Recent Scientific Highlights
MeTRC Scientific Highlights
1. An effective molecular vaccine for Chagas heart disease was generated by a collaborative effort between MeTRC investigators at Meharry Medical College and the University of Alabama at Birmingham.
This molecular vaccine was discovered via a collaborative effort involving: Dr. Pius Nde (a previously funded METRC Pilot Project PI) who utilized the MeTRC/RCMI Morphology Core (directed by Dr. Shawn Goodwin), in collaboration with the MeTRC Bioinformatics Core (directed by Dr. Sidd Pratap), as well as the laboratory of Dr. Fernando Villalta, (Co-Director of METRC Pilot Projects), and Dr. Quiana Mathews from the University of Alabama at Birmingham (UAB). In addition, postdoctoral scientists at both Meharry and UAB participated. This discovery resulted in the following publication which actually made the cover page of the issue:
Farrow AL, Rachakonda G, Gu L, Krendelchtchikova V, Nde PN, Pratap S, Lima MF, Villalta F*, Matthews QL. 2014. Immunization with hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection. PLoS. Negl. Trop.Dis. 8:e3089. PMC4140675. *Corresponding Author
Furthermore, this discovery generated a picture that was selected as the “Biomedical Picture of the Day” by the Medical Research Council Clinical Sciences Centre, UK. It was photographed in the MeTRC/RCMI Morphology Core. See the following link:
Significance of the study
Chagasdisease, caused by Trypanosoma cruzi and transmitted by blood-sucking triatomine insects affects 8 million people in Latin America causing significant morbidity and mortality. Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global due to human migration, becoming a new worldwide challenge with no vaccines nor effective drug available. Currently, 2-7 million Hispanics with Chagas disease live in North America, posing significant health disparity. Insect vectors have been reported in 43 US states and the disease is now endemic to Central and South Texas and exists there as a zoonosis. As a zoonosis, Chagas disease has proven to be a serious threat to military working dogs, decreasing military operational effectiveness in San Antonio, TX. We used a novel strategy using adenovirus vectors delivering a T. cruzi neutralizing epitope expressed on the invasive forms of the parasite that is highly conserved among strains of T. cruzi to immunized animal modes of Chagas disease with success. The results from this study indicate that the vaccine induced significant protection and elicited neutralizing antibodies that blocked the infection. We conclude that the neutralizing T. cruzi epitope is an essential epitope in the development of an effective molecular vaccine for Chagas disease.
Based on the collaborative studies between both institutions, an NIAID RO1 grant entitled “Novel Adenovirus-Based Chagas Vaccines” was submitted to NIH with two PIs, one from Meharry and the other from the UAB.
2. Oral Presentation from a MeTRC investigator at two important Scientific Meetings
a) Dr. Alcendor was recently invited as a distinguished speaker and panelist to the 7th Annual Ocular Disease and Drug Discovery Conference in San Diego on March 19-20, 2015 in San Diego, CA. This conference is known to showcase novel targets and innovative technologies impacting ocular disease. He will present his latest research published in the Journal of Neuroinflammation on “Retinal Pericytes” that was original funded as a Meharry MeTRC pilot grant.
b) In addition, Dr. Alcendor’s research findings were selected for an oral presentation at the distinguished Gordon Conference (Barriers of the CNS) held in New London, New Haven on June 15-20, 2014. His presentation was entitled “Retinal pericytes of the inner blood retinal barrier and cytomegalovirus infectivity: Implications for both CMV induced retinopathy and congenital ocular disease. Dr. Alcendor was also awarded with a Travel Award to give an oral presentation at the meeting. This presentation is a collaborative effort between Meharry and Vanderbilt scientists.
3. Members of the Center for AIDS Health Disparities Research, who were supported by MeTRC Research Pilot Projects, have made significant advancements with regard to the understanding of the pathogenesis of HIV/AIDS infections.
The scientists listed below have elucidated the roles of critical HIV-1 and host molecules that participate in the process of HIV infection, the mechanisms involved in the pathogen/host interface, and the molecular basis of pathology of drug abuse in HIV infection. These studies are significant because they have identified new targets for intervention. These significant developments will facilitate new treatments for HIV/AIDS patients. Moreover, it will help with the management of HIV/AIDS in drug-abusing patients. Below, we briefly indicate their key discoveries and the publications associated with their studies.
3.1 Dr. CV Dash. Dr. Dash has significantly advanced the understanding of how cocaine and methamphetamine act in HIV infection. These studies are significant because they have implications in HIV-1 pathogenesis in drug-abusing patients. Additionally, these studies are advancing the understanding of the pathology caused by HIV- positive patients abusing drugs. The goal is to develop better strategies to manage HIV infection in drug-abusing patients. Dr. Dash’s laboratory has discovered that cocaine regulates HIV-integration in primary CD4+ T cells, induces CD4+ T cell apoptosis, and enhances HIV replication in CD4+ T cells by down regulating MiR-125b. These important discoveries resulted in the following 4 recent publications:
a) Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients. Addai AB, Pandhare J, Paromov V, Mantri CK, Pratap S, Dash C. J Leukoc Biol. 2015 Feb 17. pii: jlb.4A0714-356R. [Epub ahead of print] PMID: 25691383 (PMCID in process)
b) Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients. Pandhare J, Addai AB, Mantri CK, Hager C, Smith RM, Barnett L, Villalta F, Kalams SA, Dash C. Am J Pathol. 2014 Apr;184(4):927-36. Epub 2014 Jan 31.PMID: 24486327; PMCID: PMC3970001
c) Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression. Mantri CK, Mantri JV, Pandhare J, Dash C. Am J Pathol. 2014 Jan;184(1):92-100. PMID: 24434277; PMCID: PMC3873480
d) Cocaine enhances HIV-1 replication in CD4+ T cells by down-regulating MiR-125b. Mantri CK, Pandhare Dash J, Mantri JV, Dash C. PLoS One. 2012;7(12):e51387. PMID: 23251514; PMCID: PMC3520918
3.2 Dr. Bindong Liu. Dr. Liu’s laboratory has discovered two novel approaches which are important to inhibiting HIV replication. His group has discovered that a molecule from an oral bacteria Streptococcus cristatus, which is part of the normal oral flora, induces APOBEC3 expression to actually inhibit HIV-1 replication. This discovery is significant because the new bacterial molecule will be used as a new treatment for HIV infection. In his second important discovery, he found that an E2 protein of the GB virus Type C inhibits HIV-1 assembly through interference with HIV-1 gag plasma membrane. This discovery is significant because it has the potential to be used as a new treatment for HIV infection. In addition, he has discovered that the passage of HIV through vaginal epithelia cells is dependent on trafficking to the endocytic-recycling pathway. This study is significant because it documents that manipulating the endocytic recycling pathway is important to prevent vaginal HIV infection. These important discoveries resulted in the following 3 recent publications:
a) Heat-stable molecule derived from Streptococcus cristatus induces APOBEC3 expression and inhibits HIV-1 replication. Wang Z, Luo Y, Shao Q, Kinlock BL, Wang C, Hildreth JE, Xie H, Liu B. PLoS One. 2014 Aug 28;9(8):e106078. PMID: 25165817; PMCID: PMC4148350.
b) Transcytosis of HIV-1 through vaginal epithelial cells is dependent on trafficking to the endocytic recycling pathway. Kinlock BL, Wang Y, Turner TM, Wang C, Liu B. PLoS One. 2014 May 15;9(5):e96760. PMID: 24830293; PMCID: PMC4022679.
c) GB virus type C E2 protein inhibits human immunodeficiency virus type 1 assembly through interference with HIV-1 gag plasma membrane targeting. Timmons CL, Shao Q, Wang C, Liu L, Liu H, Dong X, Liu B. J Infect Dis. 2013 Apr;207(7):1171-80. PMID: 23303812; PMCID: PMC3583272.
3.3 Dr. Waldemar Popik. Dr. Popik’s laboratory has discovery that the innate immune factor apolipoprotein L1 inhibits HIV-1 replication by multiple mechanisms. His group found that the APOL1 protein targeted HIV-1 Gag for degradation by the endolysosomal pathway. They found that APOL1 stimulated both endocytosis and lysosomal biogenesis by promoting nuclear localization of transcription factor EB (TFEB) and expression of TFEB target genes. Moreover, they demonstrated that APOL1 depletes the cellular viral accessory protein Vif, which counteracts the host restriction factor APOBEC3G, via a pathway involving degradation of Vif in lysosomes and by secretion of Vif in microvesicles. As a result of Vif depletion by APOL1, APOBEC3G was not degraded and reduced infectivity of progeny virions. In support of this model, Dr. Popik’s group also showed that endogenous expression of APOL1 in differentiated U937 monocytic cells stimulated with IFN-γ resulted in a reduced production of virus particles. This finding supports the hypothesis that induction of APOL1 contributes to HIV-1 suppression in differentiated monocytes. This study is significant because deciphering the precise mechanism of APOL1-mediated HIV-1 restriction may facilitate the design of unique therapeutics to target HIV-1 replication. This crucial discovery resulted in the following recent publication:
a) The innate immune factor apolipoprotein L1 restricts HIV-1 infection. Taylor HE, Khatua AK, Popik W. J Virol. 2014 Jan;88(1):592-603. PMID: 24173214; PMCID: PMC3911732.
3.4 Dr. Xinhong Dong. Dr. Dong’s lab has elucidated the mechanism of HIV-1 particle release. His research findings demonstrated that the intact and stable AP-3 complex, a heterotetramer that is involved in signal-mediated protein sorting to endosomal-lysosomal organelles, is required for HIV-1 assembly and release, and the involvement of the AP-3 complex in late stages of the HIV-1 replication cycle is independent of clathrin-mediated endocytosis. This study is significant because untangling the detailed mechanism of HIV-1 particle assembly may facilitate the design of novel therapeutics to block HIV-1 infection.
Dr. Dong’s important discovery resulted in the following recent publication:
a) Defective HIV-1 particle assembly in AP-3-deficient cells derived from patients with Hermansky-Pudlak syndrome type 2. Liu L, Sutton J, Woodruff E, Villalta F, Spearman P, Dong X. J Virol. 2012 Oct;86(20):11242-53. PMID: 22875976; PMCID: PMC3457180.
This publication was spotlighted by the Editors of the Journal of Virology in the Journal Issue.
3.5 Dr. Donald Alcendor. Dr. Alcendor studies the mechanisms of pathogenesis of the Human cytomegalovirus (HCMV), which is the leading infectious cause of vision loss among congenitally infected children. Retinal pericytes play an essential role in maintaining the retinal vascular and endothelial cell proliferation. However, the role of retinal pericytes in ocular HCMV pathogenesis is still unknown. Dr. Alcendor’s findings indicate that in retinal pericytes, HCMV induces proinflammatory and angiogenic cytokines. In the Tricell culture model of the inner blood-retinal barrier (IBRB) (retinal endothelial, pericytes, Müller cells), pericytes likely serve as an amplification reservoir, which contributes, to retinal inflammation and angiogenesis. These studies are significant because they point out that it is necessary to develop IBRB model systems to better understand the mechanisms involved in progressive retinopathies and to provide more efficient methods for a timely evaluation of systemic therapies that must circumvent the IBRB.
Dr. Alcendor, in collaboration with scientists at Vanderbilt University, has developed for the first timea “neurovascular unit on a chip” with implications for translational applications including HIV-I infection. This novel technological platform, which combines innovative microfluidics, cell culture, analytical instruments, bioinformatics, control theory, neuroscience, and drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. The platform will enable targeted and clinically relevant nutritional and pharmacologic interventions for or prevention of such chronic diseases as obesity and acute injury such as stroke, and will uncover potential adverse effects of drugs. If successful, this project will produce clinically useful technologies and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and diseases. These novel studies resulted in the following two recent publications:
a) Retinal pericytes and cytomegalovirus infectivity: implications for HCMV-induced retinopathy and congenital ocular disease. Wilkerson I, Laban J, Mitchell JM, Sheibani N, Alcendor DJ. J Neuroinflammation. 2015 Jan 9;12(1):2. PMID: 25573478; PMCID: PMC4314746.
b) Neurovascular unit on a chip: implications for translational applications. Alcendor DJ, Block FE 3rd, Cliffel DE, Daniels JS, Ellacott KL, Goodwin CR, Hofmeister LH, Li D, Markov DA, May JC, McCawley LJ, McLaughlin B, McLean JA, Niswender KD, Pensabene V, Seale KT, Sherrod SD, Sung HJ, Tabb DL, Webb DJ, Wikswo JP. Stem Cell Res Ther. 2013;4 Suppl 1:S18. PMID: 24564885; PMCID: PMC4029462.
4) Several faculty members in the Center for AIDS Health Disparities Research at Meharry, (that were previously funded through MeTRC Pilot Project funding), have effectively collaborated with scientists at Vanderbilt and the TN Department of Health in writing and submitting a successful Tennessee Center for AIDS Research (TN-CFAR) grant-1P30AI110527-01A1, which has received a fundable impact score of 12.
The TN-CFAR involves Vanderbilt University, Meharry Medical College and the TN Health Department, with separate budget components for each institution. Meharry scientists will participate by leading and co-leading components of the TN-CFAR. Meharry’s participation will facilitate the expansion of various types of HIV research at Meharry and will enhance the HIV biological and clinical research enterprise.
5) School of Graduate Studies and Research Students Are Top Winners at Health Disparities Conference
Two graduate students won the first and second place awards at the recent ISMHHD NIH Conference 2014 in Bethesda, MD.
Both students are mentored by MeTRC investigator, Dr. CV. Dash.
Amma Addai (top photo) and LaKeisha Summers (bottom photo) were winners of first and second place, respectively, in the Graduate Student Category at the Minority Health and Health Disparities Grantees’ Conference held in National Harbor, Maryland in December, 2014.
Addai’s presentation was titled "Cocaine enhances HIV-1 integration in CD4+ T cells" and Summers’ presented a poster called "Role of Prolidase in Neuronal Dysfunction of Cocaine Abuse."
The 2014 Student Poster Competition is a program designed and developed to foster and support the innovation, ingenuity and intellectual integrity of future scientists dedicated to the improvement of minority health and the elimination of health disparities from a global perspective. Furthermore, the competition supports the future of education and the evolution of science and excellence in developing students to lead the charge of discovery and leadership.
6) MeTRC Pilot Project investigators have played important roles in the scientific peer review community serving as Editors, Editors in Chief, Academic Editors, and members of Editorial Boards for Scientific Journals.
- Dr. Bindong Liu, Editor-In-Chief, Journal of Antivirals and Antiretroviral
- Dr. CV. Dash, Academic Editor, PLOS ONE
- Dr. Xinhong Dong, Editor, AIDS and RecentAdvancements & Editorial Board member, The Journal ofHIV/AIDS Research and Therapy, the Journal JSM Microbiology, the Journal of AIDS & Its Research and Austin Journal of Clinical Immunology
- Dr. Donald Alcendor, Editorial Board member, Journal of Bioengineering and Biomedical Science, The Journal HIV/AIDS Research and Therapy, The Journal of Immunology and ClinicalResearch, Austin Journal of HIV/AIDS Research, Journal of Clinical Oncology & Research, Journal of CancerPrevention & Current Research, andAnnals of Clinical and Medical Microbiology
- Dr. Bindong Liu, Editorial Board member, The Journal of AIDS and Clinical Research
- Dr. Waldemar Popik, Editorial Board member,Frontiers of Virology
- Dr. Stella Nowicki, Editorial Board member The World Journal of Clinical Infectious Diseases, Advances in Medicine (OB/GYN subject area) and The Journal of Immunology and Clinical Research
- Dr. Xua Xi, Editorial Board member, Frontiers in Cellular and Infection Microbiology
7) The Collaborations & Partnerships Key Activity has been active in creating an environment that has enhanced research activities through the collaborative efforts of internal and external investigators resulting in scholarly publications and partnerships. Examples are listed in items 1,2,3 and 4 of these MeTRC scientific highlights.