Medical Microbiology Commons^™

Iron-Dependent Gene Expression In Actinomyces Oris, Matthew P. Mulé, David Giacalone, Kayla Lawlor, Alexa Golden, Caroline Cook, Thomas Lott, Elizabeth Aksten, George A. O'Toole, Lori J. Bergeron

Dartmouth Scholarship

Actinomyces oris is a Gram-positive bacterium that has been associated with healthy and diseased sites in the human oral cavity. Most pathogenic bacteria require iron to survive, and in order to acquire iron in the relatively iron-scarce oral cavity A. oris has been shown to produce iron-binding molecules known as siderophores. The genes encoding these siderophores and transporters are thought to be regulated by the amount of iron in the growth medium and by the metal-dependent repressor, AmdR, which we showed previously binds to the promoter of proposed iron-regulated genes.

Characterization Of The Paracoccidioides Hypoxia Response Reveals New Insights Into Pathogenesis Mechanisms Of This Important Human Pathogenic Fungus, Patrícia De Sousa Lima, Dawoon Chung, Alexandre Melo Bailão, Robert A. Cramer, Célia Maria De Almeida Soares

Dartmouth Scholarship

Background: Hypoxic microenvironments are generated during fungal infection. It has been described that to survive in the human host, fungi must also tolerate and overcome in vivo microenvironmental stress conditions including low oxygen tension; however nothing is known how Paracoccidioides species respond to hypoxia. The genus Paracoccidioides comprises human thermal dimorphic fungi and are causative agents of paracoccidioidomycosis (PCM), an important mycosis in Latin America.

Viability Of Developmental Stages Of Schistosoma Mansoni Quantified With Xcelligence Worm Real-Time Motility Assay (Xworm)., Gabriel Rinaldi, Alex Loukas, Paul J. Brindley, Jeff T. Irelan, Michael J. Smout

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Infection with helminth parasites causes morbidity and mortality in billions of people and livestock worldwide. Where anthelmintic drugs are available, drug resistance is a major problem in livestock parasites, and a looming threat to public health. Monitoring the efficacy of these medicines and screening for new drugs has been hindered by the lack of objective, high-throughput approaches. Several cell monitoring technologies have been adapted for parasitic worms, including video-, fluorescence-, metabolism enzyme- and impedance-based tools that minimize the screening bottleneck. Using the xCELLigence impedance-based system we previously developed a motility-viability assay that is applicable for a range of helminth parasites. …

Functional Analysis Of The Unique Cytochrome P450 Of The Liver Fluke Opisthorchis Felineus., Mariya Y. Pakharukova, Valentin A. Vavilin, Banchob Sripa, Thewarach Laha, Paul J. Brindley, Viatcheslav A. Mordvinov

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium) are considered …

Role Of B Cell Receptor Signaling In Il-10 Production By Normal And Malignant B-1 Cells., Sara S Alhakeem, Vishal J Sindhava, Mary K Mckenna, Beth W Gachuki, John C Byrd, Natarajan Muthusamy, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B-1 cells are considered innate immune cells, which produce the majority of natural antibodies. B-1 cell responses to B cell receptor (BCR) and Toll-like receptor ligation are tightly regulated owing to the cross-reactivity to self-antigens. CD5 has been shown to play a major role in downregulation of BCR responses in B-1 cells. Here, we provide evidence for another mechanism by which BCR response is regulated in B-1 cells. B-1 cells, as well as their malignant counterpart, B cell chronic lymphocytic leukemia (B-CLL) cells, produce interleukin-10 (IL-10) constitutively. IL-10 secretion by normal B-1 cells downregulates their proliferation responses to BCR ligation. …

Post Operative Fungal Endopthalmitis Due To Geotrichum Candidum, Thein Myint, Matthew J. Dykhuizen, Carolyn H. Mcdonald, Julie A. Ribes

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Geotrichum species have been rarely reported as the cause of sepsis, disseminated infection in immunosuppressed patients. The patient we describe developed indolent endophthalmitis four months after her routine right eye cataract surgery. The intraoperative sample from right vitreous fluid grew Geotrichum candidum. The patient underwent vitrectomy, artificial lens explantation and intravitreal injection of amphotericin B followed by oral voriconazole. Despite these interventions, she underwent enucleation. This is the first published case of Geotrichum candidum endophthalmitis.

Immunomodulation Of Myeloid-Derived Suppressor Cells By Particulate B-Glucan In Cancer., Sabrin Husein Albeituni

Electronic Theses and Dissertations

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we investigated the effect of dectin-1 stimulation by yeast-derived particulate β-glucan in MDSC function and differentiation in cancer. In vivo treatment of mice bearing lewis lung carcinoma and mammary cell carcinoma with particulate β-glucan decreased tumor weight and splenomegaly, and reduced the accumulation of polymorphonuclear-MDSC (PMN-MDSC) but not monocytic-MDSC (M-MDSC) in the spleen and tumor. In addition, particulate β-glucan differentially modulated the function of different MDSC subsets; it enhanced PMN-MDSC respiratory burst and apoptosis, and induced the differentiation of M-MDSC into …

Genetic Control Of Survival And Weight Loss During Pneumonic Burkholderia Pseudomallei (Bp) Infection, Felicia D. Emery

Theses and Dissertations (ETD)

Burkholderia pseudomallei (Bp) is a saprophytic, gram-negative aerobe and the causative agent of the disease melioidosis. Melioidosis is an infectious disease that occurs in humans and animals and is prevalent in Southeast Asia, northern Australia and other tropical areas. Transmission occurs through direct contact with the organism via ingestion, inhalation, or through open wounds and skin abrasions. Clinical presentation is extremely variable and can range from acute septicemia with bacterial dissemination to distant sites, to an isolated pulmonary infection. Treatment of melioidosis can be problematic because it is often difficult to diagnose and Bp is resistant to a diverse group …

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes To Adopt A Tumorigenic Phenotype, Sujittra Chaidayet, Javier Sotillo, Michael Smout, Cinzia Cantacessi, Malcolm Jones, Paul J. Brindley, Jeffrey M. Bethony, +9 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background. Throughout Asia there is an unprecedented link between cholangiocarcinoma and infection with the liver fluke Opisthorchis viverrini. Multiple processes including chronic inflammation and secretion of parasite proteins into the biliary epithelium drive infection towards cancer. Until now, the mechanism and effects of parasite protein entry into cholangiocytes was unknown.

Methods. Various microscopy techniques were used to identify O. viverrini extracellular vesicles (EVs) and their internalization by human cholangiocytes. Using mass spectrometry we characterised the EV proteome and associated changes in cholangiocytes after EV uptake, and detected EV proteins in bile of infected hamsters and humans. Cholangiocyte proliferation and …

Evaluation Of Cytosine Dna Methylation Of The Biomphalaria Glabratahe At Shock Protein 70 Locus After Biological And Physiological Stresses, Wannaporn Ittiprasert, Andre Miller, Matty Knight, Matt Tucker, Michael H. Hsieh

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Deoxyribonucleic (DNA) methylation is one of the widespread epigenetic modifications of genomic DNA, and has been postulated to be a predisposing influence on disease onset and infections. The ability to quantify differences in DNA methylation between the genomes of normal vs.stressed Biomphalaria glabrata would help to profile changes potentially linked to resistance to Schistosoma mansoni infection. Thus, this study sought to measure differences in cytosine DNA methylation of various B. glabrata tissues responding over time to either biological or physiological stresses (S. mansoni exposure vs. heat shock). Here, this study measured DNA methylation at the B. glabrataheat …

Lipid Metabolism In Patients Infected With Nef-Deficient Hiv-1 Strain., Hann Low, Lesley Cheng, Maria-Silvana Di Yacovo, Melissa J Churchill, Peter Meikle, Michael Bukrinsky, Andrew F Hill, Dmitri Sviridov

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: HIV protein Nef plays a key role in impairing cholesterol metabolism in both HIV infected and bystander cells. The existence of a small cohort of patients infected with Nef-deficient strain of HIV presented a unique opportunity to test the effect of Nef on lipid metabolism in a clinical setting.

METHODS: Here we report the results of a study comparing six patients infected with Nef-deficient strain of HIV (ΔNefHIV) with six treatment-naïve patients infected with wild-type HIV (WT HIV). Lipoprotein profile, size and functionality of high density lipoprotein (HDL) particles as well as lipidomic and microRNA profiles of patient plasma …

Neuroinflammatory Paradigms In Lysosomal Storage Diseases., Megan Bosch, Tammy Kielian

Journal Articles: Pathology and Microbiology

Lysosomal storage diseases (LSDs) include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to …

Tuberculosis And Cardiovascular Disease: Linking The Epidemics, Moises A. Huaman, David Henson, Eduardo Ticona, Timothy R. Sterling, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, …

Tobramycin-Treated Pseudomonas Aeruginosa Pa14 Enhances Streptococcus Constellatus 7155 Biofilm Formation In A Cystic Fibrosis Model System, Katherine E. E. Price, Amanda A. Naimie, Edward F. Griffin, Charles Bay, George A. O'Toole

Dartmouth Scholarship

Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with …

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Biochemistry and Microbiology

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …

Primary Sclerosing Epithelioid Fibrosarcoma Of Kidney With Variant Histomorphologic Features: Report Of 2 Cases And Review Of The Literature., Dilek Ertoy Baydar, Kemal Kosemehmetoglu, Oguz Aydin, Julia A. Bridge, Berrin Buyukeren, Fazil Tuncay Aki

Journal Articles: Pathology and Microbiology

The authors present two cases of primary sclerosing epithelioid fibrosarcoma (SEF) of the kidney. Both patients had a mass in the upper part of the left kidney without any primary extrarenal neoplastic lesions. Grossly, the tumors were solid masses both measuring 7.5 cm in the greatest diameter. Histologically, one of the lesions exhibited a predominantly lobular growth of round or oval small uniform epithelioid cells in variable cellularity. Circular zones of crowded tumor cells alternating with hypocellular collagenous tissue in a concentric fashion around entrapped native renal tubules were distinctive. The second case was distinctive with significant cytological atypia in …

A Tail Of Two Phages: Genomic And Functional Analysis Of Listeria Monocytogenes Phages Vb_Lmos_188 And Vb_Lmos_293 Reveal The Receptor-Binding Proteins Involved In Host Specificity, Aidan Casey, Kieran Jordan, Horst Neve, Aidan Coffey, Olivia Mcauliffe

Department of Biological Sciences Publications

The physical characteristics of bacteriophages establish them as viable candidates for downstream development of pathogen detection assays and biocontrol measures. To utilize phages for such purposes, a detailed knowledge of their host interaction mechanisms is a prerequisite. There is currently a wealth of knowledge available concerning Gram-negative phage-host interaction, but little by comparison for Gram-positive phages and Listeria phages in particular. In this research, the lytic spectrum of two recently isolated Listeria monocytogenes phages (vB_LmoS_188 and vB_LmoS_293) was determined, and the genomic basis for their observed serotype 4b/4e host-specificity was investigated using comparative genomics. The late tail genes of these …

Advances In The Diagnosis Of Human Opisthorchiasis: Development Of Opisthorchis Viverrini Antigen Detection In Urine, Chanika Worasith, Christine Kamamia, Anna Yakovleva, Kunyarat Duenngai, Chompunoot Wangboon, Jeffrey M. Bethony, +8 Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Many strategies to control opisthorchiasis have been employed in Thailand, but not in the other neighbouring countries. Specific control methods include mass drug administration (MDA) and health education to reduce raw fish consumption. These control efforts have greatly shifted the epidemiology of Opisthorchis viverrini (OV) infection over the last decade from presenting as densely concentrated "heavy" infections in single villages to widespread "light" OV infections distributed over wide geographical areas. Currently, the "gold standard" detection method for OV infection is formalin ethyl-acetate concentration technique (FECT), which has limited diagnostic sensitivity and diagnostic specificity for light OV infections, with OV …

Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing And Potentially Promotes Neoplasia., Michael J. Smout, Javier Sotillo, Thewarach Laha, Atiroch Papatpremsiri, Gabriel Rinaldi, Rafael N. Pimenta, Paul J. Brindley, +11 More

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated …

Parasite Manipulation Of The Invariant Chain And The Peptide Editor H2-Dm Affects Major Histocompatibility Complex Class Ii Antigen Presentation During Toxoplasma Gondii Infection, Louis-Philippe Leroux, Manami Nishi, Sandy El-Hage, Barbara A. Fox, David I Bzik, Florence Dzierszinsk

Dartmouth Scholarship

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, …