My interest in parasite biology is driven by the desire to understand (A) RNA editing pathway and Molecular Mechanism of Drug Resistance in Leishmania donovani, causative agent of Visceral Leishmaniasis (VL) or Kala-azar and (B) the molecular mechanism behind the transformation of filarial parasite, Brugia malayi, causative agent of Lymphatic Filariasis (LF) from larval stage (resides in vector) to adult worms (resides in host) and to identify novel drug target thorough proteomic and genomic approach.
(A) Visceral leishmaniasis (VL) or kala azar
Caused by the protozoan parasite, L. donovani occurs in 98 countries worldwide. The global estimates for the incidence and prevalence of kala-azar cases per year are 0.5 and 2.5 million, respectively. It poses a major health problem in the state of Bihar, which accounts for nearly 90% of the total cases in India. Although chemotherapy has proven to be the only effective way of controlling infections, drug resistance is a major problem in the chemotherapy of kala-azar. So the comprehensive understanding of the resistance mechanism and to find out new drug target and/or new drug is urgent need of the hour and therefore we are interested in elucidating the molecular mechanism of drug resistance in L. donovani using modern molecular biological techniques like Knockout, Reverse Genetic Approach etc and finally to find out the important pathway or molecule(s) which may be used as drug target or resistance marker.
We are also interested in exploring the RNA editing pathway which is a unique posttranscriptional modification of mitochondrial mRNAs in L. donovani. RNA editing regulates parasite gene expression which is necessary for parasite survival inside host. Therefore, we aim to target this pathway of L. donovani. We are aiming to functionally characterize the important molecule(s) (which is absent in human) of this pathway in the context of parasite survival and infectivity inside host and finally to design and synthesize inhibitors against these molecules and to test the effectiveness of those inhibitors against experimental visceral leishmaniasis.
(B) Lymphatic filariasis (LF),
Caused by parasitic nematodes is the mosquito-transmitted neglected tropical disease. Approximately, 120 million people suffer from this disease with nearly 1.2 billion people at risk. Lymphatic filariasis occurs upon infection of the lymphatic system by Wuchereria bancrofti, Brugia malayi, or Brugia timori and clinically manifests as lymphedema, hydrocele, and in the most extreme cases, elephantiasis. Mass drug administration of albendazole in conjunction with diethylcarbamazine or ivermectin is recommended for controlling LF. But, these available drugs are mainly microfilaricidal in nature and have only modest adulticidal activity, but do not kill the adult worm. So, there is an urgent need to develop adulticidal drug. Moreover, no vaccine is available for LF till now.
Therefore, new validated drug targets are required to allow development of new classes of anti-filarial drugs. My lab is working in this direction for finding out novel pathway or molecules and to validate them as new drug target. Some genes/proteins are essential and synthesized by filarial parasite but are neither required nor synthesized by mammalian cells. We are targeting those genes/proteins for chemotherapeutic intervention using genomic, proteomic and insilico approach.
Comparative proteomic approach will also be employed to identify differentially expressed proteins of B. malayi in between vector and host. We will then functionally characterize those differentially expressed proteins in the context of parasite transformation inside host. Approaches will also be made for functional blocking of differentially expressed proteins by chemical inhibitors or siRNA to specify their role in parasite transformation.