Rationale​

 

Most infectious diseases such as parasitic diseases exhibit a gradient of multifaceted phenotypes and have complex genetic control and multiple interactions with environmental factors. They involve the interaction of several integrated biological systems including a virulent pathogen, a susceptible host and an environment favourable to disease development, so called "disease triangle". The concept of "triangle disease model" has been formalized by phytopathologists in 1960 "to study the interrelationships of various factors in an epidemic". The so-called triangle disease model is a coarse-grained view of how host immune system, genetics, the environment, and the parasite interact to give rise to the complex, heterogeneous phenotypes observed during infection. All three components and especially their interactions are critical and still only partially understood. The successful application of the "disease triangle" concept in agriculture has had a huge socio-economical impact. Surprisingly, this concept was ignored in the field of human infectious diseases.

We propose to use this concept as a holistic approach for modelling temporal relationships between environmental factors (level of transmission, population genetics), immune responses and infection and their effect on protection or severe disease. Considering the multi-factorial character of parasitic infection, SIGID has implemented an integrated approach that will address numerous interconnected aspects of infection and disease. Systems Biology approaches shall help us to understand the mechanisms that control the equilibrium between these different elements.

To start the project will focus on three parasitic diseases, Malaria, Filariasis and Leishmaniasis, which have a high incidence in India. SIGID efforts will be put to get insight into immunopathogenesis associated with these infectious diseases. The project will combine technological developments and detailed generic clinical, cellular and molecular studies on infected patients manifesting different disease phenotypes and/or on experimental models. The ultimate objective is to analyse, integrate and model data obtained to: i) identify immunological, genetics and environmental factors involved in pathogenesis and protection, ii) define biomarkers of parasitic disease sub phenotypes in India, and iii) develop effective alternative therapeutics strategies. drugs and/or and vaccine

This study on the one hand provides novel, essential data to better characterize the host-pathogen, host-environment, and pathogen-environment interactions on a molecular level, and on the other hand aims at providing an integrated and robust view of the detailed cause and effect relationships exerted on the molecular and genetic levels. For the latter analysis part two main challenges can be identified: (i) the interactions happen on multiple time and space scales, and (ii) non-decomposability (triangular and higher-order interactions).

​Project 1 - Malaria

Background

Malaria caused by Plasmodium (P) parasite transmitted by the Anopheles mosquito affects about 2 million individuals with to 200,000 deaths per year in India. P. vivax is the predominant species but P. falciparum is known to be endemic and dramatically reemerging (Sharma et al., 2004). About 25% of malarial cases in India are contributed by the state of Orissa where the forest areas are hyperendemic (Cuttack) and the urban pockets hypoendemic (Rourkela). P. falciparum malaria is characterized by a spectrum of clinical phenotypes which may range from uncomplicated to severe malaria responsible for a high mortality rate in the absence of prompt diagnosis and appropriate treatment. The clinical pattern and ethnic signatures of severe malaria in India widely differ from those in Africa. The rise of malaria incidence in India highlights the importance of studies in endemic human populations for a better understanding of the immunobiology of the host-parasite interaction.

Objective

  • To define divergent patterns of immune responses associated to malaria phenotypes and involved in two epidemiological environments (endemic/epidemic; urban/rural);
  • To identify genetic and gender factors associated to these immune and physiopathological mechanisms.

Project Coordinator

Dr. Sylviane Pied

 

Actions / Work Packages

 

Funding

This work has been supported by CEFIPRA3703-2: Role of immune and genetic factors in the outcome of Plasmodium falciparum malaria (Co-coordinators: S. Sharma & S. Pied), LIA SIGID CNRS and University of Lille.

Project 2 - Lymphatic filariasis

Background

Lymphatic filariasis (LF) contributes to 40% of the total global burden in India and 25 states/union territories of India are endemic. LF which, is prevalent in both urban and rural areas, is a chronic and debilitating tropical disease caused by vector borne nematode parasites Wuchereria bancrofti, Brugia malayi, and Brugia timori transmitted by the ubiquitous vector, Culex quinquefasciatus. ~120 million people suffer from at least one form of the disease, and ~1.3 billion are at risk of infection that often leads to clinical manifestations such as lymphedema, elephantiasis, and/or hydrocele. The clinical manifestations of LF may vary from one endemic area to another in the absence of any preventive vaccine and effective chemotherapy to kill lymphatic-dwelling adult-stage parasites which persist in infected hosts for several years. Considerable progress has been made in diagnosis and treatment of filariasis in the last decade and new strategy for filariasis elimination aims at transmission control through mass drug administration and at disease control through individual patient management. However, several important issues remain to be resolved, before the disease can be eliminated from India. These include uncertainty about the required coverage and duration of annual treatment to achieve elimination and its relation to endemicity levels and vector/parasite complexes. There is an urgent need for appropriate tools, procedures and criteria for monitoring and evaluating the impact of elimination programmes. It is also becoming increasingly important to be able to predict and demonstrate the public health and socioeconomic impacts of the elimination efforts (especially for areas where interruption may not be easily/completely achieved). Thus, India must intensify the efforts to eliminate filariasis.

The disease is associated with a high inflammatory state with a state of dominant Th1 filarial specific immune response while a presence of active infection is associated a hyporesponsive immune phenotype. Investigations conducted by us so far has indicated the possibility of genetic polymorphism of critical molecules of both innate and adaptive responses of immune system  such TLR-2, TLR-4, CD14, TNFalpha, IL-4, IL-10, INFgammaR...

Objectives

  • To study TLR function in different clinical categories of patients in response to appropriate ligands,
  • To analyse the ability of APCs of infected subjects to process and present nominal antigens,
  • To identify T-effector and T-regulatory cell population in different clinical categories in endemic areas.  

Project Coordinator

Dr. Ravindran Balachandran

 

Actions / Work Packages

 

Funding

Project 3 - Visceral leishmaniasis

Background 

Visceral leishmaniasis (VL), also known as Kala-azar has re-emerged from near eradication to become a public health problem in India,. From 65 million people estimated to be at risk, more than 20,000 cases of VL and about 200 deaths are reported annually in India. Untreated cases of kala-azar are associated with up to 90% mortality, which is reduced to 15% by treatment. VL is caused by Leishmania donovani transmitted by the vector Phlebotomus argentipes. Post-kala-azar dermal leishmaniasis (PKDL) is a low frequency (5–10%) dermal sequela of VL affected individuals whom are speculated to be parasite reservoirs. It is also associated with up to 20% subclinical infection. Also, lymphadenopathy, a major presenting feature in India raises the possibility of a new vector or a variant of the disease. Spraying of DDT and the use of anti-leishmanial drugs helped to control kala-azar. However, those measures remain unsatisfactory for several reasons: 1) development of resistance to DDT of the sandfly, 2) unresponsiveness to sodium antimony gluconate of many VL cases and furthermore, the tendency to relapse at a later stage of cases that do respond, 3) impossibility to use of Pentamidine, as a first line treatment due to its toxicity and 4) expensive cost and hospitalization requirement of Amphotericin B and its liposomal formulation even if effective.

Objective

Considering the present scenario, therefore, the specific objectives of the project are:
  • Identify possible drug targets and test their validity as targets in vitro and in vivo,
  • Identify a vaccine candidate; test efficacy in an L. donovani susceptible experimental model,
  • Find a compound that may work as an adjuvant, increasing the efficacy of the vaccine.

Project coordinator:

Dr. Shekar Mande

 

Actions / Work Packages

 

Funding

LIA SIGID CNRS and University of Lille

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