Research Projects

To exert complete control over malaria disease, we need to understand the basics of parasite biology and various aspects of host-parasite interactions.

We are exploring various aspects of biology of the malaria parasite and the host-parasite interactions during the red blood cell (RBC) stages of the infection. Along with studying the molecular basis of acquired immunity to malaria, in collaboration with chemists of TIFR, we assess protein structure and metabolic changes caused by the infection in the host, through the course of the disease. Recently we have identified proteins and processes that play a role in the crucial lipid sensing and uptake at the onset of parasite cell division. We also assess flexibility and dynamics of parasite infected RBCs using optical tweezers with physicists of TIFR. In collaboration with ICT, Mumbai, we are exploring nanolipid carrier-mediated delivery of antimalarials. With Dr. Vidita Vaidya of our department, we have initiated a study on the effect of mild malaria in the brain of the vertebrate host.

Our Group has been addressing several questions regarding the biology of malaria parasite.

Why does Plasmodium transport a ribosomal protein to the surface of infected red cells? Is it a sensor protein that assesses conditions conducive to cell division?

Read More

What are the molecular players in acquired immunity to Plasmodium? How do Plasmodium house-keeping proteins such as ribosomal P0 protein translocate to the infective merozoite surface and play a protective role?

Read More

Can we exploit unique nanolipid import pathways of malaria parasites for selective drug delivery?

Read More

Can we dissect and distinguish the types of severe clinical malarial disease based on host immune responses? Is the sex of the host important in its immune and metabolomic response to the parasite?

Read More

How does Plasmodium modulate the red cell rigidity? Does it have an effect on the fluid dynamic properties of our circulatory system?

Read More

Can a mild malarial infection affect learning and memory? Does a mild malarial attack affect adult neurogenesis?

Read More

Why does Plasmodium transport a ribosomal protein to the surface of infected red cells? Is it a sensor protein that assesses conditions conducive to cell division

We have demonstrated that an acidic parasite ribosomal P protein (P2) undergoes stage-specific oligomerisation, and the P2-homotetramer is exported to the RBC surface at the onset of parasite cell division (Das et al., 2012). Blockage of RBC surface localized P2 protein with specific antibodies arrests parasite cell division at the first division of the nucleus. These antibodies also impair lipid uptake by the parasite. Our observations suggest that P2 protein may be involved in sensing the lipid environment of the Plasmodium-infected red cell when it is poised to start cell division. This suggests that the RBC surface exposed P2 protein may help monitor the external milieu and thus may play a role at a cell division checkpoint.

To date, the targeting of parasite infected RBCs have proved challenging because only variant malarial proteins are expressed on the surfaces of infected RBCs. The finding that an invariant parasite protein is expressed on infected RBCs, therefore, opens up the exciting possibility of selective targeting of parasite-infected red cells.

Selected publications ×

What are the molecular players in acquired immunity to Plasmodium? How do Plasmodium house-keeping proteins such as ribosomal P0 protein translocate to the infective merozoite surface and play a protective role?

Although a vaccine for malaria has proved elusive, a certain form of naturally acquired immunity to malaria does exist in hyperendemic areas. Such immunity develops gradually, after multiple malarial attacks over several years, and manifests in adults living in such areas. Cohen and McGregor demonstrated in the 1960s (Nature. 1961. 192:733) that the passive transfer of immunoglobulins from immune adults can be used to control malaria. We have identified several novel erythrocytic stage-specific proteins through a differential immunoscreen of cDNA expression library of P. falciparum, using sera from malaria-immune and acute patients from endemic areas of Odisha, India. Antibodies against these proteins reacted exclusively with immune sera samples (Lobo et al., 1994). Proteins identified include a ribosomal protein P0 (Goswami et al. 1997), epitopes homologous to SEC65 protein of yeast (Goswami et al., 1996), ion-channel protein of influenza virus (Sharma and Bhattacharya, 1997), the switching antigen of Paramoecium, amongst others (Singh et al., 2002; Sehgal et al., 2004). Recently, we have shown the P. falciparum enolase protein to be yet another conserved protective protein (Pal-Bhowmick et al., 2007). The P0 protein and Pf enolase in particular have been found to be localized on the Plasmodium merozoite surface. Antibodies to these proteins provide considerable growth inhibition in P. falciparum cultures. However, vaccination studies show that these proteins induce deviant immune responses (Pathak et al., 2012). Investigations are now in progress to understand how and why house-keeping proteins like Pfenolase and P0 are translocated to the merozoites surface.

Related publications ×

Can we exploit unique nanolipid import pathways of malaria parasites for selective drug delivery?

Our investigations into nanolipid-carrier (NLC)-mediated delivery of antimalarial drugs show that such nanoformulations allow reduction in drug dosage through extended bio-availability. Unexpectedly, we found that a particular formulation of NLC by itself (that is, not loaded with a drug) conferred a significant degree of protection against the malarial parasite (Joshi et al., 2008). We are examining this remarkable phenomenon in detail. We find that these NLCs home to parasite-infected RBCs in particular to the parasite mitochondria. These also destroy the parasite-induced membranous network, thereby restoring the flexibility of the infected cell. Capillary blockage by rigid malaria-infected RBCs is a major factor in the precipitation of cerebral malaria, and we are exploring the use of these NLCs in the prevention of cerebral malaria.

Related publications ×

Can we dissect and distinguish the types of severe clinical malarial disease based on host immune responses? Is the sex of the host important in its immune and metabolomic response to the parasite?

Recently we have also studied the epidemiology of urban malaria in low-malaria transmission regions of India, such as Mumbai and Rourkela. The annual parasite-prevalence rate in both regions is between 2–4%. Such low incidence implies that adults should not possess pre-clinical immunity and hence all ages should be equally susceptible to clinical malaria. Yet, our observations show a significant adult male bias in clinical disease. A sex bias was not observed in children aged ≤10. Post-puberty, the rates of clinical disease in males were significantly greater than those of females. This age-dependent sex bias in clinical disease was observed for both P. vivax and P. falciparum species of the parasite, in two different hypoendemic regions of the country infested with two different species of mosquito vectors (Pathak et al., 2012). Ours is the first report clearly documenting sexual dimorphism in susceptibility to malaria disease in humans. Metabonomic studies in rodent models are allowing us to understand some of the pathways that may contribute to this sexual dimorphism (Basant et al., 2010; Ghosh et al., under preparation).

Global warming is projected to result in the spread of malaria to new geographic areas, exposing non-immune adult populations to the parasite. Our epidemiological study suggests that adult males are more likely to suffer from malarial symptoms severe enough to seek hospital referral, but both males and females, whether adult or children, are equally likely to harbor the parasites. These results will therefore be relevant in the formulation and implementation of effective global anti-malarial public health strategies and educational campaigns.

Selected publications ×

How does Plasmodium modulate the red cell rigidity? Does it have an effect on the fluid dynamic properties of our circulatory system?

Exported and excreted parasite molecules alter host membrane rigidity of infected as well as uninfected erythrocytes, possibly by interacting with the underlying spectrin network. Also the dynamics of parasite-infected red cells are likely to be very different from normal RBCs. Using a parallel plate flow-cell, fluorescence microscopy and optical tweezing we have quantified membrane rigidity of such infected red blood cells. This method was used to determine the effect of conditioned culture medium on membrane rigidity, and can be used to dissect out the molecular players. We envisage that such studies will help us understand the nature of forces operational in the host-parasite interactions. It has also allowed us to assess the unique properties of normal and infected red cells such as tank-treading.

Changes in the erythrocyte deformability and dynamics exhibit a strong correlation with several blood disorders including cerebral malaria. Our method, which can quantify such changes in single erythrocytes with increased sensitivity and ease, should be useful as predictors for the propensity to develop severe malaria.

Selected publications ×

Can a mild malarial infection affect learning and memory? Does a mild malarial attack affect adult neurogenesis?

Our immune and central nervous system shares a complex bidirectional relationship. Cells and molecules of the immune system modulate various homeostatic functions of the brain. Aberrant immune responses associated with stress, disease and senescence are responsible for cognitive dysfunction and psychological disorders. Epidemiological data suggests that chronic, mild, non-cerebral malarial infection is associated with cognitive deficits.

Our study aims to characterize the neurological symptoms that a non-cerebral malarial infection might have and the role played by immune responses. To address this question, we use confocal microscopy, flow cytometry and a combination of cell and molecular biology techniques. We find that a single mild malarial infection results in increased neuronal death and decreased neurogenesis in the murine model.

Cerbral malaria is known to cause neuronal death. It is interesting note that even a mild malarial infection can also affect neurogenesis. The long term consequences of such effects therefore need to be investigated.

Related Publications ×