Newton001 Leishmaniasis in the Brazilian Amazon: the role of accessory microbiota in disease progression, pathobiology and immunity.

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School

Abstract

Leishmania spp. infection represents a serious public health burden in Brazil, with 35,000 suspected cases annually. Disfiguring and occasionally fatal cutaneous and muco-cutaneous forms of Leishmaniasis are most common in the Amazon region of Brazil. Differential clinical severity and drug-resistance profiles are widely reported between patients. There is thus an urgent need to identify what factors might be responsible for different patient outcomes. Leishmania species and genotype have a role in defining disease severity, as does the host immune response. Less commonly considered is the role that secondary bacterial infections and commensal skin microbiota have in modulating pathology and immunity. In this multidisciplinary project we propose to use state-of-the-art techniques to monitor Leishmania lesion-associated microbial diversity and host immune response to reveal the factors that underlie cutaneous Leishmaniasis severity and progression in Amazonian Brazil.

Technical Summary

Leishmania are protozoan parasites that cause a variety of debilitating, disfiguring and fatal diseases in humans. Cutaneous leishmaniasis (CL) is transmitted during vector feeding. Infection progresses over the course of a few weeks or months. Lesions are painful, debilitating and carry a high risk of secondary infections. Untreated CL metastasizes in 25% of cases to become severe and potentially fatal mucocutaneous leishmaniasis (MCL). An effective immune response to CL is associated with the Th1 cell-mediated pathway. In addition to TNF-alpha and IFN-gamma, cytokines IL10&12 are associated with healing CL. In contrast IL4 and TNF-beta are associated with non-healing disease and pathology.

There is significant potential interaction between the skin microbiome and Leishmania infection. Mouse models of L. major suggest that skin microbiota have an autonomous role in tuning resident T-lymphocyte function. More broadly, commensal microbiota have an important role in the development and regulation of the immune system. While there is some evidence for a role of the microbiome in defining immunity to Leishmania challenge, the role of endogenous microbiota associated with CL lesions has not been explored. Secondary pathogenic bacterial infections are common in CL. However, recent analysis of the micriobiota associated with chronic wounds suggests a more complex role for microbiota. As such, commensal bacteria associated with wounds may modulate local immune function, interact with opportunistic pathogens (e.g. Stapholococcus aureus), and ultimately define healing efficiency.

The aim of this project is to evaluate the CL lesion-associated microbial metacommunity in a pilot cohort of 50 Brazilian clinical cases through diagnosis, treatment and cure in terms of immunity, disease progression and severity. Our goal is to evaluate the potential of microbiota to modulate immunity and/or as act as biomarkers for disease progression.

Planned Impact

N/A

Publications

10 25 50
 
Description Wellcome Trust Institutional Strategic Support Fund (ISSF) Consolidator Funding
Amount £7,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 08/2016
 
Description FIOCRUZ, Brazil, Universities of Warwick and Glasgow 
Organisation Oswaldo Cruz Foundation (Fiocruz)
Country Brazil 
Sector Public 
PI Contribution The project involves a new and close collaboration between two UK research institutions and two branches of FIOCRUZ in Brazil (Rio and Rhondonia). The UK research partners have made two collaborative visits to establish and monitor the progress of the project .
Collaborator Contribution Two Brazilian research degree students have visited the UK partners. First to take part in a microbial metasequencing workshop. Subsequently one research students has made two extended visits (3 months) to the UK to undertake research and undergo training is aspects of the project.
Impact Research and training outputs include: 1) Training in microbial metasequencing and host transcriptional profiling. 2) A panel of 100 microbiome and tissue samples from a cohort of Leishmania patients in Norther Brazil 3) Microbial metasequence data from the above cohort of patients 4) Patient lesion gene expression profile data from the above cohort
Start Year 2015
 
Description FIOCRUZ, Brazil, Universities of Warwick and Glasgow 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution The project involves a new and close collaboration between two UK research institutions and two branches of FIOCRUZ in Brazil (Rio and Rhondonia). The UK research partners have made two collaborative visits to establish and monitor the progress of the project .
Collaborator Contribution Two Brazilian research degree students have visited the UK partners. First to take part in a microbial metasequencing workshop. Subsequently one research students has made two extended visits (3 months) to the UK to undertake research and undergo training is aspects of the project.
Impact Research and training outputs include: 1) Training in microbial metasequencing and host transcriptional profiling. 2) A panel of 100 microbiome and tissue samples from a cohort of Leishmania patients in Norther Brazil 3) Microbial metasequence data from the above cohort of patients 4) Patient lesion gene expression profile data from the above cohort
Start Year 2015
 
Description FIOCRUZ, Brazil, Universities of Warwick and Glasgow 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution The project involves a new and close collaboration between two UK research institutions and two branches of FIOCRUZ in Brazil (Rio and Rhondonia). The UK research partners have made two collaborative visits to establish and monitor the progress of the project .
Collaborator Contribution Two Brazilian research degree students have visited the UK partners. First to take part in a microbial metasequencing workshop. Subsequently one research students has made two extended visits (3 months) to the UK to undertake research and undergo training is aspects of the project.
Impact Research and training outputs include: 1) Training in microbial metasequencing and host transcriptional profiling. 2) A panel of 100 microbiome and tissue samples from a cohort of Leishmania patients in Norther Brazil 3) Microbial metasequence data from the above cohort of patients 4) Patient lesion gene expression profile data from the above cohort
Start Year 2015