Agnes C. Cheruiyot

United States Army Medical Research Directorate - Africa

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Hoseah M. Akala

United States Army Medical Research Directorate - Africa

Dennis W. Juma

Kenya Medical Research Institute

Ben Andagalu

United States Army Medical Research Directorate - Africa

Redemptah Yeda

United States Army Medical Research Directorate - Africa

Benjamin Opot

Kenya Medical Research Institute

Edwin Kamau

Walter Reed National Military Medical Center

Raphael Okoth

Kenya Medical Research Institute

Gladys Chemwor

United States Army Medical Research Directorate - Africa

Charles Okudo

United States Army Medical Research Directorate - Africa

Edwin W. Mwakio

United States Army Medical Research Directorate - Africa

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Kenya Medical Research Institute

United States Army Medical Research Directorate - Africa

Assistance Publique – Hôpitaux de Paris

Université Paris Cité

Inserm

Institut de Recherche pour le Développement

Centre National de la Recherche Scientifique

Walter Reed Army Institute of Research

Maseno University

Laboratoire National de Référence

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Longitudinal characterization of Plasmodium inter-species interactions during a period of increasing prevalence of Plasmodium ovale

medRxiv (Cold Spring Harbor Laboratory) (2020)

Hoseah M. Akala Oliver J. Watson Kenneth K. Mitei Dennis W. Juma Robert Verity

Abstract Background The epidemiology and severity of non-falciparum malaria in endemic settings has garnered limited attention. We aimed to characterize the prevalence, interaction, clinical risk factors and temporal trends of non-falciparum malaria in endemic settings of Kenya. Methods We diagnosed and analyzed infecting malaria species via PCR in 2027 clinical samples collected between 2008 and 2016. Descriptive statistics were used to describe the prevalence and distribution of Plasmodium species. A statistical model was designed and used for estimating the frequency of Plasmodium species and assessing inter-species interactions. Mixed effect linear regression models with random intercepts for each location was used to test for change in prevalence over time. Findings 72•5% of the samples were P. falciparum single species infections, 25·8% were mixed infections and only 1•7% occurred as single non-falciparum species infections. 23•1% were mixed infections containing P. ovale . A likelihood-based model calculation of the population frequency of each species estimated a significant within-host interference between P. falciparum and P. ovale curtisi . Mixed-effect logistic regression models identified a significant increase of P. ovale wallikeri and P. ovale curtisi species over time with reciprocal decrease in P. falciparum single species and P. malariae . The risk of P. falciparum infections presenting with fever was 0•43 times less likely if co-infected with P. malariae . Interpretation Findings show higher prevalence of non-falciparum malaria than expected. The proportion of infections that were positive for infection by P. ovale wallikeri and P. ovale curtisi was observed to significantly increase over the period of study which could be due to attenuated responsiveness to malaria drug treatment on these species. The increase in frequency of P. ovale spp in Kenya could threaten malaria control effort in Kenya and pose increased risk of malaria to travelers. Funding AFHSB and its GEIS Section

Plasmodium ovale

Plasmodium malariae

10.1101/2019.12.28.19015941

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Citations (1)

Plasmodium interspecies interactions during a period of increasing prevalence of Plasmodium ovale in symptomatic individuals seeking treatment: an observational study

The Lancet Microbe (2021)

Hoseah M. Akala Oliver J. Watson Kenneth K. Mitei Dennis W. Juma Robert Verity

The epidemiology and severity of non-falciparum malaria in endemic settings has garnered little attention. We aimed to characterise the prevalence, interaction, clinical risk factors, and temporal trends of non-falciparum Plasmodium species among symptomatic individuals presenting at health-care facilities in endemic settings of Kenya.We diagnosed and analysed infecting malaria species (Plasmodium falciparum, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium malariae) via PCR in clinical samples collected between March 1, 2008, and Dec 31, 2016, from six hospitals located in different regions of Kenya. We recruited patients aged 6 months or older who presented at outpatient departments with symptoms of malaria or tested positive for uncomplicated malaria by malaria rapid diagnostic test. Descriptive statistics were used to describe the prevalence and distribution of Plasmodium species. A statistical model was designed and used for estimating the frequency of Plasmodium species and assessing interspecies interactions. Mixed-effect linear regression models with random slopes for each location were used to test for change in prevalence over time.Samples from 2027 symptomatic participants presenting at care facilities were successfully analysed for all Plasmodium species. 1469 (72·5%) of the samples were P falciparum single-species infections, 523 (25·8%) were mixed infections, and only 35 (1·7%) were single non-falciparum species infections. 452 (22·3%) were mixed infections containing P ovale spp. A likelihood-based model calculation of the population frequency of each species estimated a significant within-host interference between P falciparum and P ovale curtisi. Mixed-effect logistic regression models identified a significant increase in P ovale wallikeri (2·1% per year; p=0·043) and P ovale curtisi (0·7% per year; p=0·0002) species over time, with a reciprocal decrease in P falciparum single-species infections (2·5% per year; p=0·0065). The frequency of P malariae infections did not significantly change over time. Risk of P falciparum infections presenting with fever was lower if co-infected with P malariae (adjusted odds ratio 0·43, 95% CI 0·25-0·74; p=0·0023).Our results show a prevalence of non-falciparum species infections of 27·5% among symptomatic individuals presenting at care facilities, which is higher than expected from previous cross-sectional surveys. The proportion of infections with P ovale wallikeri and P ovale curtisi was observed to significantly increase over the period of study, which could be due to attenuated responsiveness of these species to malaria drug treatment. The increase in frequency of P ovale spp could threaten the malaria control efforts in Kenya and pose increased risk of malaria to travellers.Armed Forces Health Surveillance Branch and its Global Emerging Infections Surveillance Section.

Plasmodium ovale

Plasmodium malariae

Plasmodium (life cycle)

Rapid diagnostic test

10.1016/s2666-5247(21)00009-4

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The Role of Pfmdr1 and Pfcrt in Changing Chloroquine, Amodiaquine, Mefloquine and Lumefantrine Susceptibility in Western-Kenya P. falciparum Samples during 2008–2011

PLoS ONE (2013)

Fredrick Eyase Hoseah M. Akala Luiser A. Ingasia Agnes C. Cheruiyot Angela A. Omondi

Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008–2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.

Amodiaquine

Lumefantrine

10.1371/journal.pone.0064299

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Analysis of Major Genome Loci Underlying Artemisinin Resistance and pfmdr1 Copy Number in pre- and post-ACTs in Western Kenya

Scientific Reports (2015)

Bidii S. Ngalah Luiser A. Ingasia Agnes C. Cheruiyot Lorna J. Chebon Dennis W. Juma

Abstract Genetic analysis of molecular markers is critical in tracking the emergence and/or spread of artemisinin resistant parasites. Clinical isolates collected in western Kenya pre- and post- introduction of artemisinin combination therapies (ACTs) were genotyped at SNP positions in regions of strong selection signatures on chromosome 13 and 14, as described in Southeast Asia (SEA). Twenty five SNPs were genotyped using Sequenom MassArray and pfmdr 1 gene copy number by real-time PCR. Parasite clearance half-life and in vitro drug sensitivity testing were performed using standard methods. One hundred twenty nine isolates were successfully analyzed. Fifteen SNPs were present in pre-ACTs isolates and six in post-ACTs. None of the SNPs showed association with parasite clearance half-life. Post-ACTs parasites had significantly higher pfmdr 1 copy number compared to pre-ACTs. Seven of eight parasites with multiple pfmdr 1 were post-ACTs. When in vitro IC 50 s were compared for parasites with single vs. multiple gene copies, only amodiaquine and piperaquine reached statistical significance. Data showed SNPs on chromosome 13 and 14 had different frequency and trend in western Kenya parasites compared SEA. Increase in pfmdr 1 gene copy is consistent with recent studies in African parasites. Data suggests genetic signature of artemisinin resistance in Africa might be different from SEA.

Piperaquine

SNP

SNP array

10.1038/srep08308

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Harboring of Plasmodium Falciparum and Plasmodium Ovale Wallikeri Multiple Species Associated with Symptomatic Malaria in Endemic Population

Juma A. Jackline Oliver J. Watson Dennis W. Juma Benjamin Opot Gladys Chemwor

Plasmodium ovale

Plasmodium (life cycle)

10.2139/ssrn.4962460

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Therapeutic response to artemisinin combination therapies among individuals with Plasmodium falciparum single infection vs mixed Plasmodium species infections: a retrospective posthoc analysis in Kisumu County, western Kenya

International Journal of Infectious Diseases (2023)

Gladys Chemwor Ben M. Andagalu Irene Onyango Benjamin Opot Raphael Okoth

This study examined the treatment response of mixed vs single-species Plasmodium falciparum infections to artemisinin-based combination therapies (ACTs).A total of 1211 blood samples collected on days 0, 7, 14, 21, 28, 35, and 42 from 173 individuals enrolled in two randomized ACT efficacy studies were tested for malaria using 18s ribosomal RNA-based real-time polymerase chain reaction. All recurrent parasitemia were characterized for Plasmodium species composition and time to reinfection during 42-day follow-up compared across ACTs.Day 0 samples had 71.1% (116/163) single P. falciparum infections and 28.2% (46/163) coinfections. A total of 54.0% (88/163) of individuals tested positive for Plasmodium at least once between days 7-42. A total of 19.3% (17/88) of individuals with recurrent infections were infected with a different Plasmodium species than observed at day 0, with 76.5% (13/17) of these "hidden" infections appearing after clearing P. falciparum present at day 0. Artesunate-mefloquine (16.4 hours) and dihydroartemisinin-piperaquine (17.6 hours) had increased clearance rates over artemether-lumefantrine (21.0 hours). Dihydroartemisinin-piperaquine exhibited the longest duration of reinfection prophylaxis. Cure rates were comparable across each species composition.No differences in clearance rates were found depending on whether the infection contained species other than P. falciparum. Significantly longer durations of protection were observed for individuals treated with dihydroartemisinin-piperaquine.

Piperaquine

Dihydroartemisinin

Artesunate

10.1016/j.ijid.2023.04.008

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Reduced In Vitro Doxycycline Susceptibility in Plasmodium falciparum Field Isolates from Kenya Is Associated with PfTetQ KYNNNN Sequence Polymorphism

Antimicrobial Agents and Chemotherapy (2014)

Angela O. Achieng Luiser A. Ingasia Dennis W. Juma Agnes C. Cheruiyot Charles A. Okudo

Doxycycline is widely used for malaria prophylaxis by international travelers. However, there is limited information on doxycycline efficacy in Kenya, and genetic polymorphisms associated with reduced efficacy are not well defined. In vitro doxycycline susceptibility profiles for 96 Plasmodium falciparum field isolates from Kenya were determined. Genetic polymorphisms were assessed in P. falciparum metabolite drug transporter (Pfmdt) and P. falciparum GTPase tetQ (PftetQ) genes. Copy number variation of the gene and the number of KYNNNN amino acid motif repeats within the protein encoded by PftetQ were determined. Reduced in vitro susceptibility to doxycycline was defined by 50% inhibitory concentrations (IC50s) of ≥35,000 nM. The odds ratio (OR) of having 2 PfTetQ KYNNNN amino acid repeats in isolates with IC50s of >35,000 nM relative to those with IC50s of <35,000 nM is 15 (95% confidence interval [CI], 3.0 to 74.3; P value of <0.0002). Isolates with 1 copy of the Pfmdt gene had a median IC50 of 6,971 nM, whereas those with a Pfmdt copy number of >1 had a median IC50 of 9,912 nM (P = 0.0245). Isolates with 1 copy of PftetQ had a median IC50 of 6,370 nM, whereas isolates with a PftetQ copy number of >1 had a median IC50 of 3,422 nM (P < 0.0007). Isolates with 2 PfTetQ KYNNNN motif repeats had a median IC50 of 26,165 nM, whereas isolates with 3 PfTetQ KYNNNN repeats had a median IC50 of 3,352 nM (P = 0.0023). PfTetQ sequence polymorphism is associated with a reduced doxycycline susceptibility phenotype in Kenyan isolates and is a potential marker for susceptibility testing.

IC50

10.1128/aac.02788-13

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Citations (12)

Polymorphisms in Pf mdr1 , Pf crt , and Pf nhe1 Genes Are Associated with Reduced In Vitro Activities of Quinine in Plasmodium falciparum Isolates from Western Kenya

Antimicrobial Agents and Chemotherapy (2014)

Jelagat Cheruiyot Luicer A. Ingasia Angela A. Omondi Dennis W. Juma Benjamin Opot

ABSTRACT In combination with antibiotics, quinine is recommended as the second-line treatment for uncomplicated malaria, an alternative first-line treatment for severe malaria, and for treatment of malaria in the first trimester of pregnancy. Quinine has been shown to have frequent clinical failures, and yet the mechanisms of action and resistance have not been fully elucidated. However, resistance is linked to polymorphisms in multiple genes, including multidrug resistance 1 (Pf mdr1 ), the chloroquine resistance transporter (Pf crt ), and the sodium/hydrogen exchanger gene (Pf nhe1 ). Here, we investigated the association between in vitro quinine susceptibility and genetic polymorphisms in Pf mdr1 codons 86 and 184, Pf crt codon 76, and Pf nhe1 ms4760 in 88 field isolates from western Kenya. In vitro activity was assessed based on the drug concentration that inhibited 50% of parasite growth (the IC 50 ), and parasite genetic polymorphisms were determined from DNA sequencing. Data revealed there were significant associations between polymorphism in Pf mdr1 -86Y, Pf mdr1 -184F, or Pf crt -76T and quinine susceptibility ( P < 0.0001 for all three associations). Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pf mdr1 -86Y, Pf mdr1 -184F, and Pf crt -76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pf mdr1 -N86, Pf mdr1 -Y184, and Pf crt -K76, respectively). In addition, quinine IC 50 values for parasites with Pf nhe1 ms4760 3 DNNND repeats were significantly higher than for those with 1 or 2 repeats ( P = 0.033 and P = 0.0043, respectively). Clinical efficacy studies are now required to confirm the validity of these markers and the importance of parasite genetic background.

Quinine

10.1128/aac.02472-14

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Citations (27)

Trends in drug resistance codons in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in Kenyan parasites from 2008 to 2012

Malaria Journal (2014)

Dennis W. Juma Angela A. Omondi Luiser A. Ingasia Benjamin Opot Agnes C. Cheruiyot

Sulphadoxine-pyrimethamine (SP), an antifolate, was replaced by artemether-lumefantrine as the first-line malaria drug treatment in Kenya in 2004 due to the wide spread of resistance. However, SP still remains the recommended drug for intermittent preventive treatment in pregnant women and infants (IPTP/I) owing to its safety profile. This study assessed the prevalence of mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes associated with SP resistance in samples collected in Kenya between 2008 and 2012. Field isolates collected from Kisumu, Kisii, Kericho and Malindi district hospitals were assessed for genetic polymorphism at various loci within Pfdhfr and Pfdhps genes by sequencing. Among the Pfdhfr mutations, codons N51I, C59R, S108N showed highest prevalence in all the field sites at 95.5%, 84.1% and 98.6% respectively. Pfdhfr S108N prevalence was highest in Kisii at 100%. A temporal trend analysis showed steady prevalence of mutations over time except for codon Pfdhps 581 which showed an increase in mixed genotypes. Triple Pfdhfr N51I/C59R/S108N and double Pfdhps A437G/ K540E had high prevalence rates of 86.6% and 87.9% respectively. The Pfdhfr/Pfdhps quintuple, N51I/C59R/S108N/A437G/K540E mutant which has been shown to be the most clinically relevant marker for SP resistance was observed in 75.7% of the samples. SP resistance is still persistently high in western Kenya, which is likely due to fixation of key mutations in the Pfdhfr and Pfdhps genes as well as drug pressure from other antifolate drugs being used for the treatment of malaria and other infections. In addition, there is emergence and increasing prevalence of new mutations in Kenyan parasite population. Since SP is used for IPTP/I, molecular surveillance and in vitro susceptibility assays must be sustained to provide information on the emergence and spread of SP resistance.

Dihydropteroate synthase

Sulfadoxine/pyrimethamine

Sulfadoxine

Antifolate

10.1186/1475-2875-13-250

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Citations (25)

PLoS ONE (2017)

Reagan M. Mogire Hoseah M. Akala Rosaline W. Macharia Dennis W. Juma Agnes C. Cheruiyot

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

DrugBank

Druggability

Approved drug

10.1371/journal.pone.0186364

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Citations (22)