Life Sciences Commons^™

T-Cell Responses Targeting Hiv Nef Uniquely Correlate With Infected Cell Frequencies After Long-Term Antiretroviral Therapy., Allison S Thomas, Kimberley L Jones, Rajesh T Gandhi, Deborah K Mcmahon, Joshua C Cyktor, Dora Chan, Szu-Han Huang, Ronald Truong, Alberto Bosque, Amanda B Macedo, Colin Kovacs, Erika Benko, Joseph J Eron, Ronald J Bosch, Christina M Lalama, Samuel Simmens, Bruce D Walker, John W Mellors, R Brad Jones

Microbiology, Immunology, and Tropical Medicine Faculty Publications

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of …

Anti-Herv-K (Hml-2) Capsid Antibody Responses In Hiv Elite Controllers., Miguel De Mulder, Devi Sengupta, Steven G Deeks, Jeffrey N Martin, Christopher D Pilcher, Frederick M Hecht, Jonah B Sacha, Douglas F Nixon, Henri-Alexandre Michaud

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and while the majority are transcriptionally silent, the most recently integrated HERV, HERV-K (HML-2), remains active. During HIV infection, HERV-K (HML-2) specific mRNA transcripts and viral proteins can be detected. In this study, we aimed to understand the antibody response against HERV-K (HML-2) Gag in the context of HIV-1 infection.

Results

We developed an ELISA assay using either recombinant protein or 164 redundant “15mer” HERV-K (HML-2) Gag peptides to test sera for antibody reactivity. We identified a total of eight potential HERV-K (HML-2) Gag immunogenic domains: two on …

Parasite Microbiome Project: Systematic Investigation Of Microbiome Dynamics Within And Across Parasite-Host Interactions., Nolwenn M Dheilly, Daniel Bolnick, Seth Bordenstein, Paul J Brindley, Cédric Figuères, Edward C Holmes, Joaquín Martínez Martínez, Anna J Phillips, Robert Poulin, Karyna Rosario

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Understanding how microbiomes affect host resistance, parasite virulence, and parasite-associated diseases requires a collaborative effort between parasitologists, microbial ecologists, virologists, and immunologists. We hereby propose the Parasite Microbiome Project to bring together researchers with complementary expertise and to study the role of microbes in host-parasite interactions. Data from the Parasite Microbiome Project will help identify the mechanisms driving microbiome variation in parasites and infected hosts and how that variation is associated with the ecology and evolution of parasites and their disease outcomes. This is a call to arms to prevent fragmented research endeavors, encourage best practices in experimental approaches, and …

Helminth Infection-Induced Malignancy., Paul J Brindley, Alex Loukas

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Infectious diseases cause more than 20% of cancers in the developing world [1]. About a dozen pathogens including Epstein-Barr virus and human T cell lymphocytotropic virus 1 are among the well-known examples. In addition, infection with several trematodes, which are eukaryotes, can cause malignancy. The International Agency for Research on Cancer categorizes infection with the fish-borne trematodes Opisthorchis viverrini and Clonorchis sinensis and the blood fluke Schistosoma haematobium as Group 1 biological carcinogens [2]. In addition to parasitism directly damaging development, health, and prosperity of infected populations, infection with these helminths leads to cholangiocarcinoma (CCA) (bile duct cancer) and squamous …

Subsets Of Inflammatory Cytokine Gene Polymorphisms Are Associated With Risk Of Carcinogenic Liver Fluke Opisthorchis Viverrini-Associated Advanced Periductal Fibrosis And Cholangiocarcinoma., Arpa Surapaitoon, Sutas Suttiprapa, Eimorn Mairiang, Narong Khuntikeo, Chawalit Pairojkul, Jeffrey Bethony, Paul J Brindley, Banchob Sripa

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF−, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, …

Whole Genome Analysis Of A Schistosomiasis-Transmitting Freshwater Snail., Coen M Adema, Ladeana W Hillier, Catherine S Jones, Eric S Loker, Matty Knight, Patrick Minx, +Several Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify …

Safety And Immunogenicity Of The Na-Gst-1 Hookworm Vaccine In Brazilian And American Adults., David J Diemert, Janaína Freire, Vanderson Valente, Carlos Geraldo Fraga, Frederico Talles, Shannon Grahek, Doreen Campbell, Amar Jariwala, Maria Victoria Periago, Martin Enk, Maria Flávia Gazzinelli, Maria Elena Bottazzi, Robert Hamilton, Jill Brelsford, Anna Yakovleva, Guangzhao Li, Jin Peng, Rodrigo Correa-Oliveira, Peter Hotez, Jeffrey Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant …

Dynamic Transcriptomes Identify Biogenic Amines And Insect-Like Hormonal Regulation For Mediating Reproduction In Schistosoma Japonicum., Jipeng Wang, Ying Yu, Haimo Shen, Tao Qing, Yuanting Zheng, Qing Li, Xiaojin Mo, Shuqi Wang, Nana Li, Riyi Chai, Bin Xu, Mu Liu, Paul J Brindley, Donald P Mcmanus, Zheng Feng, Leming Shi, Wei Hu

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Eggs produced by the mature female parasite are responsible for the pathogenesis and transmission of schistosomiasis. Female schistosomes rely on a unique male-induced strategy to accomplish reproductive development, a process that is incompletely understood. Here we map detailed transcriptomic profiles of male and female Schistosoma japonicum across eight time points throughout the sexual developmental process from pairing to maturation. The dynamic gene expression pattern data reveal clear sex-related characteristics, indicative of an unambiguous functional division between males and females during their interplay. Cluster analysis, in situ hybridization and RNAi assays indicate that males likely use biogenic amine neurotransmitters through the …

The Role Of Estradiol Metabolism In Urogenital Schistosomiasis-Induced Bladder Cancer, Nuno Vale, Maria Gouveia, Gabriel Rinaldi, Julio Santos, Lucio Lara Santos, Paul J. Brindley, Jose Correia Da Costa

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Urogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasisinduced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these …

Elevated Prevalence Of Helicobacter Species And Virulence Factors In Opisthorchiasis And Associated Hepatobiliary Disease., Raksawan Deenonpoe, Eimorn Mairiang, Pisaln Mairiang, Chawalit Pairojkul, Yaovalux Chamgramol, Gabriel Rinaldi, Alex Loukas, Paul J. Brindley, Banchob Sripa

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Recent reports suggest that Opisthorchis viverrini serves as a reservoir of Helicobacter and implicate Helicobacter in pathogenesis of opisthorchiasis-associated cholangiocarcinoma (CCA). Here, 553 age-sex matched cases and controls, 293 and 260 positive and negative for liver fluke O. viverrini eggs, of residents in Northeastern Thailand were investigated for associations among infection with liver fluke, Helicobacter and hepatobiliary fibrosis. The prevalence of H. pylori infection was higher in O. viverrini-infected than uninfected participants. H. pylori bacterial load correlated positively with intensity of O. viverrini infection, and participants with opisthorchiasis exhibited higher frequency of virulent cagA-positive H. pylori than those free of …

Advances In Neglected Tropical Disease Vaccines: Developing Relative Potency And Functional Assays For The Na-Gst-1/Alhydrogel Hookworm Vaccine., Jill B. Brelsford, Jordan L Plieskatt, Anna Yakovleva, Amar Jariwala, Brian P Keegan, Jin Peng, Pengjun Xia, Guangzhao Li, Doreen Campbell, Maria Victoria Periago, Rodrigo Correa-Oliveira, Maria Elena Bottazzi, Peter J. Hotez, David Diemert, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

A new generation of vaccines for the neglected tropical diseases (NTDs) have now advanced into clinical development, with the Na-GST-1/Alhydrogel Hookworm Vaccine already being tested in Phase 1 studies in healthy adults. The current manuscript focuses on the often overlooked critical aspects of NTD vaccine product development, more specifically, vaccine stability testing programs. A key measure of vaccine stability testing is "relative potency" or the immunogenicity of the vaccine during storage. As with most NTD vaccines, the Na-GST-1/Alhydrogel Hookworm Vaccine was not developed by attenuation or inactivation of the pathogen (Necator americanus), so conventional methods for measuring relative potency are …

Parasite Infection, Carcinogenesis And Human Malignancy., Hoang Van Tong, Paul J. Brindley, Christian G Meyer, Thirumalaisamy P Velavan

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in …

Yeast Help Identify Cytopathic Factors Of Zika Virus, Michael I. Bukrinsky

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Accumulating evidence implicates Zika virus (ZIKV) in pathogenesis of microcephaly in newborns and Guillain-Barré syndrome in adults. However, it remains unclear which viral proteins are responsible for these effects and what are the underlying mechanisms of their pathogenic activity. A recent paper by Drs. Zhao and Gallo, and their colleagues at University of Maryland in Baltimore used fission yeast for genome-wide analysis of ZIKV proteins. They demonstrated cytopathogenic activity for seven ZIKV proteins, anaC, C, prM, M, E, NS2B and NS4A. This activity was shown to be dependent on oxidative stress, and for NS4A they demonstrated involvement of the TOR …

A Comparison Of The Quality Of Informed Consent For Clinical Trials Of An Experimental Hookworm Vaccine Conducted In Developed And Developing Countries., David J. Diemert, Lucas Lobato, Ashley Styczynski, Maria Zumer, Amanda Soares, Maria Flávia Gazzinelli

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Informed consent is one of the principal ethical requirements of conducting clinical research, regardless of the study setting. Breaches in the quality of the informed consent process are frequently described in reference to clinical trials conducted in developing countries, due to low levels of formal education, a lack of familiarity with biomedical research, and limited access to health services in these countries. However, few studies have directly compared the quality of the informed consent process in developed and developing countries using the same tool and in similar clinical trials. This study was conducted to compare the quality of the informed …

Identification Of Candidate Infection Genes From The Model Entomopathogenic Nematode Heterorhabditis Bacteriophora., Jonathan Vadnal, Ramesh Ratnappan, Melissa Keaney, Eric Kenney, Ioannis Eleftherianos, Damien O'Halloran, John M. Hawdon

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: Despite important progress in the field of innate immunity, our understanding of host immune responses to parasitic nematode infections lags behind that of responses to microbes. A limiting factor has been the obligate requirement for a vertebrate host which has hindered investigation of the parasitic nematode infective process. The nematode parasite Heterorhabditis bacteriophora offers great potential as a model to genetically dissect the process of infection. With its mutualistic Photorhabdus luminescens bacteria, H. bacteriophora invades multiple species of insects, which it kills and exploits as a food source for the development of several nematode generations. The ability to culture …

Genomes Of Fasciola Hepatica From The Americas Reveal Colonization With Neorickettsia Endobacteria Related To The Agents Of Potomac Horse And Human Sennetsu Fevers., Samantha N Mcnulty, Jose F Tort, Gabriel Rinaldi, Bruce A Rosa, Victoria H. Mann, Patricia S. Latham, Paul J. Brindley, +Several Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Food borne trematodes (FBTs) are an assemblage of platyhelminth parasites transmitted through the food chain, four of which are recognized as neglected tropical diseases (NTDs). Fascioliasis stands out among the other NTDs due to its broad and significant impact on both human and animal health, as Fasciola sp., are also considered major pathogens of domesticated ruminants. Here we present a reference genome sequence of the common liver fluke, Fasciola hepatica isolated from sheep, complementing previously reported isolate from cattle. A total of 14,642 genes were predicted from the 1.14 GB genome of the liver fluke. Comparative genomics indicated that F. …

Fit For Genomic And Proteomic Purposes: Sampling The Fitness Of Nucleic Acid And Protein Derivatives From Formalin Fixed Paraffin Embedded Tissue., Anna Yakovleva, Jordan L Plieskatt, Sarah Jensen, Razan Humeida, Jonathan Lang, Guangzhao Li, Paige Bracci, Sylvia Silver, Jeffrey Michael Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered “unfit” for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by …

Schistosoma Mansoni Reinfection: Analysis Of Risk Factors By Classification And Regression Tree (Cart) Modeling., Andréa Gazzinelli, Roberta Oliveira-Prado, Leonardo Ferreira Matoso, Bráulio M Veloso, Gisele Andrade, Helmut Kloos, Jeffrey M Bethony, Renato M Assunção, Rodrigo Correa-Oliveira

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Praziquantel (PZQ) is an effective chemotherapy for schistosomiasis mansoni and a mainstay for its control and potential elimination. However, it does not prevent against reinfection, which can occur rapidly in areas with active transmission. A guide to ranking the risk factors for Schistosoma mansoni reinfection would greatly contribute to prioritizing resources and focusing prevention and control measures to prevent rapid reinfection. The objective of the current study was to explore the relationship among the socioeconomic, demographic, and epidemiological factors that can influence reinfection by S. mansoni one year after successful treatment with PZQ in school-aged children in Northeastern Minas …

Ancylostoma Ceylanicum Infective Third-Stage Larvae Are Activated By Co-Culture With Ht-29-Mtx Intestinal Epithelial Cells, Caitlin Feather, John M. Hawdon, John March

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Human hookworm larvae arrest development until they enter an appropriate host. This makes it difficult to access the larvae for studying larval development or host-parasite interactions. While there are in vivo and in vitro animal models of human hookworm infection, there is currently no human, in vitro model. While animal models have provided much insight into hookworm biology, there are limitations to how closely this can replicate human infection. Therefore, we have developed a human, in vitro model of the initial phase of hookworm infection using intestinal epithelial cell culture.

Results

Co-culture of the human hookworm Ancylostoma ceylanicum with …