Publications by authors named "Prakasha Kempaiah"

38 Publications

Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies.

Methods 2021 Feb 25. Epub 2021 Feb 25.

Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India. Electronic address:

Novel coronavirus SARS-CoV-2continues tospread rapidly worldwide and causing serious health and economic loss. In the absence of any effective treatment, various in-silico approaches are being explored towards the therapeutic discovery against COVID-19. Targeting multiple key enzymes of SARS-CoV-2 with a single potential drug could be an important in-silico strategy to tackle the therapeutic emergency. A number of Food and Drug Administration (FDA) approved drugs entered into clinical stages were originated from multi-target approaches with an increased rate, 16-21% between 2015 and 2017. In this study, we selected an FDA-approved library (Prestwick Chemical Library of 1520 compounds) and implemented in-silico virtual screening against multiple protein targets of SARS-CoV-2 on the Glide module of Schrödinger software (release 2020-1). Compounds were analyzed for their docking scores and the top-ranked against each targeted protein were further subjected to Molecular Dynamics (MD) simulations to assess the binding stability of ligand-protein complexes. A multi-targeting approach was optimized that enabled the analysis of several compounds' binding efficiency with more than one protein targets. It was demonstrated that Diosmin (6) showed the highest binding affinity towards multiple targets with binding free energy (kcal/mol) values of -63.39 (nsp3); -62.89 (nsp9); -31.23 (nsp12); and -65.58 (nsp15). Therefore, our results suggests that Diosmin (6) possesses multi-targeting capability, a potent inhibitor of various non-structural proteins of SARS-CoV-2, and thus it deserves further validation experiments before using as a therapeutic against COVID-19 disease.
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http://dx.doi.org/10.1016/j.ymeth.2021.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904494PMC
February 2021

Comparative genomic and phenotypic characterization of invasive non-typhoidal Salmonella isolates from Siaya, Kenya.

PLoS Negl Trop Dis 2021 Feb 1;15(2):e0008991. Epub 2021 Feb 1.

Los Alamos National Laboratory, Los Alamos, New Mexico, United States.

Non-typhoidal Salmonella (NTS) is a major global health concern that often causes bloodstream infections in areas of the world affected by malnutrition and comorbidities such as HIV and malaria. Developing a strategy to control the emergence and spread of highly invasive and antimicrobial resistant NTS isolates requires a comprehensive analysis of epidemiological factors and molecular pathogenesis. Here, we characterize 11 NTS isolates that caused bloodstream infections in pediatric patients in Siaya, Kenya from 2003-2010. Nine isolates were identified as S. Typhimurium sequence type 313 while the other two were S. Enteritidis. Comprehensive genotypic and phenotypic analyses were performed to compare these isolates to those previously identified in sub-Saharan Africa. We identified a S. Typhimurium isolate referred to as UGA14 that displayed novel plasmid, pseudogene and resistance features as compared to other isolates reported from Africa. Notably, UGA14 is able to ferment both lactose and sucrose due to the acquisition of insertion elements on the pKST313 plasmid. These findings show for the first time the co-evolution of plasmid-mediated lactose and sucrose metabolism along with cephalosporin resistance in NTS further elucidating the evolutionary mechanisms of invasive NTS phenotypes. These results further support the use of combined genomic and phenotypic approaches to detect and characterize atypical NTS isolates in order to advance biosurveillance efforts that inform countermeasures aimed at controlling invasive and antimicrobial resistant NTS.
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http://dx.doi.org/10.1371/journal.pntd.0008991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877762PMC
February 2021

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays.

Methods 2021 Jan 14. Epub 2021 Jan 14.

Loyola University Chicago Stritch School of Medicine, Chicago, IL 60153, USA; Department of Medicine, Loyola University Medical Center, Chicago, IL 60153, USA. Electronic address:

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.
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http://dx.doi.org/10.1016/j.ymeth.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807167PMC
January 2021

A Review of the Preclinical and Clinical Efficacy of Remdesivir, Hydroxychloroquine, and Lopinavir-Ritonavir Treatments against COVID-19.

SLAS Discov 2020 12 17;25(10):1108-1122. Epub 2020 Sep 17.

Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA.

In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei Province, China. The pathogen has been identified as a novel enveloped RNA beta-coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus SARS-CoV-2 is associated with a disease characterized by severe atypical pneumonia known as coronavirus 2019 (COVID-19). Typical symptoms of this disease include cough, fever, malaise, shortness of breath, gastrointestinal symptoms, anosmia, and, in severe cases, pneumonia. The high-risk group of COVID-19 patients includes people over the age of 60 years as well as people with existing cardiovascular disease and/or diabetes mellitus. Epidemiological investigations have suggested that the outbreak was associated with a live animal market in Wuhan. Within the first few months of the outbreak, cases were growing exponentially all over the world. The unabated spread of this deadly and highly infectious virus is a health emergency for all nations in the world and has led to the World Health Organization (WHO) declaring a pandemic on March 11, 2020. In this report, we consolidate and review the available clinically and preclinically relevant results emanating from in vitro animal models and clinical studies of drugs approved for emergency use as a treatment for COVID-19, including remdesivir, hydroxychloroquine, and lopinavir-ritonavir combinations. These compounds have been frequently touted as top candidates to treat COVID-19, but recent clinical reports suggest mixed outcomes on their efficacies within the current clinical protocol frameworks.
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http://dx.doi.org/10.1177/2472555220958385DOI Listing
December 2020

Author Correction: Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model.

Sci Rep 2020 Aug 24;10(1):14146. Epub 2020 Aug 24.

Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, 110007, India.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70608-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445261PMC
August 2020

Oseltamivir analogs with potent anti-influenza virus activity.

Drug Discov Today 2020 08 15;25(8):1389-1402. Epub 2020 Jun 15.

Department of Chemistry, Miranda House University Enclave, University of Delhi, Delhi, 110007, India. Electronic address:

Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.
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http://dx.doi.org/10.1016/j.drudis.2020.06.004DOI Listing
August 2020

Discovery of New Hydroxyethylamine Analogs against 3CL Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure-Activity Relationship Studies.

J Chem Inf Model 2020 12 18;60(12):5754-5770. Epub 2020 Jun 18.

Laboratory for Translational Chemistry and Drug Discovery, Hansraj College, University of Delhi, Delhi 110007, India.

The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (M) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CL) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of within the binding pocket. Largely, our results supported that this novel compound binds with domains I and II, and the domain II-III linker of the 3CL protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
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http://dx.doi.org/10.1021/acs.jcim.0c00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304236PMC
December 2020

Bioactive Chemical Entities: Pre-clinical and Clinical Aspects - Part-II.

Curr Top Med Chem 2020;20(8):606

Department of Medicine Loyola University Health Sciences Division 2160 South 1st Avenue Chicago, IL 60153, United States.

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http://dx.doi.org/10.2174/156802662008200331074457DOI Listing
December 2020

Bioactive Chemical Entities: Pre-Clinical and Clinical Aspects - Part-VIII.

Curr Top Med Chem 2020;20(5):336

Department of Medicine Loyola University Health Sciences Division 2160 South 1st Avenue Chicago, IL 60153, United States.

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http://dx.doi.org/10.2174/156802662005200304123756DOI Listing
December 2020

Fluorinated scaffolds for antimalarial drug discovery.

Expert Opin Drug Discov 2020 06 21;15(6):705-718. Epub 2020 Mar 21.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi , Delhi, India.

Introduction: The unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria.

Areas Covered: In this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery.

Expert Opinion: Fluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F and SF used for fluorination, are not considered as safe, and therefore, this process remains challenging, particularly for the pharmaceutical industry.
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http://dx.doi.org/10.1080/17460441.2020.1740203DOI Listing
June 2020

Outwitting an Old Neglected Nemesis: A Review on Leveraging Integrated Data-Driven Approaches to Aid in Unraveling of Leishmanicides of Therapeutic Potential.

Curr Top Med Chem 2020 ;20(5):349-366

Department of Medicine, Loyola University Chicago, Loyola University Medical Center, Maywood, IL 60153, United States.

The global prevalence of leishmaniasis has increased with skyrocketed mortality in the past decade. The causative agent of leishmaniasis is Leishmania species, which infects populations in almost all the continents. Prevailing treatment regimens are consistently inefficient with reported side effects, toxicity and drug resistance. This review complements existing ones by discussing the current state of treatment options, therapeutic bottlenecks including chemoresistance and toxicity, as well as drug targets. It further highlights innovative applications of nanotherapeutics-based formulations, inhibitory potential of leishmanicides, anti-microbial peptides and organometallic compounds on leishmanial species. Moreover, it provides essential insights into recent machine learning-based models that have been used to predict novel leishmanicides and also discusses other new models that could be adopted to develop fast, efficient, robust and novel algorithms to aid in unraveling the next generation of anti-leishmanial drugs. A plethora of enriched functional genomic, proteomic, structural biology, high throughput bioassay and drug-related datasets are currently warehoused in both general and leishmania-specific databases. The warehoused datasets are essential inputs for training and testing algorithms to augment the prediction of biotherapeutic entities. In addition, we demonstrate how pharmacoinformatics techniques including ligand-, structure- and pharmacophore-based virtual screening approaches have been utilized to screen ligand libraries against both modeled and experimentally solved 3D structures of essential drug targets. In the era of data-driven decision-making, we believe that highlighting intricately linked topical issues relevant to leishmanial drug discovery offers a one-stop-shop opportunity to decipher critical literature with the potential to unlock implicit breakthroughs.
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http://dx.doi.org/10.2174/1568026620666200128160454DOI Listing
December 2020

Genetic variation in interleukin-7 is associated with a reduced erythropoietic response in Kenyan children infected with Plasmodium falciparum.

BMC Med Genet 2019 08 16;20(1):140. Epub 2019 Aug 16.

University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya.

Background: Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood.

Methods: We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina's® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and - 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) < 2.0 in anemic children (Hb < 11.0 g/dL). Children presenting with P. falciparum malaria (< 3 years, n = 883) were stratified into two groups: Uncomplicated malaria (UM, n = 718) and SMA (n = 165).

Results: Regression modeling, controlling for anemia-related confounders, revealed that carriage of the TC genotype at position 72194 T/C was associated with enhanced susceptibility to inefficient erythropoiesis (OR = 1.90; 95% CI 1.09-3.30; P = 0.02) as was homozygous CC (OR 5.14; 95% CI = 1.20-21.99; P = 0.03). Consistent with this finding, individuals with the CA (72194C/-2440A) haplotype had an increased risk of inefficient erythropoiesis (OR = 1.90; 95% CI = 1.10-3.30; P = 0.02), whereas TA haplotype carriers had marginal protection against inefficient erythropoiesis (OR = 0.24; 95% CI = 0.06-1.21; P = 0.05). These observations were supported by Cochran-Armitage trend test for inefficient erythropoiesis (CA > TA > CG; P < 0.01). Although none of the genotype and/or haplotypic variants were significantly associated with SMA, the direction of the risk profiles were consistent with the erythropoiesis results.

Conclusion: Taken together, variation in IL7 is associated with erythropoietic responses in children with falciparum malaria, a central physiological feature contributing to development of SMA.
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http://dx.doi.org/10.1186/s12881-019-0866-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698010PMC
August 2019

An electrochemiluminescence based assay for quantitative detection of endogenous and exogenously applied MeCP2 protein variants.

Sci Rep 2019 05 28;9(1):7929. Epub 2019 May 28.

Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, Vienna, Austria.

Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional chromosomal protein that plays a key role in the central nervous system. Its levels need to be tightly regulated, as both deficiency and excess of the protein can lead to severe neuronal dysfunction. Loss-of-function mutations affecting MeCP2 are the primary cause of Rett syndrome (RTT), a severe neurological disorder that is thought to result from absence of functional protein in the brain. Several therapeutic strategies for the treatment of RTT are currently being developed. One of them is the use of stable and native TAT-MeCP2 fusion proteins to replenish its levels in neurons after permeation across the blood-brain barrier (BBB). Here we describe the expression and purification of various transactivator of transcription (TAT)-MeCP2 variants and the development of an electrochemiluminescence based assay (ECLIA) that is able to measure endogenous MeCP2 and recombinant TAT-MeCP2 fusion protein levels in a 96-well plate format. The MeCP2 ECLIA produces highly quantitative, accurate and reproducible measurements with low intra- and inter-assay error throughout a wide working range. To underline its broad applicability, this assay was used to analyze brain tissue and study the transport of TAT-MeCP2 variants across an in vitro model of the blood-brain barrier.
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http://dx.doi.org/10.1038/s41598-019-44372-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538716PMC
May 2019

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.

ACS Infect Dis 2019 02 2;5(2):184-198. Epub 2019 Jan 2.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry , Hansraj College University Enclave, University of Delhi , Delhi 110007 , India.

The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs.
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http://dx.doi.org/10.1021/acsinfecdis.8b00197DOI Listing
February 2019

Apicoplast Metabolism: Parasite's Achilles' Heel.

Curr Top Med Chem 2018 ;18(22):1987-1997

Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131-0001, United States.

Malaria continues to impinge heavily on mankind, with five continents still under its clasp. Widespread and rapid emergence of drug resistance in the Plasmodium parasite to current therapies accentuate the quest for novel drug targets and antimalarial compounds. Plasmodium parasites, maintain a non-photosynthetic relict organelle known as Apicoplast. Among the four major pathways of Apicoplast, biosynthesis of isoprenoids via Methylerythritol phosphate (MEP) pathway is the only indispensable function of Apicoplast that occurs during different stages of the malaria parasite. Moreover, the human host lacks MEP pathway. MEP pathway is a validated repertoire of novel antimalarial and antibacterial drug targets. Fosmidomycin, an efficacious antimalarial compound against IspC enzyme of MEP pathway is already in clinical trials as a combination drugs. Exploitation of other enzymes of MEP pathway would provide a much-needed impetus to the antimalarial drug discovery programs for the elimination of malaria. We outline the cardinal features of the MEP pathway enzymes and progress made towards the characterization of new inhibitors.
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http://dx.doi.org/10.2174/1568026619666181130134742DOI Listing
January 2019

Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions.

Curr Top Med Chem 2019 ;18(23):2022-2028

Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, Accra, Ghana.

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.
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http://dx.doi.org/10.2174/1568026619666181130133548DOI Listing
January 2019

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors.

Bioorg Med Chem 2018 07 28;26(13):3837-3844. Epub 2018 Jun 28.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India; South Ural State University, Laboratory of Computational Modeling of Drugs, 454080, Russia. Electronic address:

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K, 1.93 ± 0.29 µM for Plm II; K, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC, 2.27 ± 0.95 µM for 10f; IC, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.
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http://dx.doi.org/10.1016/j.bmc.2018.06.037DOI Listing
July 2018

Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model.

Sci Rep 2017 07 27;7(1):6724. Epub 2017 Jul 27.

Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi, 110007, India.

A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.
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http://dx.doi.org/10.1038/s41598-017-06097-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532363PMC
July 2017

CD4 T-cell expression of IFN-γ and IL-17 in pediatric malarial anemia.

PLoS One 2017 20;12(4):e0175864. Epub 2017 Apr 20.

University of New Mexico Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.

In Plasmodium falciparum holoendemic transmission regions of western Kenya, life-threatening pediatric malaria manifests primarily as severe malarial anemia (SMA, Hb≤6.0 g/dL with any density parasitemia). To determine the role that CD4+ T-cell-driven inflammatory responses have in the pathogenesis of SMA, peripheral CD4+ T-cell populations and their intracellular production of pro-inflammatory cytokines (IFN-γ and IL-17) were characterized in children aged 12-36 months of age stratified into two groups: non-severe malarial anemia (non-SMA, Hb≥6.0 g/dL, n = 50) and SMA (n = 39). In addition, circulating IFN-γ and IL-17 were measured as part of a Cytokine 25-plex Antibody Bead Kit, Human (BioSource™ International). Children with SMA had higher overall proportions of circulating lymphocytes (P = 0.003) and elevated proportions of lymphocytes expressing IFN-γ (P = 0.014) and comparable IL-17 (P = 0.101). In addition, SMA was characterized by decreased memory-like T-cells (CD4+CD45RA-) expressing IL-17 (P = 0.009) and lower mean fluorescence intensity in memory-like CD4+ T-cells for both IFN-γ (P = 0.063) and IL-17 (P = 0.006). Circulating concentrations of IFN-γ were higher in children with SMA (P = 0.009), while IL-17 levels were comparable between the groups (P = 0.164). Furthermore, circulating levels of IFN-γ were negatively correlated with IL-17 levels in both groups of children (SMA: r = -0.610, P = 0.007; and non-SMA: r = -0.516, P = 0.001), while production of both cytokines by lymphocytes were positively correlated (SMA: r = 0.349, P = 0.037; and non-SMA: r = 0.475, P = 0.001). In addition, this correlation was only maintained by the memory-like CD4+ T cells (r = 0.365, P = 0.002) but not the naïve-like CD4+ T cells. However, circulating levels of IFN-γ were only associated with naïve-like CD4+ T cells producing IFN-γ (r = 0.547, P = 0.028), while circulating levels of IL-17 were not associated with any of the cell populations. Taken together, these results suggest that enhanced severity of malarial anemia is associated with higher overall levels of circulating lymphocytes, enhanced intracellular production of IFN-γ by peripheral lymphocytes and high circulating IFN-γ levels. In addition, the observed inverse relationship between the circulating levels of IFN-γ and IL-17 together with the reduction in the levels of memory-like CD4+ T cells expressing IL-17 in children with SMA may suggest possible relocation of these cells in the deeper tissues for their pathological effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175864PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398558PMC
September 2017

Calcium Dependent Protein Kinases (CDPKs): Key to Malaria Eradication.

Curr Top Med Chem 2017 ;17(19):2215-2220

Department of Internal Medicine, University of New Mexico School of Medicine, Health Sciences Center, MSC10-5550, Albuquerque, NM87131-0001. United States.

Introduction: The family of calcium-dependent protein kinases (CDPKs) carries a kinase domain fused to a calmodulin-like domain. The presence of protein kinases devoid of clear mammalian eukaryotic protein kinase orthologues makes them potential targets for therapeutic development. Recent studies on CDPKs have inspired an important primary regulator of calcium (intracellular Ca2+ signaling), which is extensively reported to play a critical role in various stages of the apicomplexan life cycle such as microneme secretion of adhesions, cell invasion, gamete maturation, gliding motility and egress of Plasmodium Spp.

Conclusion: Understanding and identifying these essential cytoregulatory components of the parasite is important for drug targets development and therapeutic intervention.
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http://dx.doi.org/10.2174/1568026617666170130112714DOI Listing
August 2017

Antimalarials: Molecular Drug Targets and Mechanism of Action.

Curr Top Med Chem 2017 ;17(19):2114-2128

Department of Internal Medicine, Center for Global Health, University of New Mexico Health Sciences Center, MSC10-5550, Albuquerque, NM 87131-0001. United States.

Background: Despite a reduction in the global burden of malaria, the disease remains responsible for 214 million cases and 438,000 deaths annually with 88% of the mortality occurring in sub-Saharan Africa. Malaria control largely depends on effective chemotherapy. However, the historic and current emergence and spread of multi-drug resistant parasite strains provides significant challenges to malaria control and consequently, reduction of malaria-associated morbidity and mortality. Combating parasite drug resistance requires pharmacological compounds that target both known and novel metabolic pathways that are crucial for parasite survival. In addition, the identification of novel therapeutic agents that target distinct molecular pathways, apart from those of the conventional antimalarials, offers an approach for minimizing drug resistance.

Conclusion: This review summarizes current anti-malarial approaches and strategies, therapeutic efficacy for conventional and non-conventional antimalarials, parasitic targets, and the mechanisms responsible for the development of drug resistance.
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http://dx.doi.org/10.2174/1568026617666170130115323DOI Listing
August 2017

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of Hemozoin in Suppressing Hsp70 and NF-κB activation.

Mol Med 2016 Oct 30;22:570-584. Epub 2016 Aug 30.

Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.

Severe malarial anemia [SMA, hemoglobin (Hb) <5.0 g/dL] is a leading cause of global morbidity and mortality among children residing in transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased , a heat shock protein (Hsp) 70 coding gene. Hsp70 is a ubiquitous chaperone that regulates Nuclear Factor-kappa B (NF-κB) signaling and production of pro-inflammatory cytokines known to be important in malaria pathogenesis (e.g., IL-1β, IL-6 and TNF-α). Since the role of host Hsp70 in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocytic transcripts were reduced in SMA relative to non-severe malaria, and that intraleukocytic hemozoin (Hz) was associated with lower . was correlated with reticulocyte production and Hb. Since glutamine (Gln) up-regulates Hsp70, modulates NF-κB activation, and attenuates over-expression of pro-inflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA. Treatment of cultured peripheral blood mononuclear cells (PBMCs) with Hz caused a time-dependent decrease in Hsp70 transcripts/protein, and NF-κB activation. Gln treatment of PBMCs overcame Hz-induced suppression of transcripts/protein, reduced NF-κB activation, and suppressed over-expression of IL-1β, IL-6 and TNF-α. Findings here demonstrate that SMA is characterized by reduced intraleukocytic and circulating Gln, and that Hz-induced suppression of can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.
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http://dx.doi.org/10.2119/molmed.2016.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082292PMC
October 2016

Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation.

Mediators Inflamm 2016 22;2016:4286576. Epub 2016 Jun 22.

Center for Global Health, Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA; University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.

Bacteremia and malaria coinfection is a common and life-threatening condition in children residing in sub-Saharan Africa. We previously showed that coinfection with Gram negative (G[-]) enteric Bacilli and Plasmodium falciparum (Pf[+]) was associated with reduced high-density parasitemia (HDP, >10,000 parasites/μL), enhanced respiratory distress, and severe anemia. Since inflammatory mediators are largely unexplored in such coinfections, circulating cytokines were determined in four groups of children (n = 206, aged <3 yrs): healthy; Pf[+] alone; G[-] coinfected; and G[+] coinfected. Staphylococcus aureus and non-Typhi Salmonella were the most frequently isolated G[+] and G[-] organisms, respectively. Coinfected children, particularly those with G[-] pathogens, had lower parasite burden (peripheral and geometric mean parasitemia and HDP). In addition, both coinfected groups had increased IL-4, IL-5, IL-7, IL-12, IL-15, IL-17, IFN-γ, and IFN-α and decreased TNF-α relative to malaria alone. Children with G[-] coinfection had higher IL-1β and IL-1Ra and lower IL-10 than the Pf[+] group and higher IFN-γ than the G[+] group. To determine how the immune response to malaria regulates parasitemia, cytokine production was investigated with a multiple mediation model. Cytokines with the greatest mediational impact on parasitemia were IL-4, IL-10, IL-12, and IFN-γ. Results here suggest that enhanced immune activation, especially in G[-] coinfected children, acts to reduce malaria parasite burden.
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http://dx.doi.org/10.1155/2016/4286576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933845PMC
June 2017

Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon.

EBioMedicine 2015 Sep 29;2(9):1186-92. Epub 2015 Jul 29.

Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany ; Servicio Autónomo Centro Amazónico para la Investigación y Control de Enfermedades Tropicales 'Simón Bolívar' (SACAICET), Puerto Ayacucho, Estado Amazonas, Venezuela.

Background: The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now.

Methods: We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing.

Findings: Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys.

Interpretation: This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.
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http://dx.doi.org/10.1016/j.ebiom.2015.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588399PMC
September 2015

Suppressed circulating bicyclo-PGE2 levels and leukocyte COX-2 transcripts in children co-infected with P. falciparum malaria and HIV-1 or bacteremia.

Biochem Biophys Res Commun 2013 Jul 3;436(4):585-90. Epub 2013 Jun 3.

University of New Mexico, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.

In holoendemic Plasmodium falciparum transmission regions, malarial anemia is a leading cause of childhood morbidity and mortality. Identifying biomarkers of malaria disease severity is important for identifying at-risk groups and for improved understanding of the molecular pathways that influence clinical outcomes. We have previously shown that decreased cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) levels are associated with enhanced clinical severity in cerebral malaria, malarial anemia, and malaria during pregnancy. Since children with malaria often have increased incidence of additional infections, such as bacteremia and HIV-1, we extend our previous findings by investigating COX-2 and PGE2 in children with falciparum malaria and co-infection with either bacteremia or HIV-1. Plasma bicyclo-PGE2/creatinine levels and peripheral blood COX-2 transcripts were significantly reduced in co-infected children relative to those with malaria mono-infection. Furthermore, suppression of circulating bicyclo-PGE2 was significantly associated with reduced hemoglobin levels in both mono- and co-infected children with malaria, suggesting that bicyclo-PGE2 may represent both a marker and mediator of malaria pathogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2013.05.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703399PMC
July 2013

Cystic fibrosis CFBE41o- cells contain TLR1 SNP I602S and fail to respond to Mycobacterium abscessus.

J Cyst Fibros 2013 Dec 9;12(6):773-9. Epub 2013 Feb 9.

The University of New Mexico School of Medicine, Center for Global Health, Albuquerque, NM 87131, USA.

Background: Mycobacterium abscessus causes lung infection in patients with cystic fibrosis. M. abscessus stimulates the host innate immune response via TLR2 on respiratory epithelial cells. Signaling through TLR2 requires the formation of TLR2/TLR1 heterodimers on the cell surface.

Methods: The ability of M. abscessus to stimulate the innate immune response of cystic fibrosis CFBE41o- respiratory epithelial cells was measured as expression of HβD2 by RT PCR, and release of IL-8 by ELISA. Genotyping of CFBE41o- TLR polymorphisms was carried out.

Results: CFBE41o- cells are hyporesponsive to M. abscessus. They are homozygous for the TLR1 SNP I602S which has been demonstrated to cause diminished cellular responses to TLR2 agonists.

Conclusions: Homozygosity for I602S is prevalent in Western Europeans and North American Caucasians, the same demographic in which the ΔF508 mutation is present. This SNP may play a role in the pathogenesis of M. abscessus lung infection in patients with cystic fibrosis.
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http://dx.doi.org/10.1016/j.jcf.2013.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712101PMC
December 2013

Reduced systemic bicyclo-prostaglandin-E2 and cyclooxygenase-2 gene expression are associated with inefficient erythropoiesis and enhanced uptake of monocytic hemozoin in children with severe malarial anemia.

Am J Hematol 2012 Aug 23;87(8):782-9. Epub 2012 Jun 23.

Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, University of New Mexico, Kisumu, Kenya.

In holoendemic Plasmodium falciparum transmission areas, severe malaria primarily occurs in children aged <48 months and manifests as severe malarial anemia [SMA; hemoglobin (Hb) < 6.0 g/dL]. Induction of high levels of prostaglandin-E(2) (PGE(2)) through inducible cyclooxygenase-2 (COX-2) is an important host-defense mechanism against invading pathogens. We have previously shown that COX-2-derived PGE(2) levels are reduced in children residing in hyperendemic transmission regions with cerebral malaria and in those with mixed sequelae of anemia and hyperparasitemia. Our in vitro studies further demonstrated that reduced PGE(2) was due to downregulation of COX-2 gene products following phagocytosis of malarial pigment (hemozoin, PfHz). However, as COX-2-PGE(2) pathways and the impact of naturally acquired PfHz on erythropoietic responses have not been determined in children with SMA, plasma and urinary bicyclo-PGE(2)/creatinine and leukocytic COX-2 transcripts were determined in parasitized children (<36 months) stratified into SMA (n = 36) and non-SMA (Hb ≥ 6.0 g/dL; n = 38). Children with SMA had significantly reduced plasma (P = 0.001) and urinary (P < 0.001) bicyclo-PGE(2)/creatinine and COX-2 transcripts (P = 0.007). There was a significant positive association between Hb and both plasma (r = 0.363, P = 0.002) and urinary (r = 0.500, P = 0.001)] bicyclo-PGE(2)/creatinine. Furthermore, decreased systemic bicyclo-PGE(2)/creatinine was associated with inefficient erythropoiesis (i.e., reticulocyte production index; RPI < 2.0, P = 0.026). Additional analyses demonstrated that plasma (P = 0.031) and urinary (P = 0.070) bicyclo-PGE(2)/creatinine and COX-2 transcripts (P = 0.026) progressively declined with increasing concentrations of naturally acquired PfHz by monocytes. Results presented here support a model in which reduced COX-2-derived PGE(2), driven in part by naturally acquired PfHz by monocytes, promotes decreased erythropoietic responses in children with SMA.
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http://dx.doi.org/10.1002/ajh.23253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703400PMC
August 2012

Reduced interferon (IFN)-α conditioned by IFNA2 (-173) and IFNA8 (-884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality.

Hum Genet 2012 Aug 9;131(8):1375-91. Epub 2012 May 9.

Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, MSC10-5550, Albuquerque, NM 87131-0001, USA.

Severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-α in SMA has not been reported. As such, we investigated the relationship between IFN-α promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-α production in children (n = 663; <36 months) residing in a holoendemic P. falciparum transmission region of Kenya. Children with SMA had lower circulating IFN-α than malaria-infected children without severe anemia (P = 0.025). Multivariate logistic regression analyses revealed that heterozygosity at -884 (TA) was associated with an increased risk of SMA [OR 2.80 (95 % CI 1.22-6.43); P = 0.015] and reduced IFN-α relative to wild type (TT; P = 0.038). Additional analyses demonstrated that carriage of the -173T/-884A (TA) haplotype was associated with increased susceptibility to SMA [OR 3.98 (95 % CI 1.17-13.52); P = 0.026] and lower IFN-α (P = 0.031). Follow-up of these children for 36 months revealed that carriers of TA haplotype had greater all-cause mortality than non-carriers (P < 0.001). Generation of reporter constructs showed that the IFNA8 wild-type -884TT exhibited higher levels of luciferase expression than the variant alleles (P < 0.001). Analyses of malaria-associated inflammatory mediators demonstrated that carriers of TA haplotype had altered production of IL-1β, MIG, and IL-13 compared to non-carriers (P < 0.050). Thus, variation at IFNA2 -173 and IFNA8 -884 conditions reduced IFN-α production, and increased susceptibility to SMA and mortality.
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http://dx.doi.org/10.1007/s00439-012-1175-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665420PMC
August 2012

Mycobacterium abscessus glycopeptidolipid prevents respiratory epithelial TLR2 signaling as measured by HβD2 gene expression and IL-8 release.

PLoS One 2011 21;6(12):e29148. Epub 2011 Dec 21.

Department of Medicine, New Mexico Veterans Health Care System, Albuquerque, New Mexico, USA.

Mycobacterium abscessus has emerged as an important cause of lung infection, particularly in patients with bronchiectasis. Innate immune responses must be highly effective at preventing infection with M. abscessus because it is a ubiquitous environmental saprophyte and normal hosts are not commonly infected. M. abscessus exists as either a glycopeptidolipid (GPL) expressing variant (smooth phenotype) in which GPL masks underlying bioactive cell wall lipids, or as a variant lacking GPL which is immunostimulatory and invasive in macrophage infection models. Respiratory epithelium has been increasingly recognized as playing an important role in the innate immune response to pulmonary pathogens. Respiratory epithelial cells express toll-like receptors (TLRs) which mediate the innate immune response to pulmonary pathogens. Both interleukin-8 (IL-8) and human β-defensin 2 (HβD2) are expressed by respiratory epithelial cells in response to toll-like receptor 2 (TLR2) receptor stimulation. In this study, we demonstrate that respiratory epithelial cells respond to M. abscessus variants lacking GPL with expression of IL-8 and HβD2. Furthermore, we demonstrate that this interaction is mediated through TLR2. Conversely, M. abscessus expressing GPL does not stimulate expression of IL-8 or HβD2 by respiratory epithelial cells which is consistent with "masking" of underlying bioactive cell wall lipids by GPL. Because GPL-expressing smooth variants are the predominant phenotype existing in the environment, this provides an explanation whereby initial M. abscessus colonization of abnormal lung airways escapes detection by the innate immune system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029148PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244437PMC
May 2012

Severe malarial anemia: innate immunity and pathogenesis.

Int J Biol Sci 2011 2;7(9):1427-42. Epub 2011 Nov 2.

Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque NM, USA.

Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naïve infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naïve African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naïve children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221949PMC
http://dx.doi.org/10.7150/ijbs.7.1427DOI Listing
May 2012