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. 2021 Aug 2;46(1):296–303. doi: 10.1007/s12639-021-01425-7

An analysis of Plasmodium falciparum-K13 mutations in India

Laxman Kumar Murmu 1, Tapan Kumar Barik 1,✉
PMCID: PMC8901923  PMID: 35299922

Abstract

Malaria is one of the deadliest parasitic diseases in human. Currently, Artemisinin-based combination therapy is considered as the gold standard and most common treatment option. However, the origin and transmission of Plasmodium falciparum from the Greater Mekong Subregion, which has decreased artemisinin (ART) sensitivity, has sparked global concern. The reduced ART sensitivity has been associated with mutations in the Atpase6 and Kelch13 propeller domain of Plasmodium falciparum. A molecular marker is critically needed to monitor the spread of artemisinin resistance. In this article, we reviewed the k13 mutations and potential marker for ART resistance in India. There have been fourteen mutations identified, three of which have been validated by the World Health Organization (WHO) as artemisinin resistance mutations (F446I, R561H/C, and R539T). Among them, the role of F446I and R561H/C in ART resistance is conflicting. R539T and G625R mutation has been identified as an ART- resistance marker in India.

Keywords: Artemisinin, K13 Mutation, Sensitivity, India

Introduction

The tremendous efforts on malaria elimination and containments over the recent past decades have reduced malaria-related morbidity and mortality globally (WHO 2019). However still, malaria remains a significant health burden in an endemic region. There were an estimated 228 million cases and 4,05,000 death in 2018 (WHO 2019). The WHO African region recorded 93 per cent of malaria cases in 2018, followed by the WHO South-East Asia region with 3.4 per cent. India accounts for most patients in South-East Asia, with 6.7 million cases (WHO 2019). Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium knowlesi are the six Plasmodium parasites that causes malaria in humans (Lalremruata et al. 2017; Joste et al. 2018). Plasmodium knowlesi is a zoonotic, crucial human pathogen in Africa and South-East Asia (Oguike et al. 2011; Antinori et al. 2013; Ansari et al. 2016; Lalremruata et al. 2017). The malaria parasite Plasmodium falciparum is predominant to cause malaria in India, along with Plasmodium vivax, and rarely Plasmodium malariae. The map shows India's region with death due to malaria (Fig. 1). Plasmodium ovale curtisi, and Plasmodium ovale wallikeri, two newly described parasites have also been found to cause malaria in India (Chaturvedi et al. 2015).

Fig. 1.

Fig. 1

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The map shows India’s region with death due to malaria

(Source: NVBDCP)

Traditionally, anti-malarial drugs are employed to treat uncomplicated malaria as no effective vaccine is available (Wykes 2013; Barik 2015; Draper et al. 2018). Chloroquine was the first synthetic quinine-based anti-malarial compound used to treat uncomplicated malaria and has been a front-line drug for more than three decades. The rise and development of Plasmodium falciparum malaria resistance to the then existing anti-malarial drugs have jeopardized the malaria situation in the endemic region. The past reports of rampant use of counterfeit and substandard drugs (Lon et al.2006) resulted in the loss of chloroquine (CQ) susceptibility in Plasmodium falciparum independently in South America and Southeast Asia (Payne 1987; Chen et al. 2003; Packard 2014). The spread of CQ resistance from these foci was seen in the high infant mortality in South America, Southeast Asia, and Africa (Müller et al. 2019). In 1973, the first evidence of CQ resistance to Plasmodium falciparum was reported in India (Sehgal et al. 1973). Subsequently, a significant rise in the resistance to this drug was reported (Sharma et al. 1996; Vinayak et al. 2003). The Indian agency for prevention and control of disease, the National vector-borne disease control program (NVBDCP), had to drop CQ treatment for Plasmodium falciparum due to rising resistance to the drug. In 1982, sulphadoxine-pyrimethamine (SP) was prescribed as a second-line treatment for falciparum malaria in the CQ resistance region. In the midst of this, a low degree of in vivo SP resistance had previously been established, and an increase in resistant SP allele frequency from low frequencies was observed (Ahmed et al. 2004; Kumar et al. 2015). Thus, in 2005, SP, which was used as a second-line treatment for CQ resistance, was replaced with artesunate plus sulphadoxine-pyrimethamine. As a result, in 2007, artesunate plus sulphadoxine-pyrimethamine (AS + SP) was approved as the first-line treatment for areas with SP resistance. This protocol became the first-line treatment in India in 2010. In 2012, the North-eastern state recorded declining efficacy results for artesunate plus sulphadoxine-pyrimethamine (AS + SP), and treatment failure report was widespread. As a result, the AS + SP protocol was updated with artemether-lumefantrine for uncomplicated malaria cases (Mishra et al. 2014, 2016). Artemisinin (ART) is a fast-acting drug best suited to combine with long-lived partner drugs for better post-treatment prophylactic effects, reducing recurrence probability (Li and Hickman 2015; Tse et al. 2019). Artemether-lumefantrine (A.L.), artesunate-sulphadoxine-pyrimethamine (AS + SP), artesunate-amodiaquine (AS-AQ), artesunate-mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DHA-PPQ) are the most commonly prescribed regimens for uncomplicated malaria (Sinclair et al. 2009; WHO 2018). Oral artesunate and artemether are self-active compounds converted by blood esterase to the active metabolite dihydroartemisinin (DHA), which is effective against Plasmodium parasites (Woodrow and White 2017; Tse et al. 2019). Artemisinin and its derivatives have a short elimination half-life and kill malaria parasite, thus reducing parasite infliction (Bridgford et al. 2018). However, artemisinin monotherapy does not destroy all parasites, as a subpopulation of ring-stage malaria parasites may escape and enter a state of dormancy, only to re-emerge days to weeks after treatment failure (Codd et al. 2011; Woodrow and White 2017). Since artemisinin has been used in India for decades, it is critical to track the spread of resistance and therapeutic efficacy. This article reviews the current status of Kelch13 mutations, the emergence of artemisinin-resistant malaria, and potential artemisinin resistance marker in India.

The current landscape of Artemisinin resistance in India

India is a gateway to spread resistance to Africa and the rest of the world and shares a porous border with hotbeds for the emergence of drug resistance in Southeast Asia. Thus, it is imperative to have the region's drug resistance profile to manage better and contain the drug resistance menace. The North-eastern Indian bordering terrains are densely covered with hills, forests and receive high rainfall favors conducive climatic conditions for high malaria transmission and parasite load. In 2013–14, an emergence of artemisinin resistance malaria was recorded in India, and known drug failure (Das et al. 2018, 2019; WHO 2018). The first global report of K13 mutation was discovered in western Cambodia, with the most common mutations being C580Y, Y493H, and R539T (Ariey et al. 2014). Since then, more than 300 mutations have been identified around the world (Fairhurst 2015). Table 1 provides the k13 validated associated/candidates for artemisinin resistance in the global malaria-endemic region. Indian bordering areas of China-Myanmar have prevalent F446I, R539T, P574L, N458Y, R561H, and A676D mutations (Ariey et al. 2014; Feng et al. 2015; Wang et al. 2015; Ye et al. 2016). It assumed that the resistant strain Plasmodium falciparum in Myanmar's Sagaing region might spread to neighboring India (Tun et al. 2015). Thus, the threat of the spread of resistance to mainland endemic regions is enormous and requires strict surveillance of resistant parasite strain.

Table 1.

Distribution of K13 mutations in the global endemic region

Country Mutations References
Cambodia

R539T*, C580Y*, Y493H*, I543T*, N458Y*, R561H*, G449A#, V568G#, P574L#, P553L#,

T474I**, A481V**, T508N**, P527T**, G533S**, N537I**, S623C**

 (Ariey et al. 2014; Dwivedi et al. 2016; Kheang et al. 2017)
Myanmar C580Y*, R539T*, N458Y*, R561H*, G449A#, P441L#, P574L#, P553L#, A675V#, F446I# M476I**, A481V**, R515T**, N537I**, D452E**, K479I**, C469F**, R528T**, R575K**, V496F**, P667T**, M476I**, T474I**, M476V**, C469F**, N490T**, Y511H**, G533A**, G538V**, N537I**, E556D**, F673I**, N458I**, E252Q**, A676D** (Tun et al. 2015;Nyunt et al. 2015; Wang et al. 2017;Nyunt et al. 2017)
Thailand C580Y*, R539T*, Y493H*, R561H*, N458Y*, P441L#, G449A#, P574L#, A481V**, P527H**, E556D**, Y604H**, E605G**, N609S**, N632D**, R575K**, S621F** (Talundzic et al. 2015; Putaporntip et al. 2016)
Nigeria E433G**, F434I**, F434S**, I684N**, I684T**, E688K** (Abubakar et al. 2020)
Democratic Republic of the Congo A578S## (Nzoumbou-Boko et al. 2020)
United Republic of Tanzania R561H*, A578S## (Bwire et al. 2020)
Burkina Faso C469C**, Y493Y**, G496G**, V589V** (Somé et al. 2016)
Mozambique V494I** (Escobar et al. 2015)
Niger M472I**, Y558C**, K563R**, P570L**, P615S** (Laminou et al. 2018)
Uganda A578S## (Hawkes et al. 2015)
Kenya, Malawi P553L# (Taylor et al. 2014)
Mali P553L#, F446I#, A578S## (Taylor et al. 2014; Kamau et al. 2015; Ouattara et al. 2015)
Angola, Equatorial Guinea, Rwanda R539T*, P574L# (Nzoumbou-Boko et al. 2020)
Congo, Gabon, Ghana, Kenya A578S## (Kamau et al. 2015; Nzoumbou-Boko et al. 2020)
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*Validated K13 mutations; # Associated K13 mutations; ## Common mutation but not associated; ** mutation

Recent studies from Indian field isolates show the mutation in the Plasmodium falciparum chromosome kelch13 propeller region. Mishra et al. (2015) conducted a sentinel site study in fifteen Indian states to determine the therapeutic efficacy of ACT (artesunate + sulphadoxine), enrolling 389 subjects in a prospective study. G533A/S, S549Y, R561 H/C, non-synonymous mutations have been found in isolates from Gomati (Tripura), Jalpaiguri (West Bengal), and Changlang (Arunachal Pradesh) (Mishra et al. 2015). Nonetheless, their involvement was not linked to treatment failure. Furthermore, In 254 patients from Mizoram, Tripura, and Arunachal Pradesh, Mishra et al. (2016) discovered non-synonymous mutations F446I and A578S K13propeller region, as well as K189T in the K13 non-propeller region. The therapeutics efficacy studies of ACT in central India reveal the 1.5 per cent incidence of single non-synonymous mutation at codon M579T/H and 37% double mutation at codon M579T/H, N657H (Mishra et al. 2017). Besides that, non-synonymous mutations at A481V, A675V, and D702N were discovered in 134 patients from three northeast states during a routine analysis of the pfk13 propeller domain (Das et al. 2017). Recent research from the Eastern Indian state also discovered a novel mutation, G625R, and a WHO-validated R539T mutation, linked to artemisinin resistance. Table 2 depicts the distribution of Plasmodium falciparum K13 mutations in India. This artemisinin resistance assay was based on criteria of parasite clearance half-life > 5 hrs and parasite survival rate greater than 10% based on ex vivo RSA0-3 h (Das et al. 2018). However, F446I, R539T, R561H/C mutations are validated for artemisinin resistance in Greater Mekong Subregion (WHO 2018). Map showing the reported malaria cases due to Plasmodium falciparum in India and reported k-13 validated mutations (Fig. 2).

Table 2.

Plasmodium falciparum-K13 mutations in India

States/Districts Year of study Mutation observed Mutation in k13 Propeller region Assay employed References
Arunachal Pradesh (Changlang)

2014–2015

2009–2013

2014–2015

F446I

R561H

A481V

A675V

D702N

F446I

R561H

A481V A675V D702N

Molecular marker studies

Prospective therapeutics studies

Molecular marker studies

Mishra et al. (2016)

Mishra et al. (2015)

Das et al. (2017)
Mizoram (Lunglei) 2014–2015 A578S, K189T A578S Molecular marker studies Mishra et al. (2016)
Tripura (Gomati) 2014–2015

K189T

G533A

 G533A Molecular marker studies Mishra et al. (2016); Mishra et al. (2015)
West Bengal

2013–2014

2009–2013

G625R

N672S

R539T

R539T

G625R

N672S

S549Y

Ex vivo Ring-stage survival Assay (RSA 0-3 h)

Prospective therapeutics studies

Das et al. (2018)

Mishra et al. (2015)
Madhya Pradesh 2012–2014

M579T

N657H

M579T

N657H

 Molecular marker studies Mishra et al. (2017)
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Fig. 2.

Fig. 2

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Map showing the reported malaria cases due to Plasmodium falciparum in India

Source: NVBDCP and reported k-13 validated mutations

Single nucleotide polymorphism as a molecular marker for ART Resistance

The F446I and R561 H/C, Single nucleotide polymorphism, has recently been identified from north-eastern India. This polymorphism was previously discovered to be the validated gene marker for ART resistance along with delayed parasite clearance in the bordering area of China and Myanmar (Mishra et al. 2016; WHO, 2018). In India, however, no correlation has been found between this polymorphism and parasite clearance or treatment outcome (Mishra et al. 2016). Since alleles in the k13 propeller domain are heterogeneous, its critical to double-check the ART- resistance marker. The R539T polymorphism is common in Cambodia and has been identified as an ART- resistance marker (Ariey et al. 2014; Straimer et al. 2015). This polymorphism, along with the G625R polymorphism, has been linked to parasite clearance half-life positivity and high survival rates in eastern India, as determined by a ring-stage survival assay (0-3 h), and has been proposed as an ART resistance marker in India.

Surveillance of artemisinin resistance

The surveillance system enables diagnosis and track real-time information on the emergence and spread of anti-malarial drug resistance. This allows prompt steps to mitigate malaria-related morbidity and mortality. Ring-stage survival assay (RSA), either vitro ring-stage survival assay (RSA 0–3 h) or ex vivo RSA, as well as molecular marker studies of validated signatures in the Plasmodium falciparum parasites are currently used to track down artemisinin resistance (Witkowski et al. 2013a; Ariey et al. 2014; WHO 2018; Murmu et al. 2021). The RSA consists of parasite culture (0-3 h) either obtained directly from the infected patient or adapted parasite lines being synchronized by 5% sorbitol solution and then exposed to 700 nM dihydroartemisinin (DHA) for 6 h, maintaining the 37 °C, humid atmosphere,5% O2, 5% CO2, and 90% N2 condition. Then parasites are harvested, DHA is washed out and again cultivated for 66 h. Finally, the viable parasites are determined (Witkowski et al. 2013b) (https://www.wwarn.org/tools-resources/procedures/ring-stage-survival-assays-rsa-evaluate-vitro-and-ex-vivo-susceptibility).However, Genomic DNA is extracted from either Giemsa-stained clinical thick blood films or directly collected finger pricked blood spots from patients in molecular marker studies for validated single nucleotide polymorphism (SNP). The extracted parasite DNA is then PCR amplified, accompanied by PCR products sequencing and SNP analysis.

Concluding remarks

ACT is an effective regimen for severe malaria. Nevertheless, the spread of resistant strain Plasmodium falciparum to India with delay in parasite clearance time and reduced susceptibility is a threat to malaria control and eradication strategy. Artemisinin resistance must be monitored on a large scale by PCHL, RSA, or kelch13 molecular marker studies. The information gleaned from such investigation may aid in the successful management of the Plasmodium falciparum parasites. G625R polymorphism has been verified as a validated marker for ART resistance in eastern India, along with R539T, which was also identified as an ART-resistance marker in Cambodia. Thus, proper mitigation for the containment of parasites is highly essential.

Acknowledgements

The authors want to acknowledge all researchers whose publications were used in our review.

Author contributions

Both authors LKM and TKB conceived the idea, searched the literature, and drafted the final version of the manuscript.

Declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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