News Article | February 15, 2017
Global Lyme Alliance (GLA), the leading private nonprofit dedicated to conquering Lyme disease through research and education, announced today that it is awarding a record total of approximately $2 million in grants to top researchers at leading academic and medical research institutions across the U.S. These recipients of GLA’s 2016-2017 grant cycle are working on a wide array of projects to develop a greater understanding of the disease, improve diagnostics, treatment and prevention. “For years our organization has led the Lyme community in identifying and backing innovative research, so we’re especially proud and excited that we’ve doubled our research funding since last year,” said Scott Santarella, GLA’s CEO. “The more funds we raise, the faster we can solve the mystery of Lyme disease and bring about change for millions who suffer from tick-borne illnesses.” “GLA prides itself for providing the vision to drive the research agenda, initiating the teaming of top researchers to collaborate on projects and evaluating research proposals received globally. We continue to provide the leadership in scientific research that others follow and build upon,” said GLA Chairman and Scientific Advisory Board member Robert Kobre. In announcing the new grants, Santarella noted that GLA had received the most grant applications in its history—$4.3 million in funding requests. “While we were pleased to receive so many quality grant applications this year, such a profusion underscores the fact that there are far more talented scientists eager to focus on Lyme disease than there is funding to support them,” Santarella said. He noted, for example, that $25 million is allocated by the National Institutes of Health annually for Lyme research, which infects more than 330,000 in the U.S. each year, compared with $42 million for the mosquito-transmitted West Nile virus, which affected about 2,000 in the U.S. last year. “Federal funding for Lyme research is miniscule, yet the Lyme threat keeps growing,” he said. “This speaks to GLA’s importance in working with private donors to fill the void and drive advancements in the field.” GLA’s 2016-2017 grants were awarded to researchers at the following institutions: Columbia University; Cornell University; Institute for Systems Biology; Johns Hopkins University; Northeastern University; State University of New York-Stony Brook; Tulane National Primate Research Center; University of California-Davis; University of California-San Francisco; University of Illinois-Chicago; University of North Dakota; University of Pennsylvania, and University of Texas-San Antonio. “As the number of Lyme and tick-borne disease cases continues to grow, there is a tremendous impetus to keep the science moving forward,” said Mayla Hsu, GLA’s Director of Research and Science. “GLA is proud to support the important research being conducted by some of the best and brightest men and women in the field today.” GLA’s research portfolio includes a broad range of projects such as persistence of infection after antibiotic treatment and the development of new diagnostics. Studies focus on microbial physiology; genetic work to determine how the bacteria that causes Lyme survives in a host; efficacy of different modes of antibiotic therapy, and why some people continue to have symptoms despite the seeming absence of bacteria. Researchers were selected following a rigorous evaluation process using guidelines established by the National Institutes of Health (NIH). Each proposal was evaluated by Grant Review Committee members of GLA’s Scientific Advisory Board and met the same scientific standards that NIH applies to its own grant review process. The resulting 2016-2017 grant awards represent projects judged to have exceptional prospects of delivering measurable advances. Lyme disease is the most common vector-borne disease in the U.S. There are no accurate diagnostic tests for the disease, no tests to prove that Lyme bacteria are eradicated or that an individual is cured. Some 20 percent of individuals with Lyme end up with long-term health problems. _______________________________________________________________________________________________________________ ABOUT GLOBAL LYME ALLIANCE Global Lyme Alliance is a leading private nonprofit dedicated to conquering Lyme and other tick-borne diseases through research and education. The 501(c)(3) nonprofit is headquartered in Greenwich, CT. For more information go to GLA.org.
Serra-Moreno R.,Harvard University |
Jia B.,Harvard University |
Breed M.,Tulane National Primate Research Center |
Alvarez X.,Tulane National Primate Research Center |
Evans D.T.,Harvard University
Cell Host and Microbe | Year: 2011
Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. Whereas HIV-1 Vpu and HIV-2 Env counteract human tetherin, most SIVs use Nef to antagonize the tetherin proteins of their nonhuman primate hosts. Here, we show that compensatory changes in the cytoplasmic domain of SIV gp41, acquired by a nef-deleted virus that regained a pathogenic phenotype in infected rhesus macaques, restore resistance to tetherin. These changes facilitate virus release in the presence of rhesus tetherin, but not human tetherin, and enhance virus replication in interferon-treated primary lymphocytes. The substitutions in gp41 result in a selective physical association with rhesus tetherin, and the internalization and sequestration of rhesus tetherin by a mechanism that depends on a conserved endocytosis motif in gp41. These results are consistent with HIV-2 Env antagonism of human tetherin and suggest that the ability to oppose tetherin is important for lentiviral pathogenesis. © 2011 Elsevier Inc.
Yu J.M.,Tulane National Primate Research Center
Methods in molecular biology (Clifton, N.J.) | Year: 2011
While adult stem cells can be induced to transdifferentiate into multiple lineages of cells or tissues, their plasticity and utility for human therapy remains controversial. In this chapter, we describe methods for the transdifferentiation of human adipose tissue-derived stem cells (ASCs) along neural lineages using in vitro and in vivo systems. The in vitro neural differentiation of ASCs has been reported by several groups using serum-free cytokine induction, butylated hydroxyanisole (BHA) chemical induction, and neurosphere formation in combination with the cytokines, such as brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF). For in vivo neurogenic induction, ASCs are treated with BDNF and bFGF to form neurospheres in vitro and then delivered directly to the brain. In this chapter, several detailed protocols for the effective neurogenic induction of ASCs in vitro and in vivo are described. The protocols described herein can be applied to further molecular and mechanistic studies of neurogenic induction and differentiation of ASCs. In addition, these methods can be useful for differentiating ASCs for therapeutic intervention in central nervous system disorders.
Bhaskaran M.,Tulane National Primate Research Center |
Mohan M.,Tulane National Primate Research Center
Veterinary Pathology | Year: 2014
The discovery of microRNAs (miRNAs) in 1993 followed by developments and discoveries in small RNA biology have redefined the biological landscape by significantly altering the longstanding dogmas that defined gene regulation. These small RNAs play a significant role in modulation of an array of physiological and pathological processes ranging from embryonic development to neoplastic progression. Unique miRNA signatures of various inherited, metabolic, infectious, and neoplastic diseases have added a new dimension to the studies that look at their pathogenesis and highlight their potential to be reliable biomarkers. Also, altering miRNA functionality and the development of novel in vivo delivery systems to achieve targeted modulation of specific miRNA function are being actively pursued as novel approaches for therapeutic intervention in many diseases. Here we review the current body of knowledge on the role of miRNAs in development and disease and discuss future implications. © The Author(s) 2013.
Embers M.E.,Tulane National Primate Research Center |
Narasimhan S.,Yale University
Frontiers in Cellular and Infection Microbiology | Year: 2013
Lyme borreliosis is a zoonotic disease caused by Borrelia burgdorferi sensu lato bacteria transmitted to humans and domestic animals by the bite of an Ixodes spp. tick (deer tick). Despite improvements in diagnostic tests and public awareness of Lyme disease, the reported cases have increased over the past decade to approximately 30,000 per year. Limitations and failed public acceptance of a human vaccine, comprised of the outer surface A (OspA) lipoprotein of B. burgdorferi, led to its demise, yet current research has opened doors to new strategies for protection against Lyme disease. In this review we discuss the enzootic cycle of B. burgdorferi, and the unique opportunities it poses to block infection or transmission at different levels. We present the correlates of protection for this infectious disease, the pros and cons of past vaccination strategies, and new paradigms for future vaccine design that would include elements of both the vector and the pathogen. © 2013 Embers and Narasimhan.
Parthasarathy G.,Tulane National Primate Research Center |
Philipp M.T.,Tulane National Primate Research Center
Apoptosis | Year: 2014
Lyme neuroborreliosis (LNB) affects both the central and peripheral nervous systems. In a rhesus macaque model of LNB we had previously shown that brains of rhesus macaques inoculated with Borrelia burgdorferi release inflammatory mediators, and undergo oligodendrocyte and neuronal cell death. In vitro analysis of this phenomenon indicated that while B. burgdorferi can induce inflammation and apoptosis of oligodendrocytes per se, microglia are required for neuronal apoptosis. We hypothesized that the inflammatory milieu elicited by the bacterium in microglia or oligodendrocytes contributes to the apoptosis of neurons and glial cells, respectively, and that downstream signaling events in NFkB and/or MAPK pathways play a role in these phenotypes. To test these hypotheses in oligodendrocytes, several pathway inhibitors were used to determine their effect on inflammation and apoptosis, as induced by B. burgdorferi. In a human oligodendrocyte cell line (MO3.13), inhibition of the ERK pathway in the presence of B. burgdorferi markedly reduced inflammation, followed by the JNK, p38 and NFkB pathway inhibition. In addition to eliciting inflammation, B. burgdorferi also increased total p53 protein levels, and suppression of the ERK pathway mitigated this effect. While inhibition of p53 had a minimal effect in reducing inflammation, suppression of the ERK pathway or p53 reduced apoptosis as measured by active caspase-3 activity and the TUNEL assay. A similar result was seen in primary human oligodendrocytes wherein suppression of ERK or p53 reduced apoptosis. It is possible that inflammation and apoptosis in oligodendrocytes are divergent arms of MAPK pathways, particularly the MEK/ ERK pathway.© Springer Science+Business Media New York 2013.
Burdo T.H.,Boston College |
Lackner A.,Tulane National Primate Research Center |
Williams K.C.,Boston College
Immunological Reviews | Year: 2013
Neurological sequelae of human immunodeficiency virus (HIV) infection have been and remain a significant problem. Monocytes and macrophages in humans and monkeys are susceptible to infection by HIV and simian immunodeficiency virus (SIV), and are considered to be a main mechanism by which the central nervous system (CNS) is infected. Within the infected CNS, perivascular macrophages and, in some cases, parenchymal microglia are infected as are multinucleated giant cells when present. While neurons are not themselves directly infected, neuronal damage occurs within the infected CNS. Despite the success of antiretroviral therapy (ART) in limiting virus in plasma to non-detectable levels, neurological deficits persist. This review discusses the continued neurological dysfunctions that persist in the era of ART, focusing on the roles of monocyte and macrophage as targets of continued viral infection and as agents of pathogenesis in what appears to be emergent macrophage-mediated disease resulting from long-term HIV infection of the host. Data discussed include the biology of monocyte/macrophage activation with HIV and SIV infection, traffic of cells into and out of the CNS with infection, macrophage-associated biomarkers of CNS and cardiac disease, the role of antiretroviral therapy on these cells and CNS disease, as well as the need for effective adjunctive therapies targeting monocytes and macrophages. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Mohan M.,Tulane National Primate Research Center
PloS one | Year: 2012
The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4(+) T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression. To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma) separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (±1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNγ3 (anti-HIV/viral), activation induced cytidine deaminase (B-cell function) and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (CD38, semaphorin7A, CD109), B-cell dysfunction (CD70), intestinal microbial translocation (Lipopolysaccharide binding protein) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, CD93, NFATc1 (T-cells), TLR8, IL8, CCL18, DECTIN1 (macrophages), HLA-DOA and GPR183 (B-cells) at 90d PI suggests further deterioration of overall immune function. The reported transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and provide new opportunity for future investigation.
Gilbert M.H.,Tulane National Primate Research Center |
Baker K.C.,Tulane National Primate Research Center
Journal of Medical Primatology | Year: 2011
Background The purpose of this study was to test whether long-term pair housing of male rhesus macaques ameliorated negative responses to stressful events that can occur in the course of routine husbandry or research procedures. Methods Twelve singly housed individuals were videotaped during two potentially stressful events before and after social introduction into pairs. During each stressor, abnormal behavior and anxiety-related behavior were quantified from videotape. Results When visually exposed to the restraint and anesthesia of other monkeys, subjects showed significantly reduced frequencies of abnormal behavior when pair-housed in comparison to their reactions when housed singly. Noisy and disruptive conversation between technicians standing immediately in front of the subjects' cage did not elicit the same reduction in abnormal behavior. Neither test showed a significant difference across housing settings for anxiety-related behaviors. Conclusions These findings suggest that pair housing buffers adult male rhesus macaques against common stressors in the laboratory setting. © 2010 John Wiley & Sons A/S.
Didier E.S.,Tulane National Primate Research Center |
Weiss L.M.,Yeshiva University
Current Opinion in Infectious Diseases | Year: 2011
Purpose of Review: Microsporidia have emerged as causes of opportunistic infections associated with diarrhea and wasting in AIDS patients. This review describes recent reports of microsporidiosis in HIV-infected individuals and the growing awareness of microsporidiosis in non-HIV-infected populations. Recent Findings: Microsporidia were only rarely recognized as causes of disease in humans until the AIDS pandemic. Implementation of combination antiretroviral therapy (cART) to curtail HIV replication and restore immune status drastically reduced the occurrence of opportunistic infections, including those due to microsporidia, in HIV-infected individuals. In developing countries where cART is not always accessible, microsporidiosis continues to be problematic. Improvement of diagnostic methods over the previous 25 years led to identification of several new species of microsporidia, many of which disseminate from enteric to systemic sites of infection and contribute to some unexpected lesions. Among non-HIV-infected but immune-suppressed individuals, microsporidia have infected organ transplant recipients, children, the elderly, and patients with malignant disease and diabetes. In otherwise healthy immune-competent HIV seronegative populations, self-limiting diarrhea occurred in travelers and as a result of a foodborne outbreak associated with contaminated cucumbers. Keratitis due to microsporidiosis has become problematic and a recent longitudinal evaluation demonstrated that non-HIV-infected individuals seropositive for microsporidia who had no clinical signs continued to intermittently shed organisms in feces and urine. Summary: Greater awareness and implementation of better diagnostic methods are demonstrating that microsporidia contribute to a wide range of clinical syndromes in HIV-infected and non-HIV-infected people. As such, microsporidia should be considered in differential diagnoses if no other cause can be defined. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.