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Description
Malaria is a vector-borne parasitic disease affecting tropical and subtropical regions. Regardless control efforts, malaria incidence is still incredible high with 219 million clinical cases and an estimated 660,000 related deaths (WHO, 2012). In this project, different population genetic approaches were explored to characterize parasite populations. The goal was to create a framework that considered temporal and spatial changes of Plasmodium populations in malaria surveillance. This is critical in a vector borne disease in areas of low transmission where there is not accurate information of when and where a patient was infected. In this study, fragment analysis data and single nucleotide polymorphism (SNPs) from South American samples were used to characterize Plasmodium population structure, patterns of migration and gene flow, and discuss approaches to differentiate reinfection vs. recrudescence cases in clinical trials. A Bayesian approach was also applied to analyze the Plasmodium population history by inferring genealogies using microsatellites data. Specifically, fluctuations in the parasite population and the age of different parasite lineages were evaluated through time in order to relate them with the malaria control plan in force. These studies are important to understand the turnover or persistence of "clones" circulating in a specific area through time and consider them in drug efficacy studies. Moreover, this methodology is useful for assessing changes in malaria transmission and for more efficiently manage resources to deploy control measures in locations that act as parasite "sources" for other regions. Overall, these results stress the importance of monitoring malaria demographic changes when assessing the success of elimination programs in areas of low transmission.
ContributorsChenet, Stella M (Author) / Escalante, Ananias A (Thesis advisor) / Clark-Curtiss, Josephine (Committee member) / Rosenberg, Michael (Committee member) / Taylor, Jesse E (Committee member) / Arizona State University (Publisher)
Created2014
Description
The viscous lung mucus of cystic fibrosis (CF) patients is characterized by oxygen gradients, which creates a unique niche for bacterial growth. Pseudomonas aeruginosa and Staphylococcus aureus, two predominant microorganisms chronically infecting the airways of CF patients, typically localize in hypoxic regions of the mucus. While interspecies interactions between P. aeruginosa and S. aureus have been reported, little is known about the role of low oxygen in regulating these interactions. Studying interspecies interactions in CF lung disease is important as evidence suggests that microbial community composition governs disease progression. In this study, P. aeruginosa lab strain PAO1 and two primary clinical isolates from hypoxic tissues were cultured alone, or in combination, with methicillin resistant S. aureus (MRSA) strain N315 under hypoxic or normoxic conditions. Herein, it is shown for the first time that low oxygen conditions relevant to the CF lung affect the competitive behavior between P. aeruginosa and S. aureus. Specifically, S. aureus was able to better survive competition in hypoxic versus normoxic conditions. Competition data from different oxygen concentrations were consistent using PAO1 and clinical isolates even though differences in the level of competition were observed. PAO1 strains carrying mutations in virulence factors known to contribute to S. aureus competition (pyocyanin/phzS, elastase/lasA and lasI quorum sensing/lasI) were used to determine which genes play a role in the differential growth inhibition. The lasA and lasI mutants competed less effectively with S. aureus regardless of the oxygen level present in the culture compared to the isogenic wild type strain. These results are consistent with previous findings that elastase and lasI quorum sensing play a role in competitive behavior of P. aeruginosa and S. aureus. Interestingly, the phzS mutant competed less effectively in hypoxic conditions suggesting that pyocyanin may be important in microaerophilic conditions. This study demonstrates that oxygen plays a role in competition between P. aeruginosa and S. aureus and contributes to understanding CF environmental factors that may regulate microbial community dynamics important for disease progression with potential for development of therapeutic avenues.
ContributorsLedesma Barrera, Maria Alexandra (Author) / Nickerson, Cheryl A. (Thesis advisor) / Reyes del Valle, Jorge (Committee member) / Clark-Curtiss, Josephine (Committee member) / Stout, Valerie (Committee member) / Ott, C M (Committee member) / Arizona State University (Publisher)
Created2014
Description
Intrinsic antibiotic resistance is of growing concern in modern medical treatment. The primary action of multidrug resistant strains is through over-expression of active transporters which recognize a broad range of antibiotics. In Escherichia coli, the TolC-AcrAB complex has become a model system to understand antibiotic efflux. While the structures of these three proteins (and many of their homologs) are known, the exact mechanisms of interaction are still poorly understood. By mutational analysis of the TolC turn 1 residues, a drug hypersensitive mutant has been identified which is defective in functional interactions with AcrA and AcrB. Antibiotic resistant revertants carry alterations in both TolC and AcrA act by stabilizing functional complex assembly and opening of the TolC aperture, as monitored by stability of a labile TolC mutant and sensitivity to vancomycin, respectively. Alterations in the AcrB periplasmic hairpin loops lead to a similar antibiotic hypersensitivity phenotype and destabilized complex assembly. Likewise, alterations in TolC which constitutively open the aperture suppress this antibiotic sensitivity. Suppressor alterations in AcrA and AcrB partially restore antibiotic resistance by mediating stability of the complex. The AcrA suppressor alterations isolated in these studies map to the three crystallized domains and it is concluded they alter the AcrA conformation such that it is permanently fixed in an active state, which wild type only transiently goes through when activated by AcrB. Through this genetic evidence, a direct interaction between TolC and AcrB which is stabilized by AcrA has been proposed. In addition to stabilizing the interactions between TolC and AcrB, AcrA is also responsible for triggering opening of the TolC aperture by mediating energy flow from AcrB to TolC. By permanently altering the conformation of AcrA, suppressor mutants allow defective TolC or AcrB mutants to regain functional interactions lost by the initial mutations. The data provide the genetic proof for direct interaction between AcrB and that AcrA mediated opening of TolC requires AcrB as a scaffold.
ContributorsWeeks, Jon William (Author) / Misra, Rajeev (Thesis advisor) / Stout, Valerie (Committee member) / Shi, Yixin (Committee member) / Clark-Curtiss, Josephine (Committee member) / Arizona State University (Publisher)
Created2012
Description
First-semester student retention is a constant priority for undergraduate institutions. The transition to the collegiate level, and to a new scholastic program and format, is frequently challenging academically and socially—for this reason, many first-semester course schedules for incoming freshman undergraduates feature an introductory seminar to ease transition to an undergraduate lifestyle. Arizona State University features a required “Careers in the Life Sciences” course for its first-semester School of Life Sciences students, which has had tractable results in first semester student retention and academic success. Here, we evaluate a component of the seminar, the peer-mentorship program, for its efficacy in students’ first semester experience. Analysis of self-reports from 168 first-semester “mentees” and their 25 mentors indicates frequency of mentee-mentor contact was the best indicator of a higher first semester GPA, comfort with academic resources and study habits, and desire to engage in extracurricular activities and internships. These data indicate that access to a mentor who actively engages and verbally connects with their mentees is a valuable component of first-semester student academic integration and retention.
ContributorsMathews, Ian T. (Author) / Capco, David (Thesis director) / Clark-Curtiss, Josephine (Committee member) / Harrell, Carita (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
The study of bacterial resistance to antimicrobial peptides (AMPs) is a significant area of interest as these peptides have the potential to be developed into alternative drug therapies to combat microbial pathogens. AMPs represent a class of host-mediated factors that function to prevent microbial infection of their host and serve as a first line of defense. To date, over 1,000 AMPs of various natures have been predicted or experimentally characterized. Their potent bactericidal activities and broad-based target repertoire make them a promising next-generation pharmaceutical therapy to combat bacterial pathogens. It is important to understand the molecular mechanisms, both genetic and physiological, that bacteria employ to circumvent the bactericidal activities of AMPs. These understandings will allow researchers to overcome challenges posed with the development of new drug therapies; as well as identify, at a fundamental level, how bacteria are able to adapt and survive within varied host environments. Here, results are presented from the first reported large scale, systematic screen in which the Keio collection of ~4,000 Escherichia coli deletion mutants were challenged against physiologically significant AMPs to identify genes required for resistance. Less than 3% of the total number of genes on the E. coli chromosome was determined to contribute to bacterial resistance to at least one AMP analyzed in the screen. Further, the screen implicated a single cellular component (enterobacterial common antigen, ECA) and a single transporter system (twin-arginine transporter, Tat) as being required for resistance to each AMP class. Using antimicrobial resistance as a tool to identify novel genetic mechanisms, subsequent analyses were able to identify a two-component system, CpxR/CpxA, as a global regulator in bacterial resistance to AMPs. Multiple previously characterized CpxR/A members, as well as members found in this study, were identified in the screen. Notably, CpxR/A was found to transcriptionally regulate the gene cluster responsible for the biosynthesis of the ECA. Thus, a novel genetic mechanism was uncovered that directly correlates with a physiologically significant cellular component that appears to globally contribute to bacterial resistance to AMPs.
ContributorsWeatherspoon-Griffin, Natasha (Author) / Shi, Yixin (Thesis advisor) / Clark-Curtiss, Josephine (Committee member) / Misra, Rajeev (Committee member) / Nickerson, Cheryl (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2013