Characterization of genes involved in hemoglobin degradation in Plasmodium vivax isolates from Chennai, India, and species of non-human primate malaria

IF 2.6 4区医学 Q3 INFECTIOUS DISEASES

Infection Genetics and Evolution Pub Date : 2025-09-11 DOI:10.1016/j.meegid.2025.105823

Sneh Shalini , Neelima Mishra , Sonia Verma , Sonal Kale , Prashant K. Mallick , Surendra K. Prajapati , Anil Kumar , Nalini Srivastava , Hema Joshi , Alex Eapen , Om P. Singh

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引用次数: 0

Abstract

Background

Plasmodium vivax poses a persistent obstacle to global malaria elimination efforts. While no detectable chloroquine (CQ) resistance has been found in patient samples from India, this observation awaits confirmation. The mechanism of action of CQ continues to be debated. Hemoglobin degradation within the parasite's food vacuole (FV) is integral to its survival and serves as a promising target for antimalarial drug development.

Methods

This study investigates the molecular and structural characteristics of three key FV enzymes—plasmepsin IV (PM_IV), heme detoxification protein (HDP), and falcilysin (FLN)—in P. vivax isolates from India. Genomic DNA from 30 clinical isolates and three chloroquine (CQ)-resistant reference strains was analyzed to identify mutations and assess structural implications through homology modelling.

Results

Several nonsynonymous mutations were detected, including c.493G>A (Val165Ile) in PM_IV, c.1537A>G (Asn513Asp), and c.2027G>A (Gly676Asp) in FLN, and a novel in-frame duplication c.28_33dup (ATCGCC) in HDP. Structural modelling revealed that these mutations did not affect the active binding sites of the enzymes.

Conclusions

The genes were highly conserved across isolates, underscoring their important (essential) roles in parasite survival and their potential as drug targets. These are the first findings from the Indian subcontinent that provide critical insights into the mechanisms of chloroquine (CQ) action and resistance, paving the way for novel therapeutic strategies against Plasmodium vivax malaria.

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印度金奈间日疟原虫分离株和非人灵长类疟疾种血红蛋白降解相关基因的研究

背景：间日疟原虫对全球消除疟疾的努力构成了持续的障碍。虽然在印度患者样本中未发现可检测到的氯喹耐药性，但这一观察结果有待证实。CQ的作用机制仍有争议。寄生虫食物液泡（FV）内的血红蛋白降解是其生存所不可或缺的，也是抗疟疾药物开发的一个有希望的靶点。方法：研究印度间日疟原虫分离株中三种关键酶——plasmepsin IV （PM_IV）、血红素解毒蛋白（HDP）和falcilysin （FLN）的分子结构特征。分析了30株临床分离株和3株氯喹耐药参考株的基因组DNA，通过同源性建模鉴定突变并评估结构意义。结果：检测到多个非同同义词突变，包括PM_IV中的c.493G > A (Val165Ile)， FLN中的c.1537G > A （Asn513Asp）和c.2027G > A (Gly676Asp)，以及HDP中新的帧内重复c.36_41dup （ATCGCC）。结构模型显示，这些突变不影响酶的活性结合位点。结论：这些基因在整个分离株中高度保守，强调了它们在寄生虫生存中的重要（基本）作用和它们作为药物靶点的潜力。这些是来自印度次大陆的首次发现，为氯喹（CQ）的作用和耐药性机制提供了重要见解，为针对间日疟原虫疟疾的新治疗策略铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Infection Genetics and Evolution 医学-传染病学

CiteScore

8.40

自引率

0.00%

发文量

215

审稿时长

82 days

期刊介绍： (aka Journal of Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases -- MEEGID) Infectious diseases constitute one of the main challenges to medical science in the coming century. The impressive development of molecular megatechnologies and of bioinformatics have greatly increased our knowledge of the evolution, transmission and pathogenicity of infectious diseases. Research has shown that host susceptibility to many infectious diseases has a genetic basis. Furthermore, much is now known on the molecular epidemiology, evolution and virulence of pathogenic agents, as well as their resistance to drugs, vaccines, and antibiotics. Equally, research on the genetics of disease vectors has greatly improved our understanding of their systematics, has increased our capacity to identify target populations for control or intervention, and has provided detailed information on the mechanisms of insecticide resistance. However, the genetics and evolutionary biology of hosts, pathogens and vectors have tended to develop as three separate fields of research. This artificial compartmentalisation is of concern due to our growing appreciation of the strong co-evolutionary interactions among hosts, pathogens and vectors. Infection, Genetics and Evolution and its companion congress [MEEGID](http://www.meegidconference.com/) (for Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases) are the main forum acting for the cross-fertilization between evolutionary science and biomedical research on infectious diseases. Infection, Genetics and Evolution is the only journal that welcomes articles dealing with the genetics and evolutionary biology of hosts, pathogens and vectors, and coevolution processes among them in relation to infection and disease manifestation. All infectious models enter the scope of the journal, including pathogens of humans, animals and plants, either parasites, fungi, bacteria, viruses or prions. The journal welcomes articles dealing with genetics, population genetics, genomics, postgenomics, gene expression, evolutionary biology, population dynamics, mathematical modeling and bioinformatics. We also provide many author benefits, such as free PDFs, a liberal copyright policy, special discounts on Elsevier publications and much more. Please click here for more information on our author services .