Molecular epidemiology of Plasmodium vivax anti-folate resistance in India

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Abstract

Background

Sulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect. Point mutations in dihydrofolate reductase ( dhfr) and dihydropteorate synthatase ( dhps) cause anti-folate drug resistance phenotype in human malaria parasites. This study presents pattern of point mutations in dhfr/dhps genes among Indian sub-continent.

Methods

Microscopically diagnosed one hundred Plasmodium vivax field isolates were collected from five widely separated geographical regions of India. Dhfr and dhps genes were PCR amplified and sequenced. Previously published mutations data were collected and analyzed using Chi square test to identify geographical cluster of mutant/wild type genotypes.

Results

Sequence analysis revealed single (S58R), double (S58R/S117N) and quadruple (F57L/S58R/T61M/S117T/) point mutations at dhfr and single (A383G) to double (A383G/A553G) mutations at dhps in P. vivax field isolates. In addition, three new mutations were also observed at dhfr. Both, dhfr and dhps genes revealed tandem repeat variations in field isolates. Dhps revealed very low mutation frequency (14.0%) compared to dhfr (50.70%). Comparative analysis revealed a progressive increase in frequency of quadruple mutant dhfr genotype (p < 0.001) within five years in north-eastern state (Kamrup, Assam). Frequency of dhfr genotypes revealed three distinct geographical clusters of wild (northern India), double mutant (southern India), and quadruple mutant (north-eastern and island regions of India) on the Indian sub-continent.

Conclusion

Study suggests that SP may be susceptible to P. vivax in India, except Andaman and north-eastern state. The distinction of geographical regions with sensitive and resistant parasite phenotypes would be highly useful for designing and administering national anti-malarial drug policy.

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Most cited references 37

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Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India.

Ashish Das, Parmendra Sirohi, Abhishek Kochar … (2009)

Epidemiologic studies and clinical description of severe Plasmodium vivax malaria in adults living in malaria-endemic areas are rare and more attention is needed to understand the dynamics and its interaction with the immune system. This observational study included 1,091 adult patients admitted to medical wards of S. P. Medical College and associated group of hospitals in Bikaner, India from September 2003 through December 2005. The diagnosis of P. vivax malaria was established by peripheral blood film (PBF), rapid diagnostic test (RDT), and polymerase chain reaction (PCR), and severe malaria was categorized as per World Health Organization guidelines. Of 1,091 patients with malaria, 635 had P. falciparum malaria and 456 had P. vivax malaria. Among patients with severe manifestations, 40 had evidence of monoinfection of P. vivax malaria diagnosed by PBF, RDT, and PCR. Complications observed were hepatic dysfunction and jaundice in 23 (57.5%) patients, renal failure in 18 (45%) patients, severe anemia in 13 (32.5%) patients, cerebral malaria in 5 patients (12.5%), acute respiratory distress syndrome in 4 patients (10%), shock in 3 patients (7.5%), and hypoglycemia in 1 (2.5%) patient. Thrombocytopenia was observed in 5 (12.5%) patients, and multi-organ dysfunction was detected in 19 (47.5%) patients. Further large-scale multicentric epidemiologic studies are needed to define the basic pathology of this less known entity.

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Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.

A. Cowman, Matthew B. Biggs, M J Morry … (1988)

We describe the isolation and the sequence of the gene for the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS; EC 1.5.1.3 and EC 2.1.1.45, respectively) from two pyrimethamine-resistant clones of Plasmodium falciparum, HB3 and 7G8. We have also derived the sequence of the DHFR portion of the gene, by amplification using polymerase chain reaction, for the pyrimethamine-sensitive clone 3D7 and the pyrimethamine-resistant strains V-1, K-1, Csl-2, and Palo-alto. The deduced protein sequence of the resistant DHFR portion of the enzyme from HB3 contained a single amino acid difference from the pyrimethamine-sensitive clone 3D7. It is highly likely that this difference is involved in the mechanism of drug resistance in HB3. The sequence of the DHFR gene from other pyrimethamine-resistant strains contains the same amino acid difference from the sensitive clone 3D7. However, they all differ at one other site that may influence pyrimethamine resistance. The DHFR-TS gene is present as a single copy on chromosome 4 in all pyrimethamine-sensitive and pyrimethamine-resistant isolates tested. Therefore, the molecular basis of pyrimethamine resistance in the parasites tested is not amplification of the DHFR-TS gene.

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Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance

Bruno B. Andrade, Antonio Reis-Filho, Sebastião Souza-Neto … (2010)

Background Despite clinical descriptions of severe vivax malaria cases having been reported, data regarding immunological and inflammatory patterns are scarce. In this report, the inflammatory and immunological status of both mild and severe vivax malaria cases are compared in order to explore immunopathological events in this disease. Methods and Results Active and passive malaria case detections were performed during 2007 in Buritis, Rondônia, in the Brazilian Amazon. A total of 219 participants enrolled the study. Study individuals were classified according to the presence of Plasmodium vivax infection within four groups: non-infected (n = 90), asymptomatic (n = 60), mild (n = 50) and severe vivax infection (n = 19). A diagnosis of malaria was made by microscopy and molecular assays. Since at present no clear criteria define severe vivax malaria, this study adapted the consensual criteria from falciparum malaria. Patients with severe P. vivax infection were younger, had lived for shorter time in the endemic area, and recalled having experienced less previous malaria episodes than individuals with no malaria infection and with mild or asymptomatic infection. Strong linear trends were identified regarding increasing plasma levels of C reactive protein (CRP), serum creatinine, bilirubins and the graduation of disease severity. Plasma levels of tumour necrosis factor (TNF), interferon-gamma(IFN-gamma) and also IFN-gamma/interleukin-10 ratios were increased and exhibited a linear trend with gradual augmentation of disease severity. Both laboratory parameters of organ dysfunction and inflammatory cytokines were reduced during anti-parasite therapy in those patients with severe disease. Conclusion Different clinical presentations of vivax malaria infection present strong association with activation of pro-inflammatory responses and cytokine imbalance. These findings are of utmost importance to improve current knowledge about physiopathological concepts of this serious widespread disease.

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Author and article information

Journal

Journal ID (nlm-ta): Malar J

Title: Malaria Journal

Publisher: BioMed Central

ISSN (Electronic): 1475-2875

Publication date Collection: 2011

Publication date (Electronic): 24 April 2011

Volume: 10

Page: 102

Affiliations

[1 ]Genetics and Molecular Biology Laboratory, National Institute of Malaria Research (NIMR), Sector-8, Dwarka, New Delhi 110077, India

[2 ]NIMR field station, Assam, India

Article

Publisher ID: 1475-2875-10-102

DOI: 10.1186/1475-2875-10-102

PMC ID: 3098820

PubMed ID: 21513569

SO-VID: ff269d90-326b-4d9b-a3e0-730723516659

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular epidemiology of Plasmodium vivax anti-folate resistance in India

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Abstract

Background

Methods

Results

Conclusion

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Point-Of-Care Testing for STIs

Most cited references 37

Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India.

Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum.

Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance

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