National Institution in Science and Technology of Tropical Diseases
External Evaluation, 1-2 March, 2010

External Evaluators:
Lee Riley, Head, Division of Infectious Diseases and Vaccinology, College of Public Health, University of California at Berkeley
Phillip Scott, Associate Dean for Research, School of Veterinary Medicine, University of Pennsylvania
Mary Wilson, Departments of Internal Medicine and Microbiology, University of Iowa

Summary of Talks and Proceedings:

I. Overview of the program: Edgar Carvalho, MD, PhD

A. Overall mission: to train and develop human resources in science and technology, and to advance biomedical research activities that could benefit patients with endemic infectious diseases in Brazil

B. Goals:
(1) Identify mechanism related to pathogenesis of tropical diseases
(2) Identify markers of clinical evolution and therapeutic response
(3) Develop new strategies for treatment or control of tropical diseases
(4) Develop and implement community and school-based participatory program to promote understanding and engagement of the population on research in health and control of neglected diseases

C. Specific aims:
(1) Identify biomarkers associated with development of disease, asymptomatic infection, resistance to disease, serious manifestations, as well as biomarkers of reinfection or clinical prognosis of Chagas’ disease, Leishmaniasis, Schistosomiasis or HTLV-1 infection.
(2) Identify polymorphic genetic markers associated with susceptibility or resistance to manifestations of Chagas’ disease, leprosy and leishmaniasis, including the most serious clinical forms.
(3) Identify pathogen related markers associated with forms of disease and response to therapy, focusing on genetic polymorphisms related to virulence of L. braziliensis isolates.
(4) Clinical trials of immunomodulators focusing on novel adjuvant and alternative modes of therapy. Therapeutic goals are preventing neurological manifestations of HTLV-1 and preventing lesions in leishmaniasis
(5) Identify vaccine candidate antigens of S. mansoni using genomic and proteomic strategies. The effectiveness of antigens for vaccines will be tested in mouse models.
(6) Identify recombinant antigens of S. mansoni that can modulate the inflammatory responses due to chronic inflammatory diseases, cutaneous and mucosal leishmaniasis, and asthma in vitro and in vivo.

D. Participating institutions: Universidade Federal do Rio Grande do Norte
Instituto de Ciencias da Saude, Universidade Federal da Bahia
FIOCRUZ-CPqGM, Bahia
Universidade Federal da Minas Gerais
FIOCRUZ CPqRR, Minas Gerais
Faculdade de Medicina, Universidade Federal da Bahia

II. Andrea Gazzinelli - Community participation program: Access to schistosomiasis control and health care in an endemic area in the Jequitinhonha Valley, MG.
This project constitutes a multi-faceted approach to assessing the impediments to anti-schistosomal health care, and helping a community to lower the incidence of disease. The approaches included interview of community leaders, observations of living conditions, and assessment of the risks of infection. Methods to decrease the prevalence of schistosomiasis included methods to educate school children, increase awareness of schistosomiasis in the community, improving access to clean water through a central distribution area, remodeling a laundry and work with health agents. The impediments to each of these intervention goals were outlined.
Overall the project is proceeding very well and the reviewers are very positive. The measures to intervene in disease are difficult to implement, but the group is succeeding through a multi-faceted approach. One of the problems underscored by Professor Gazzinelli is the difficulty in ensuring interventions are long-term, given the frequent turnover of health care workers in the region. Our only suggestions are to actively employ community members and leaders in the control programs, and if possible to expand educational school programs to include assignments for interventions in the homes.

III. Rodrigo Correa Oliveira: Analysis of the immune response of endemic populations to Schistosoma mansoni infection, and the relationship to resistance and susceptibility
This project constitutes an assessment of IgE anti-SEA and anti-SWAP, and of eosinophilia in individuals exposed to Schistosoma mansoni. The intensity of the immune response is being correlated with the degree and mode of exposure, age, risk activities, pathology, and immune response.
The correlation between epidemiology and basic immunology is unique, and likely to provide perspective to the literature about immune responses in this disease. Some surprising findings are the lack of expansion of FoxP3-expressing regulatory cells, and potential involvement of regulatory B cells. The investigator did not have time to summarize, but the future correlation to genetics will be of great interest, as these biomarkers may not only be markers of disease severity but also of genetic predispositions.

IV. Sergio Costa Oliveira – Schistosoma mansoni tegument proteins with immunomodulatory properties as vaccine candidates
This was a fascinating summary of efforts to identify S. mansoni proteins that are associated with markers of protective immunity, and immunomodulatory effects in another disease, asthma. The group found an involvement of dendritic cell activation through TLRs, and that immunomodulation involves larval and adult worm antigens preferentially over egg antigens.
These studies are important and may yield useful molecules for both anti-schistosomal vaccination and for modulation of disease mediated by inflammation. The project is still in its initial stages. It will be important, as the investigator outlined, to extend findings in mice to serological studies in specimens from human disease.

V. Selma Jeronimo - Epidemiology and spatial aggregation of Hansen’s disease in Rio Grande do Norte: Active case search
Professora Jeronimo summarized a major project in which her group is discovering the incidence and form of leprosy in three cities of Rio Grande do Norte with previously reported low disease incidence. Through case detection and education of the community about self-referral to the research group, many previously unrecognized cases of the disease have been found and referred to treatment. The project involves georeferencing, examination, evaluation of epidemiology risk factors, education of health care workers, evaluation of better detection methods (quantiferon), and studies of genetic susceptibility using a candidate gene and case-control approach.
The project is going well including the educational aspects of the project. Dr. Jeronimo underscored the problem of turnover of health care workers as a worry about the longevity of the interventions. This is a difficult problem, and as in Pra. Gazzinelli’s project, if possible it may be helpful to involve community leaders and school teachers in intervention programs so that the programs can continue after this project ends.

VI. Walderez Dutra – Identification of immunological markers associated with pathology and resistance in Chagas’ disease: host gene polymorphisms and immunoregulation
This project constitutes a careful determination of immune cell phenotypes, discerned by surface markers, in the progression of Chagas’ disease. Observations are correlated with cytokines promoting progression or non-progression. The investigators are also examining genotype at candidate genes that may mark a more susceptible versus more resistant phenotype. The latter goal is supported by a network of Chagas’ disease workers providing DNA samples.
This is elegant work and it is progressing very well. The finding that the production of proinflammatory and regulatory cytokines by certain T cell subsets (CD28-, Vb5+) could be correlated with indeterminant and cardiac forms of the disease was very important. It may be worthwhile for the network to set as a future goal the gathering of enough samples for a case control genome wide association study. For this purpose one hopes controls are carefully selected from each endemic region.

VII. Geraldo Gileno – Canine visceral leishmaniasis: assessment of multiple recombinant antigens for serodiagnosis and production and assessment of recombinant canine cytokines for future immunotherapeutic studies
This is a study of canine leishmaniasis with the dual aims of detecting recombinant antigens that could be useful for serodiagnosis of subclinical disease, and cloning and purification of recombinant canine cytokines/cytokine-DNA vaccines for the purpose of immunotherapy.
The work is important for potential detection and removal of an important reservoir of L. chagasi infection in Brazil. The serodiagnostic work is going well and ample samples are being collected. The work with recombinant cytokines led reviewers to a few questions. It seems unlikely that either recombinant protein or DNA vaccines will be used for treatment of stray dogs, a major reservoir of visceral leishmaniasis, due to the high expense of cytokines and the simpler solution of dog euthanasia. A suggestion for this project is to develop a consortium of veterinarians with serum samples to test recombinant antigens in a larger group of dogs from different geographic regions of Brazil.

VIII. Edgar Carvalho – Biomarkers of disease expression in HTLV-1 infection
Dr. Carvalho and colleagues are pioneers in examining factors associated with the development of different manifestations of HTLV1 infection, particularly the spectrum of manifestations prior to the development of HAM-TSP. Immune markers of progression are used to categorize changes in cytokines and cell markers associated with progression.
The work is important and sentinel. Northeast Brazil is one of the few locations were the disease is highly endemic and the work can be done well. A suggestion is to begin a bank of DNA samples with carefully chosen subjects with different stages of infection from asymptomatic to severe, and uninfected controls of the same ethnic background and sex, for a future coordinated study of genetic markers of disease progression. A consortium of institutions would be a better forum for this goal than a single site.

IX. Overall Suggestions
A. The 2-day symposium was outstanding. The reviewers suggest opening this to scientists at the university and FIOCRUZ, so that trainees and faculty members can benefit from the work.
B. The program shows outstanding work on human immune responses and beginnings of human genetics. There is one project focused on biological and genetic variability of the pathogen (L. braziliensis). The reviewers suggest that all project leaders consider how to expand their work to examine pathogen polymorphisms and/or biological variations in the future. In addition, studies to examine pathogen factors associated with characteristic host immune response could be expanded.
C. A cataloging of trainees involved in the projects would be helpful in assessing the success of this goal in the overall project.