MRC-FAPESP: New approaches to the treatment of Paracoccidioidomycosis

Humans have evolved complex and effective ways of fighting infections caused by microbes such as bacteria, parasites, fungi and viruses, the immune system. Sometimes the immune system goes wrong and this can cause serious diseases such as rheumatoid arthritis and diabetes. Our research aims to understand at a molecular level how the cells of the immune system are able to recognise different microbes and the ways in which these cells respond to cause the familiar symptoms of an infection such as fever and tiredness, and to generate specific antibodies that fight the invading microbes. In this project we will study the way in which immune system cells are activated by sugar-binding proteins associated pathogenic yeasts and plants, in particular the way they bind and activate the Toll-like receptors of the innate immune system. Understanding the molecular basis for interactions between these pathogens and immune cells will allow us to carry out a screen to identify new candidate drugs that might be effective therapies for these important diseases.

The innate immune system of vertebrates plays a central role in the detection and clearance of infections. Pathogen associated molecules such as bacterial lipids and non-self nucleic acids are recognised by a family of pattern recognition receptors the TLRs. The TLRs activate an inflammatory response and also provide the second signal required for the development of adaptive immunity. Over the last few years the Brazilian lab has identified and characterised a novel class of pathogen associated activators of the TLRs. These molecules are lectins that bind specifically to N-linked glycans present on the receptor ectodomain and activate TLR signalling. In this project the Brazilian and UK labs will collaborate to define the mechanism by which artin M from the jack fruit, and paracoccin from the pathogenic yeast Paracoccinoides brasiliensis activate TLR signalling. We will use biochemical, biophysical and structural methods to elucidate and quantify the molecular interactions of these molecules with TLR2/1, 2/6 and 4. We will use this information to develop an early stage screen to identify small molecule agonists and antagonists that can inhibit lectin mediated innate signalling. Molecules identified in the screen will be developed further as potential therapeutics for paracoccidioidomycosis, a common disease in Brazil which has a significant economic impact.

ODA CRITERIA

(1) Seek to investigate a specific problem or seek a specific outcome which will have an
impact on a developing country or countries on the DAC list:

The project addresses a chronic and debilitating tropical disease that has a large impact on human health and healthcare systems across rural Latin America. The development of effective new therapies will significantly improve the quality of life of infected individuals and this will in turn have positive effects on economic activity and productiveness.

(2) Provide evidence as to why this is a problem for the developing country or countries;

Paracoccidioidomycosis is confined to low and middle income countries of South America including Brazil, Colombia and Ecuador and is not known to occur in northern hemisphere developed nations.

(3) Address the issue identified effectively and efficiently;

The project will investigate the interactions between an important fungal pathogen and the host immune system. This interaction is critical for the initiation and the progression of the disease and and is likely to shed light on why it is heterogeneous with infections manifesting as asymptomatic, chronic and occasionally lethal.

(4) Use the strengths of the UK to address the issue, working in collaboration with others as appropriate;

The UK labs have the infrastructure and expertise to investigate at the molecular level the way that this pathogen modulates the immune response. The Brazilian lab has experience in cell biology relevant to the work.

(5) Demonstrate that the research is of an internationally excellent standard

The project will create a new partnership with the world leading MRC Centre for Mycology, Aberdeen University (see supporting letter). The track record and environment of the Uk and Brazilian lab are recognised as internationally excellent (eg in the UK Research Excellence Framework).

(6) Identify appropriate pathways to impact to ensure that the developing country benefits from the research

A core part of the proposal is to provide mobility for the Brazilian researchers in particular so that they may acquire skills relevant to the objectives and transfer these to the home Department. This will facilitate translation to the affected LMICs of potential therapies. This will be enhanced by the new collaboration established with Dr Heloisa Blotta of the Department of Clinical Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), a clinician with expertise in the diagnosis and treatment of paracoccidioidomycosis.

Who might benefit from this research?

Academic: Undergraduate, Masters and PhD students; national and international collaborators. Economic and societal: Partners and collaborators in the pharma and biotechnology industries; patients who will benefit from new therapy arising from the studies.

How might they benefit?

The project is part of a larger critical mass of research in molecular immunology in Cambridge University which supports a substantial number of research projects for students at all levels thereby delivering and training highly skilled researchers. The project develops new methodologies which benefit other researchers working in this and other fields in the life sciences. The project is at the intersection between basic science and early stage drug discovery and the PI collaborates closely and consults with partners in pharma and biotech industries. The work offers the prospect in the medium term of new therapies for infectious diseases that could have a big impact on human health worldwide especially in the developing countries of South America.