National Institute of Cholera and Enteric Diseases

Indian Council of Medical Research
Department of Health Research, Ministry of Health and Family Welfare, Government of India
WHO Collaborating Centre for Research and Training on Diarrhoeal Diseases

Pathophysiology

About Pathophysiology

Pathophysiology

The research work of the Division of Pathophysiology is related to the understanding of pathogenesis of different diarrhoeagenic bacteria, development of candidate vaccine, Super ORS and use of proper antibiotics against diarrhoea. The scientists of this division have been working on different projects.

Highlights of some of the projects are as follows:

One of the studies reveals that oral immunization of rabbits by heat killed Shigella flexneri 2a can give 100% protection against shigellosis. Immune response has also been studied in details and a 34kDa outer membrane protein (OMP) has been identified as a protective antigen. This study may lead to develop a simple, practical and effective vaccine against shigellosis. Presently the purification of 34kDa OMP has been done along with its biophysical as well immunological characterization.

In another study the intracellular signal transduction pathway involved in the induction of intestinal secretion by E.coli heat-stable toxin (STa) has been evaluated. It has been shown that besides cyclic Guanosine -3’,5’- mono phosphate E.coli STa also involves phosphatidyl-inositol specific phospholipase C, inositol trisphosphate, diacylglycerol, calcium and protein kinase C in its mechanism of action in a human colonic carcinoma cell line COLO-205. Work is also going on to find out the cytoskeletal rearrangements caused by E.coli STa.

It has also been noted that the heat-stable enterotoxin secreted by non-O1 V.cholerae (NAG–ST) causes IP3–mediated Ca++ release from intracellular store, which then stimulates nitric oxide production by activating nitric oxide synthase (NOS). This nitric oxide through soluble cGMP activates calcium influx.

Recently, it has been shown that E.coli STa downregulates the cell proliferation through Protein Kinase G –Mitogen Activated Protein Kinase pathway and has been considered as a potent anti-angiogenic and anti- metastatic molecule.

Calcium Sensing Receptor (CaSR) is one of the important receptor, which can sense and causes the influx of extracellular calcium ions [Ca++o] with the subsequent rise of intracellular calcium level [Ca++i] and associates with fluid secretion. In the Division the cloning of the full-length cDNA of Calcium Sensing Receptor (CaSR) from a colon carcinoma cell line COLO-205 has been done. Moreover, the involvement of CaSR in the intracellular signaling mechanism of virulence factors secreted by different enteric bacteria (E.coli heat stable enterotoxin, Thermostable Direct Hemolysin) has been observed with the help of inhibitor, si-RNA transfection etc. The results reveal that CaSR is involved in the thermostable direct hemolysin-mediated downregulation of colonic carcinoma cell proliferation.

The studies of this Division in rat perfusion model have shown that hypotonic ORS made by lowering sodium is much more effective than by lowering glucose.

The pathogenic mechanism of nonO1, nonO139 V.cholerae is not yet known clearly. In a study at this Division two forms of Hemagglutinin Protease (HAP), one is mature 45-kDa and processed 35-kDa forms have been purified in the presence and absence of EDTA from culture supernatants of PL-21, which is a nonO1, nonO139 strains. Enterotoxigenicities of both forms of HAP are tested in rabbit ileal loop (RIL), Ussing chamber and tissue culture assays. The two forms show functional differences from each other. The 35-kDa form shows hemorrhagic fluid response in RIL, decrease in the intestinal short-circuit current in Ussing chamber experiment and cell rounding effect on HeLa cells. In contrast the 45-kDa form shows an increase in intestinal short-circuit current in an Ussing chamber experiment and a cell distending effect on HeLa cells. The results suggest that HAP may be an important virulence factor of these strains.

Apart from this, the scientists of the division are also involved in teaching and other academic activities of different Universities and professional societies in India. A large number of students have been trained in this laboratory for their Ph.D./ M.Sc./ M.Tech. program. Several collaborative projects are also going on with many National and International Scientists of different Organizations and Institutes.

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