scholarly journals Critical Role for Isoprenoids in Apicoplast Biogenesis by Malaria Parasites

2021 ◽  
Author(s):  
Megan Okada ◽  
Krithika Rajaram ◽  
Russell P. Swift ◽  
Amanda Mixon ◽  
J. Alan Maschek ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Fluidity ◽  
Critical Role ◽  
Vesicular Trafficking ◽  
Malaria Parasites ◽  
Therapeutic Targeting ◽  
Isopentenyl Pyrophosphate ◽  
Cellular Processes ◽  
Metabolic Output ◽  
Long Chain

Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in Plasmodium falciparum malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast lumen. PPS knockdown is lethal to parasites, rescued by IPP, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.

scholarly journals Stages of in vitro phagocytosis of Plasmodium falciparum-infected erythrocytes by human monocytes

2009 ◽  
Vol 42 (2) ◽  
pp. 103-106 ◽  
Author(s):  
Maria Imaculada Muniz-Junqueira ◽  
Carlos Eduardo Tosta
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Circulation ◽  
Defense Mechanisms ◽  
Healthy Adult ◽  
Critical Role ◽  
Immune Serum ◽  
Human Monocytes ◽  
Malaria Parasites

Monocytes/macrophages play a critical role in the defense mechanisms against malaria parasites, and are the main cells responsible for the elimination of malaria parasites from the blood circulation. We carried out a microscope-aided evaluation of the stages of in vitro phagocytosis of Plasmodium falciparum-infected erythrocytes, by human monocytes. These cells were obtained from healthy adult individuals by means of centrifugation through a cushion of Percoll density medium and were incubated with erythrocytes infected with Plasmodium falciparum that had previously been incubated with a pool of anti-plasmodial immune serum. We described the stages of phagocytosis, starting from adherence of infected erythrocytes to the phagocyte membrane and ending with their destruction within the phagolisosomes of the monocytes. We observed that the different erythrocytic forms of the parasite were ingested by monocytes, and that the process of phagocytosis may be completed in around 30 minutes. Furthermore, we showed that phagocytosis may occur continuously, such that different phases of the process were observed in the same phagocyte.

scholarly journals Characterization of Plasmodium falciparum NEDD8 and identification of cullins as its substrates

2020 ◽  
Author(s):  
Manish Bhattacharjee ◽  
Navin Adhikari ◽  
Renu Sudhakar ◽  
Zeba Rizvi ◽  
Divya Das ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasmodium Falciparum ◽  
Western Blot ◽  
Wild Type ◽  
Malaria Parasites ◽  
Post Translational Modifications ◽  
Functional Conservation ◽  
Cellular Processes ◽  
Physiological Substrates

ABSTRACTA variety of post-translational modifications of Plasmodium falciparum proteins, including phosphorylation and ubiquitination, are shown to have key regulatory roles. The neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) is a ubiquitin-like modifier of cullin-RING E3 ubiquitin ligases, which regulate diverse cellular processes, including the cell-cycle. Although neddylation pathway is conserved in eukaryotes, it is yet to be characterized in Plasmodium and related apicomplexan parasites. Towards studying the neddylation pathway in malaria parasites, we characterized P. falciparum NEDD8 (PfNEDD8) and identified cullins as its physiological substrates. PfNEDD8 is a 76 amino acid residue protein without the C-terminal tail, indicating that it can be readily conjugated. The wild type and mutant (Gly75Gly76 mutated to Ala75Ala76) PfNEDD8 were expressed in P. falciparum. Western blot of wild type PfNEDD8-expressing parasites indicated multiple high molecular weight conjugates, which were absent in the parasites expressing the mutant, indicating conjugation of NEDD8 to proteins through Gly76. Immunoprecipitation followed by mass spectrometry of wild type PfNEDD8-expressing parasites identified several proteins, including two putative cullins. Furthermore, we expressed PfNEDD8 in mutant S. cerevisiae strains that lacked endogenous NEDD8 (Δrub1) or NEDD8 conjugating E2 enzyme (ΔUbc12). The western blot of complemented strains and mass spectrometry of PfNEDD8 immunoprecipitate showed conjugation of PfNEDD8 to S. cerevisiae cullin cdc53, demonstrating functional conservation and cullins as the physiological substrates of PfNEDD8. The characterization of PfNEDD8 and identification of cullins as its substrates make ground for investigation of specific roles and drug target potential of neddylation pathway in malaria parasites.

scholarly journals Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 286
Author(s):  
Mary Frances Nakamya ◽  
Moses B. Ayoola ◽  
Leslie A. Shack ◽  
Mirghani Mohamed ◽  
Edwin Swiatlo ◽  
...  
Keyword(s):  
Stress Responses ◽  
Critical Role ◽  
Acid Stress ◽  
Arginine Decarboxylase ◽  
Arginine Deiminase ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Opportunistic Human Pathogen ◽  
Thiol Peroxidase ◽  
The Impact

Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host–pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.

scholarly journals Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yifat Ofir-Birin ◽  
Hila Ben Ami Pilo ◽  
Abel Cruz Camacho ◽  
Ariel Rudik ◽  
Anna Rivkin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Cerebral Malaria ◽  
Survival Strategy ◽  
Parasitic Disease ◽  
Malaria Parasites ◽  
Sensing System ◽  
Rich Domain ◽  
Cargo Delivery ◽  
Low Levels

AbstractPathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf ‘decision-sensing-system’ controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.

scholarly journals Confounding influences of malnutrition and Plasmodium falciparum and Schistosoma haematobium infections on haematological parameters in school children in Muyuka, Cameroon

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Irene Ule Ngole Sumbele ◽  
Ofon Vitalis Otia ◽  
Lorraine Francis ◽  
Orelien Sylvain Mtopi Bopda ◽  
Calvin Bisong Ebai ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Cell ◽  
Cell Count ◽  
Schistosoma Haematobium ◽  
Haemoglobin Concentration ◽  
Haematological Parameters ◽  
Blood Cell Count ◽  
Malaria Parasites ◽  
Mean Cell Volume ◽  
Distribution Width

Abstract Background School-aged children (SAC) are a high-risk demographic group for infectious diseases and malnutrition. The objective of this study was to assess the burden and the effect of Plasmodium falciparum and Schistosoma haematobium infections on the haematological indices in SAC and the confounding influence of malnutrition on the outcomes. Methods This cross-sectional study was conducted in SAC 4–14 years old living in Ikata, Bafia and Mile 14-Likoko in Muyuka, Cameroon. Anthropometric measures of malnutrition were obtained and blood samples collected were used for detection of malaria parasites by Giemsa-stained blood films using light microscopy and complete blood count analysis using an automated haematology analyser. Urine samples collected were used to detect micro haematuria with the aid of reagent strips and the eggs of S. haematobium by urine filtration technique. Multiple linear regression model was used to examine influence of independent variables on haematological parameters. Results Out of the 606 SAC examined, the prevalence of single infections with Plasmodium or S. haematobium and co-infection with both parasites was 16.2, 16.3 and 8.3%, respectively. Overall, malaria parasite (MP), urogenital schistosomiasis, malnutrition, anaemia, haematuria, microcytosis and thrombocytopenia was prevalent in 24.4, 24.6, 25.9, 74.4, 12.2, 45.4 and 11.1% of SAC, respectively. A significant linear decline (P = 0.023) in prevalence of P. falciparum infection with the severity of stunting was observed. Factors that significantly influenced haematological parameters included haemoglobin: age, stunting and MP; haematocrit: age and MP; white blood cell count: age; red blood cell count; age and MP; lymphocyte counts: stunting; mean cell volume: age; mean cell haemoglobin: age and stunting; mean cell haemoglobin concentration: sex, stunting and red cell distribution width-coefficient of variation: sex, age and stunting. Conclusions Malnutrition, Plasmodium and S. haematobium infections are common while anaemia is a severe public health problem in Muyuka, Cameroon. The interaction between haematological parameters with malaria parasites as well as linear growth index was negative and other interactions indicate systemic inflammation. While findings provide contextual intervention targets to ensure the judicious use of the limited resources, there is need for regular monitoring and proper treatment to improve the health of the underserved population.

scholarly journals Specialized Pro-Resolving Lipid Mediators in Neonatal Cardiovascular Physiology and Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 933
Author(s):  
Andrea Gila-Diaz ◽  
Gloria Herranz Carrillo ◽  
Pratibha Singh ◽  
David Ramiro-Cortijo
Keyword(s):  
Tissue Repair ◽  
Cardiovascular Health ◽  
Critical Role ◽  
Potential Effect ◽  
Lipid Mediators ◽  
Physiological Effects ◽  
Therapeutic Approaches ◽  
The Impact ◽  
Long Chain

Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.

scholarly journals Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration

2006 ◽  
Vol 50 (10) ◽  
pp. 3343-3349 ◽  
Author(s):  
Halima Kaddouri ◽  
Serge Nakache ◽  
Sandrine Houzé ◽  
France Mentré ◽  
Jacques Le Bras
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Active Metabolite ◽  
Inhibitory Concentration ◽  
Drug Susceptibility ◽  
Maximum Effect ◽  
Malaria Parasites ◽  
Effect Model

ABSTRACT The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-3H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC50) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (κ = 0.88) between the two methods allowed comparison by determination of the IC50s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.

scholarly journals Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

2007 ◽  
Vol 51 (10) ◽  
pp. 3485-3490 ◽  
Author(s):  
Erica L. Dahl ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Division ◽  
Antimalarial Activity ◽  
Mechanisms Of Action ◽  
Malaria Parasites ◽  
Delayed Effects ◽  
Delayed Death ◽  
Antimalarial Action ◽  
Multiple Antibiotics

ABSTRACT Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.

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