streptococcus Pneumoniae Induces Immunological Protection From Pulmonary And Systemic Infection: A Dissertation, Nang H. Maung

GSBS Dissertations and Theses

Given that Streptococcus pneumoniae can cause life-threatening pulmonary and systemic infection, an apparent paradox is that the bacterium resides, usually harmlessly, in the nasopharynx of many people. Humoral immunity is thought to be the primary defense against serious pneumococcal infection, and we hypothesized that nasopharyngeal colonization of mice results in the generation of an antibody response that provides long-term protection against lung infection. We found that survival of of C57L/6 mice after intranasal inoculation with wild-type serotype 4 strain TIGR4 pneumococci required B cells but not T cells, suggesting that nasopharyngeal colonization elicited a protective humoral immune response. In ...


Role Of Protein Flexibility In Function, Resistance Pathways And Substrate Recognition Specificity In Hiv-1 Protease: A Dissertation, Seema Mittal Aug 2011

Role Of Protein Flexibility In Function, Resistance Pathways And Substrate Recognition Specificity In Hiv-1 Protease: A Dissertation, Seema Mittal

GSBS Dissertations and Theses

In the 30 years since the Center for Disease Control's Morbidity and Mortality Weekly Report published the first mention of what later was determined to be AIDS (Acquired immunodeficiency syndrome) and HIV (Human immunodeficiency virus) recognized as the causative pathogen, much has been done to understand this disease’s pathogenesis, development of drugs and emergence of drug resistance under selective drug therapy. Highly Active Antiretroviral Therapy (HAART), a combination of drugs that includes HIV-1 reverse transcriptase, protease, and more recently, integrase and entry inhibitors, have helped stabilize the HIV prevalence at extraordinarily high levels. Despite the recent stabilization of ...


Structural Studies Of The Anti-Hiv Human Protein Apobec3g Catalytic Domain: A Dissertation, Shivender Shandilya Aug 2011

Structural Studies Of The Anti-Hiv Human Protein Apobec3g Catalytic Domain: A Dissertation, Shivender Shandilya

GSBS Dissertations and Theses

HIV/AIDS is a disease of grave global importance with over 33 million people infected world-wide and nearly 2 million deaths each year. The rapid emergence of drug resistance, due to viral mutation, renders anti-retroviral drug candidates ineffective with alarming speed and regularity. Instead of targeting mutation prone viral proteins, an alternative approach is to target host proteins that interact with viral proteins and are critical for the HIV life-cycle. APOBEC3G is a host anti-HIV restriction factor that can exert tremendous negative pressure by hypermutating the viral genome and has the potential to be a promising candidate for anti-retroviral therapeutic ...


Investigation Of The C-Terminal Helix Of Hiv-1 Matrix: A Region Essential For Multiple Functions In The Viral Life Cycle: A Dissertation, Laura A. Brandano Jul 2011

Investigation Of The C-Terminal Helix Of Hiv-1 Matrix: A Region Essential For Multiple Functions In The Viral Life Cycle: A Dissertation, Laura A. Brandano

GSBS Dissertations and Theses

Since the first cases were reported over thirty years ago, great strides have been made to control disease progression in people living with HIV/AIDS. However, current estimates report that there are about 34 million individuals infected with HIV worldwide. Critical in the ongoing fight against this pandemic is the continuing development of highly active anti-retroviral therapies, ideally those with novel mechanisms of action. Currently, there are no medications approved for use that exploit the HIV-1 MA protein, despite its central role in multiple stages of the virus life cycle.

This thesis sought to examine whether a highly conserved glutamate ...


Regulation Of Humoral Immunity By Pim Kinases: A Dissertation, Kristen N. Willems Jun 2011

Regulation Of Humoral Immunity By Pim Kinases: A Dissertation, Kristen N. Willems

GSBS Dissertations and Theses

Pim (Provirus Integration site for Moloney murine leukemia virus) kinases are a family of three serine/threonine kinases involved in cell cycle, survival and metabolism. These kinases were first identified in malignant cells and are most often associated with their role in cancer. Their role in immunity and lymphocytes is less well known. To date, it has been shown that Pim 1 and/or Pim 2 are important for T lymphocyte survival and activation when the Akt signaling pathway is inhibited by rapamycin. In addition, our laboratory has shown that Pim 2 is critical for BLyS-mediated naive B lymphocyte survival ...


Mechanisms Of Substrate Recognition By Hcv Ns3/4a Protease Provide Insights Into Drug Resistance: A Dissertation, Keith P. Romano May 2011

Mechanisms Of Substrate Recognition By Hcv Ns3/4a Protease Provide Insights Into Drug Resistance: A Dissertation, Keith P. Romano

GSBS Dissertations and Theses

HCV afflicts many millions of people globally, and antiviral therapies are often ineffective and intolerable. The Food and Drug Administration approved the HCV protease inhibitors telaprevir and boceprevir in May 2011, marking an important milestone in anti-HCV research over the past two decades. Nevertheless, severe drug side effects of combination therapy – flu-like symptoms, depression and anemia – limit patient adherence to treatment regimens. The acquisition of resistance challenges the long-term efficacy of antiviral therapies, including protease inhibitors, as suboptimal dosing allows for the selection of drug resistant viral variants. A better understanding of the molecular basis of drug resistance is therefore ...


A Global Analysis Of The Adaptations Required For Sterol Catabolism In Mycobacterium Tuberculosis: A Dissertation, Jennifer E. Griffin May 2011

A Global Analysis Of The Adaptations Required For Sterol Catabolism In Mycobacterium Tuberculosis: A Dissertation, Jennifer E. Griffin

GSBS Dissertations and Theses

Systems biology approaches have allowed for comprehensive understanding of complicated biological processes. Here, we’ve developed a global phenotypic profiling method by improving upon transposon mutagenesis methods for identifying genes required for bacterial growth in various conditions. By using the massively parallel power of Illumina sequencing, we precisely redefined the genes required for the growth of Mycobacterium Tuberculosis (Mtb) in vitro. This adapted technique provided more informative data with both increased dynamic range and resolution. As a result, we quantitatively assessed the fitness of individual mutants, as well as identified sub-genic essentiality. Mtb is well adapted to its nutrient-limiting intracellular ...


Roles Of Secreted Virulence Factors In Pathogenicity Of Haemophilus Influenzae: A Dissertation, Charles V. Rosadini May 2011

Roles Of Secreted Virulence Factors In Pathogenicity Of Haemophilus Influenzae: A Dissertation, Charles V. Rosadini

GSBS Dissertations and Theses

Haemophilus influenzae is a pathogenic Gram-negative bacterium that colonizes the upper respiratory tract of humans and can cause otitis media, upper and lower respiratory infections, and meningitis. Factors important for H. influenzae to colonize humans and cause disease are not fully understood. Different bacterial pathogens are armed with virulence mechanisms unique to their specific strategies for interacting with their hosts. Many of the proteins mediating these interactions are secreted and contain disulfide bonds required for function or stability. I postulated that identifying the set of secreted proteins in H. influenzae that require periplasmic disulfide bonds would provide better understanding of ...