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Marti, Matthias

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Marti

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Matthias

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Marti, Matthias
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    Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
    (Nature Publishing Group UK, 2018) Stone, Will J. R.; Campo, Joseph J.; Ouédraogo, André Lin; Meerstein-Kessel, Lisette; Morlais, Isabelle; Da, Dari; Cohuet, Anna; Nsango, Sandrine; Sutherland, Colin J.; van de Vegte-Bolmer, Marga; Siebelink-Stoter, Rianne; van Gemert, Geert-Jan; Graumans, Wouter; Lanke, Kjerstin; Shandling, Adam D.; Pablo, Jozelyn V.; Teng, Andy A.; Jones, Sophie; de Jong, Roos M.; Fabra-García, Amanda; Bradley, John; Roeffen, Will; Lasonder, Edwin; Gremo, Giuliana; Schwarzer, Evelin; Janse, Chris J.; Singh, Susheel K.; Theisen, Michael; Felgner, Phil; Marti, Matthias; Drakeley, Chris; Sauerwein, Robert; Bousema, Teun; Jore, Matthijs M.
    Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes.
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    Inferring Developmental Stage Composition from Gene Expression in Human Malaria
    (Public Library of Science, 2013) Joice, Regina Carol; Narasimhan, Vagheesh; Montgomery, Jacqui; Sidhu, Amar Bir; Oh, Keunyoung; Meyer, Evan; Pierre-Louis, Willythssa; Seydel, Karl; Milner, Danny; Williamson, Kim; Wiegand, Roger; Ndiaye, Daouda; Daily, Johanna; Wirth, Dyann; Taylor, Terrie; Huttenhower, Curtis; Marti, Matthias
    In the current era of malaria eradication, reducing transmission is critical. Assessment of transmissibility requires tools that can accurately identify the various developmental stages of the malaria parasite, particularly those required for transmission (sexual stages). Here, we present a method for estimating relative amounts of Plasmodium falciparum asexual and sexual stages from gene expression measurements. These are modeled using constrained linear regression to characterize stage-specific expression profiles within mixed-stage populations. The resulting profiles were analyzed functionally by gene set enrichment analysis (GSEA), confirming differentially active pathways such as increased mitochondrial activity and lipid metabolism during sexual development. We validated model predictions both from microarrays and from quantitative RT-PCR (qRT-PCR) measurements, based on the expression of a small set of key transcriptional markers. This sufficient marker set was identified by backward selection from the whole genome as available from expression arrays, targeting one sentinel marker per stage. The model as learned can be applied to any new microarray or qRT-PCR transcriptional measurement. We illustrate its use in vitro in inferring changes in stage distribution following stress and drug treatment and in vivo in identifying immature and mature sexual stage carriers within patient cohorts. We believe this approach will be a valuable resource for staging lab and field samples alike and will have wide applicability in epidemiological studies of malaria transmission.
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    Evidence for spleen dysfunction in malaria-HIV co-infection in a subset of pediatric patients
    (2015) Joice, Regina; Frantzreb, Charles; Pradham, Alana; Seydel, Karl B.; Kamiza, Steve; Wirth, Dyann; Duraisingh, Manoj; Molyneux, Malcolm E; Taylor, Terrie E.; Marti, Matthias; Milner, Danny
    The spleen has an important role in the clearance of malaria parasites, and the role of HIV co-infection on this process is yet to be described. Using a combination of histological and molecular methods, we systematically evaluated parasite load across multiple organs from HIV-positive and HIV-negative cases of an autopsy study of pediatric comatose children with malaria infection (n = 103) in Blantyre, Malawi. Quantification of parasite load across organs was done using histology. A subset of cases was further characterized for parasite localization and stage of development using immunohistochemistry-based labeling of parasite and host cells (5 HIV-positive, 10 HIV-negative), and quantitative RT-PCR (qRT-PCR) of asexual and sexual-specific genes (4 HIV-positive, 5 HIV-negative). The results were compared with clinical information including HIV status. The HIV positive rate was 21% for the group studied (20 of 95) and HIV-positive patients had a significantly shorter duration of time between onset of illness and death, and were significantly older than HIV-negative patients. We found that spleens of HIV-positive cases had significantly higher parasite loads compared to those of HIV-negative cases in each the three methods we used: (i) standard histology, (ii) immunohistochemistry-based labeling of Plasmodium lactate dehydrogenase (pLDH), and (iii) molecular detection of asexual parasite transcript apical membrane antigen 1 (AMA1). Immunohistochemistry-based labeling of macrophage marker CD163 in a subset of spleens revealed fewer activated macrophages containing engulfed parasites and a greater number of free unphagocytosed parasites in the HIV-positive cases. The mechanism by which HIV infection is associated with more rapid progression to severe cerebral malaria disease is possibly impairment of parasite destruction by splenic macrophages, supported by published in vitro studies showing inefficient phagocytosis of malaria parasites by HIV-infected macrophages.
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    Transcriptional profiling defines dynamics of parasite tissue sequestration during malaria infection
    (BioMed Central, 2015) Pelle, Karell; Oh, Keunyoung; Buchholz, Kathrin; Narasimhan, Vagheesh; Joice, Regina; Milner, Danny; Brancucci, Nicolas; Ma, Siyuan; Voss, Till S; Ketman, Ken; Seydel, Karl B; Taylor, Terrie E; Barteneva, Natasha S; Huttenhower, Curtis; Marti, Matthias
    Background: During intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood. Results: We generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion. Conclusions: This study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0133-7) contains supplementary material, which is available to authorized users.
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    Targeting Human Transmission Biology for Malaria Elimination
    (Public Library of Science, 2015) Nilsson, Sandra; Childs, Lauren; Buckee, Caroline; Marti, Matthias
    Malaria remains one of the leading causes of death worldwide, despite decades of public health efforts. The recent commitment by many endemic countries to eliminate malaria marks a shift away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Gametocytes, the only developmental stage of malaria parasites able to infect mosquitoes, have remained understudied, as they occur in low numbers, do not cause disease, and are difficult to detect in vivo by conventional methods. Here, we review the transmission biology of P. falciparum gametocytes, featuring important recent discoveries of genes affecting parasite commitment to gametocyte formation, microvesicles enabling parasites to communicate with each other, and the anatomical site where immature gametocytes develop. We propose potential parasite targets for future intervention and highlight remaining knowledge gaps.
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    Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model
    (Nature Publishing Group, 2016) Obaldía III, Nicanor; Dow, Geoffrey S.; Gerena, Lucia; Kyle, Dennis; Otero, William; Mantel, Pierre-Yves; Baro, Nicholas; Daniels, Rachel; Mukherjee, Angana; Childs, Lauren; Buckee, Caroline; Duraisingh, Manoj; Volkman, Sarah K.; Wirth, Dyann; Marti, Matthias
    Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model.
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    Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria
    (Nature Publishing Group, 2016) Mantel, Pierre-Yves; Hjelmqvist, Daisy; Walch, Michael; Kharoubi-Hess, Solange; Nilsson, Sandra; Ravel, Deepali; Ribeiro, Marina; Gruring, Christof; Ma, Siyuan; Padmanabhan, Prasad; Trachtenberg, Alexander; Ankarklev, Johan; Brancucci, Nicolas M.; Huttenhower, Curtis; Duraisingh, Manoj; Ghiran, Ionita; Kuo, Winston P.; Filgueira, Luis; Martinelli, Roberta; Marti, Matthias
    Malaria remains one of the greatest public health challenges worldwide, particularly in sub-Saharan Africa. The clinical outcome of individuals infected with Plasmodium falciparum parasites depends on many factors including host systemic inflammatory responses, parasite sequestration in tissues and vascular dysfunction. Production of pro-inflammatory cytokines and chemokines promotes endothelial activation as well as recruitment and infiltration of inflammatory cells, which in turn triggers further endothelial cell activation and parasite sequestration. Inflammatory responses are triggered in part by bioactive parasite products such as hemozoin and infected red blood cell-derived extracellular vesicles (iRBC-derived EVs). Here we demonstrate that such EVs contain functional miRNA-Argonaute 2 complexes that are derived from the host RBC. Moreover, we show that EVs are efficiently internalized by endothelial cells, where the miRNA-Argonaute 2 complexes modulate target gene expression and barrier properties. Altogether, these findings provide a mechanistic link between EVs and vascular dysfunction during malaria infection.
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    Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda
    (Nature Publishing Group, 2016) Chang, Hsiao-Han; Meibalan, Elamaran; Zelin, Justin; Daniels, Rachel; Eziefula, Alice C.; Meyer, Evan C.; Tadesse, Fitsum; Grignard, Lynn; Joice, Regina C.; Drakeley, Chris; Wirth, Dyann; Volkman, Sarah K.; Buckee, Caroline; Bousema, Teun; Marti, Matthias
    Artemisinin resistance is rapidly spreading in Southeast Asia. The efficacy of artemisinin-combination therapy (ACT) continues to be excellent across Africa. We performed parasite transcriptional profiling and genotyping on samples from an antimalarial treatment trial in Uganda. We used qRT-PCR and genotyping to characterize residual circulating parasite populations after treatment with either ACT or ACT-primaquine. Transcripts suggestive of circulating ring stage parasites were present after treatment at a prevalence of >25% until at least 14 days post initiation of treatment. Greater than 98% of all ring stage parasites were cleared within the first 3 days, but subsequently persisted at low concentrations until day 14 after treatment. Genotyping demonstrated a significant decrease in multiplicity of infection within the first 2 days in both ACT and ACT-primaquine arms. However, multiple clone infections persisted until day 14 post treatment. Our data suggest the presence of genetically diverse persisting parasite populations after ACT treatment. Although we did not demonstrate clinical treatment failures after ACT and the viability and transmissibility of persisting ring stage parasites remain to be shown, these findings are of relevance for the interpretation of parasite clearance transmission dynamics and for monitoring drug effects in Plasmodium falciparum parasites.
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    Publisher Correction: Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity
    (Nature Publishing Group UK, 2018) Stone, Will J. R.; Campo, Joseph J.; Ouédraogo, André Lin; Meerstein-Kessel, Lisette; Morlais, Isabelle; Da, Dari; Cohuet, Anna; Nsango, Sandrine; Sutherland, Colin J.; van de Vegte-Bolmer, Marga; Siebelink-Stoter, Rianne; van Gemert, Geert-Jan; Graumans, Wouter; Lanke, Kjerstin; Shandling, Adam D.; Pablo, Jozelyn V.; Teng, Andy A.; Jones, Sophie; de Jong, Roos M.; Fabra-García, Amanda; Bradley, John; Roeffen, Will; Lasonder, Edwin; Gremo, Giuliana; Schwarzer, Evelin; Janse, Chris J.; Singh, Susheel K.; Theisen, Michael; Felgner, Phil; Marti, Matthias; Drakeley, Chris; Sauerwein, Robert; Bousema, Teun; Jore, Matthijs M.
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    High prevalence of Plasmodium falciparum gametocyte infections in school-age children using molecular detection: patterns and predictors of risk from a cross-sectional study in southern Malawi
    (BioMed Central, 2016) Coalson, Jenna E.; Walldorf, Jenny A.; Cohee, Lauren M.; Ismail, Miriam D.; Mathanga, Don; Cordy, Regina Joice; Marti, Matthias; Taylor, Terrie E.; Seydel, Karl B.; Laufer, Miriam K.; Wilson, Mark L.
    Background: In endemic areas, many people experience asymptomatic Plasmodium infections, particularly older children and adults, but their transmission contribution is unknown. Though not the exclusive determinant of infectiousness, transmission from humans to mosquitoes requires blood meals containing gametocytes. Gametocytes often occur at submicroscopic densities, challenging measurement in human populations. More sensitive molecular techniques allow better characterization of gametocyte epidemiologic patterns. Methods: Approximately 30 households were selected from each of eight sites in southern Malawi during two cross-sectional surveys. Blood was sampled from 623 people during the dry season and 896 the following rainy season. Among people PCR-positive for Plasmodium falciparum, mature gametocytes were detected by qRT-PCR. Regression models evaluated predictors of gametocyte carriage and density in the total population and among those with PCR-positive infections. Results: The prevalence of gametocyte carriage by molecular testing was 3.5% during the dry season and 8.6% during the rainy season, and by microscopy 0.8 and 3.3%, respectively. Nearly half of PCR-positive infections carried gametocytes, regardless of recent symptom status. Among P. falciparum-infected people, only living in unfinished houses and age were significantly associated with gametocyte presence. Infected people in unfinished houses had higher odds of carrying gametocytes (OR 2.24, 95% CI 1.16–4.31), and 31% (95% CI 3–65%) higher gametocyte density than those in finished houses. School-age children (5–15 years), had higher odds than adults (≥16 years) of having gametocytes when infected (OR 2.77, 95% CI 1.47–5.19), but 31% (95% CI 11–47%) lower gametocyte density. Children <5 years did not have significantly higher odds of gametocyte carriage or density when infected than adults. Conclusions: School-age children frequently carry gametocytes in communities of southern Malawi and represent an under-recognized reservoir of infection. Malaria elimination strategies should address these frequently asymptomatic reservoirs, especially in highly endemic areas. Improved household construction may also reduce the infectious reservoir. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1587-9) contains supplementary material, which is available to authorized users.