Microbiology and Immunology

The following grants/studies are under way in the Department of Microbiology and Immunology within the School of Medicine.

Molecular analysis of trypanosome infection
Researcher: Fernando Villalta, Ph.D.
Funding Source: National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS)
Project Summary: Dr. Villalta's laboratory blends, genetic, genomic, imaging, structural, biochemical, pre-clinical and clinical strategies to study the interface between a pathogen and its host, the essential intracellular host and pathogen molecules required for intracellular parasitism, mechanisms of microbial immunity, and strategies for control. His work elucidates the structure, function and mechanisms of action of protozoan molecules involved in host pathogen interactions, protozoan subversion mechanisms that facilitate persistence in the host, essential protozoan genes required for parasite survival, host genes required for intracellular protozoan infection, and mechanisms of protozoan immunity.

The studies combine a genetics systems approach with protein structural analysis, knockout and transgenic animal models, genetically manipulated trypanosomes, cell and molecular biology, biochemistry, electron, video and confocal microscopy, host and protozoan functional genomics, drug discovery, gene network analysis, architecture of interactome networks in acute and chronic diseases, systems biology and mechanisms of immunity.

These approaches have allowed us to discover the cellular and molecular basis of host cell invasion by Trypanosoma cruzi, the causative agent of Chagas disease or American trypanosomiasis. We have also discovered critical T. cruzi ligands and their host receptors, including ECM molecules that participate in the process of adhesion and entry and the elaborate network of molecular cross talk that occurs as a consequence of these interactions responsible for the pathogenesis of Chagas disease. We are investigating the molecular signatures caused by T. cruzi in host cells leading to pathogenesis and disease. Fundamental questions about the structural basis of molecular interactions involved in the pathogenesis of Chagas disease are being addressed. This work will provide clues to the structure and function of the key virulence factors that are implicated in gastrointestinal and cardiac pathology of Chagas heart disease.

This work is spawning new technologies to design novel vaccines and anti-microbial therapeutics that block the ability of the protozoan to adhere to host tissues and invade them, and thus prevent its ability to establish infection. We also have discovered several beneficial mechanisms of innate immunity against protozoan parasites and elucidated their interactome networks, which when stimulated facilitate reduction of the burden of infection.

This collaborative group is also dissecting the structure and function of the key enzymes that participate in the synthesis of ergosterol, an essential component ofthe membrane structure and function of protozoan parasites that is required for intracellular parasite survival. Our group has discovered new pharmacophores that effectively target key enzymes of the trypanosome sterol pathway and block the replication of trypanosomes within cells, which in a safe manner clear the infection in pre-clinical studies and represent new promising drugs for the treatment of Chagas disease.   See publications, discoveries and other scholarly activities at PubMed, NCBI (villalta f) and Google scholar.

Mechanism of biogenesis of atypical alphaviruses
Researcher: Raju Ramasamy, Ph.D.
Funding Source: National Institute of Allergy/Infectious Diseases (NIAID)
Project Summary: Dr. Raju's long-term goal is to elucidate the pathways of alphavirus RNA genome repair and remodeling leading to the generation of atypical viruses in infected host cells. Alphaviruses are an important cause of emerging viral encephalitides in animals and humans and are significant biodefense agents. Delineating these pathways should lead to strategies to control emergence of outbreaks of alphaviruses and perhaps other mosquito-transmitted RNA viruses. Since alphaviruses are vigorously pursued as gene therapeutic and vaccine delivery vehicles, the team's work will also be useful in the development of improved RNA vectors.

Research Centers in Minority Institutions (RCMI)- Molecular Biology Core Component
Researcher: Robert Holt, Ph.D.
Funding Source: National Institute on Minority Health and Health Disparities (NIMHD)
Project Summary: Dr. Holt is the Scientific Director of the Molecular Biology Core at Meharry Medical College supported by RCMI. This core is a multi-functional facility that provides to faculty, students and staff of the college the primary service of DNA sequencing but also provides access to shared equipment housed in a centralized location and facilitates convenient and rapid access to frequently used molecular biological reagents. This core supports the enhancement of the research enterprise at the College.

Mitochondrial inner membrane protein translocase in trypanosoma brucei
Researcher:Minu Chaudhuri, Ph.D.
Funding Source: National Institute of General Medical Sciences (NIGMS)
Project Summary: African trypanosomiasis, a fatal disease in humans as well as in domestic animals, is caused by the parasitic protozoa, Trypanosoma brucei. As available drugs for this disease are inadequate, it is critical to identify targets to design new drugs. Import of essential mitochondrial proteins is crucial for survival of this parasite in mammalian hosts. Therefore the unique structure and function of mitochondrial protein import molecules could be exploited as novel drug target(s).

Enhancement of the efficacy of conventional anticancer compounds through the repression of SNAI proteins in aggressive breast cancer cells Researcher: Gautam Chaudhuri, Ph.D.   
Funding Source: Department of Defense (DOD)
Project Summary: Dr. Chaudhuri's team is studying the role of the SNAI family of transcriptional repressors in vitamin D metabolism as well as in vitamin D and anti-estrogen resistance development in breast cancer with emphasis on breast cancer in African-American breast cancer patients. Because inhibition of VDR expression and elevation of cyclin D1 are clinically associated with vitamin D3 and anti-estrogen resistance development in breast cancer patients, rational strategies to reduce the expression of SNAI proteins will enhance the therapeutic efficacy of these drugs against breast cancer. Therefore, the knowledge and the reagents to be generated from the proposed research will have a direct impact on improving the effectiveness of anti-estrogen and vitamin D therapy for patients with SNAI-high and VDR-low breast cancers.

CD55, Vitamin D3, and race in preterm labor (MeTRC)
Researcher: Stella Nowicki, D.D.S.
Funding Source: National Center for Research Resources (NCRR)
Project Summary: Preterm labor, associated with increased infant death, affects about 12 percent of pregnant women in the U.S. and occurs more often in minority women, especially among African American women in Nashville. This study is exploring a link between hormones dependent upon Vitamin D and preterm labor. Results may indicate that proper nutrition or Vitamin D supplements could alleviate preterm labor.

Novel trypanosome receptor for thrombospondin-1
Researcher: Pius N. Nde, Ph.D.
Funding Source: National Institute of Allergy and Infectious Diseases (NIAID)
Project Summary:  Trypanosoma cruzi, the causative agent of Chagas heart disease up-regulates the expression of host thrombospondin-1 (TSP-1), early during the process of infection. TSP-1 binds specifically to the surface of invasive forms of T. cruzi trypomastigotes and knocksdown of host TSP-1 by RNA interference cause significant inhibition of T. cruzi infection. Our working hypothesis is that T. cruzi trypomastigotes up-regulate host TSP-1 that interacts with trypanosome surface receptor(s) to enhance the infection of heart cells. We are interested in identifying and characterizing the novel T. cruzi TSP-1 binding molecule on the surface of the parasite and determining the in vivo role of TSP-1 gene in the process of T. cruzi infection using aTSP-1 KO mice model. Our research will facilitate the development of specific molecular intervention strategies to prevent Chagas heart disease.