publications Archives - Page 28 of 59 - Center for Tropical and Emerging Global Diseases

Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes

Donna Huber on September 19, 2019

Plasmodium relapses are attributed to the activation of dormant liver-stage parasites and are responsible for a significant number of recurring malaria blood-stage infections. While characteristic of human infections caused by P. vivax and P. ovale, their relative contribution to malaria disease burden and transmission remains poorly understood. This is largely because it is difficult to identify ‘bona fide’ relapse infections due to ongoing transmission in most endemic areas. Here, we use the P. cynomolgi–rhesus macaque model of relapsing malaria to demonstrate that clinical immunity can form after a single sporozoite-initiated blood-stage infection and prevent illness during relapses and homologous reinfections. By integrating data from whole blood RNA-sequencing, flow cytometry, P. cynomolgi-specific ELISAs, and opsonic phagocytosis assays, we demonstrate that this immunity is associated with a rapid recall response by memory B cells that expand and produce anti-parasite IgG1 that can mediate parasite clearance of relapsing parasites. The reduction in parasitemia during relapses was mirrored by a reduction in the total number of circulating gametocytes, but importantly, the cumulative proportion of gametocytes increased during relapses. Overall, this study reveals that P. cynomolgi relapse infections can be clinically silent in macaques due to rapid memory B cell responses that help to clear asexual-stage parasites but still carry gametocytes.

Joyner CJ, Brito CFA, Saney CL, Joice Cordy R, Smith ML, Lapp SA, Cabrera-Mora M, Kyu S, Lackman N, Nural MV, DeBarry JD, MaHPIC Consortium, Kissinger JC, Styczynski MP, Lee FE, Lamb TJ, Galinski MR.. (2019) Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes. PLoS Pathog 15(9): e1007974. https://doi.org/10.1371/journal.ppat.1007974

Is reliance on an inaccurate genome sequence sabotaging your experiments?

Donna Huber on September 12, 2019

Advances in genomics have made whole genome studies increasingly feasible across the life sciences. However, new technologies and algorithmic advances do not guarantee flawless genomic sequences or annotation. Bias, errors, and artifacts can enter at any stage of the process from library preparation to annotation. When planning an experiment that utilizes a genome sequence as the basis for the design, there are a few basic checks that, if performed, may better inform the experimental design and ideally help avoid a failed experiment or inconclusive result.

Baptista RP, Kissinger JC (2019) Is reliance on an inaccurate genome sequence sabotaging your experiments? PLoS Pathog 15(9): e1007901. https://doi.org/10.1371/journal.ppat.1007901

Accessing Cryptosporidium Omic and Isolate Data via CryptoDB.org

Donna Huber on August 27, 2019

Cryptosporidium has historically been a difficult organism to work with, and molecular genomic data for this important pathogen have typically lagged behind other prominent protist pathogens. CryptoDB ( http://cryptodb.org/ ) was launched in 2004 following the appearance of draft genome sequences for both C. parvum and C. hominis. CryptoDB merged with the EuPathDB Bioinformatics Resource Center family of databases ( https://eupathdb.org ) and has been maintained and updated regularly since its establishment. These resources are freely available, are web-based, and permit users to analyze their own sequence data in the context of reference genome sequences in our user workspaces. Advances in technology have greatly facilitated Cryptosporidium research in the last several years greatly enhancing and extending the data and types of data available for this genus. Currently, 13 genome sequences are available for 9 species of Cryptosporidium as well as the distantly related Gregarina niphandrodes and two free-living alveolate outgroups of the Apicomplexa, Chromera velia and Vitrella brassicaformis. Recent years have seen several new genome sequences for both existing and new Cryptosporidium species as well as transcriptomics, proteomics, SNP, and isolate population surveys. This chapter introduces the extensive data mining and visualization capabilities of the EuPathDB software platform and introduces the data types and tools that are currently available for Cryptosporidium. Key features are demonstrated with Cryptosporidium-relevant examples and explanations.

Warrenfeltz S, Kissinger JC, EuPathDB Team. Methods Mol Biol. 2020;2052:139-192. doi: 10.1007/978-1-4939-9748-0_10.

Protozoan persister-like cells and drug treatment failure

Donna Huber on August 23, 2019

Antimicrobial treatment failure threatens our ability to control infections. In addition to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive drug treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and kinetoplastid protozoa, including Trypanosoma cruzi and Leishmaniaspp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as ‘persister-like cells’. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.

Michael P. Barrett, Dennis E. Kyle, L. David Sibley, Joshua B. Radke & Rick L. Tarleton. Nat Rev Microbiol. 2019 Aug 23. doi: 10.1038/s41579-019-0238-x.

Enteropathogen antibody dynamics and force of infection among children in low-resource settings

Donna Huber on August 19, 2019

Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was <3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles demonstrated significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest antibody response can be used to measure population-level transmission of diverse enteropathogens in serologic surveillance.

Benjamin F Arnold, Diana L Martin, Jane Juma, Harran Mkocha, John B Ochieng, Gretchen M Cooley, Richard Omore, E Brook Goodhew, Jamae F Morris, Veronica Costantini, Jan Vinjé, Patrick J Lammie, Jeffrey W Priest. Elife. 2019 Aug 19;8. pii: e45594. doi: 10.7554/eLife.45594.

Five-Year Impact of Different Multi-Year Mass Drug Administration Strategies on Childhood Schistosoma mansoni-Associated Morbidity: A Combined Analysis from the Schistosomiasis Consortium for Operational Research and Evaluation Cohort Studies in the Lake Victoria Regions of Kenya and Tanzania

Donna Huber on August 12, 2019

The WHO recommends mass treatment with praziquantel as the primary approach for Schistosoma mansoni-related morbidity control in endemic populations. The Schistosomiasis Consortium for Operational Research and Evaluation implemented multi-country, cluster-randomized trials to compare effectiveness of community-wide and school-based treatment (SBT) regimens on prevalence and intensity of schistosomiasis. To assess the impact of two different treatment schedules on S. mansoni-associated morbidity in children, cohort studies were nested within the randomized trials conducted in villages in Kenya and Tanzania having baseline prevalence ≥ 25%. Children aged 7-8 years were enrolled at baseline and followed to ages 11-12 years. Infection intensity and odds of infection were reduced both in villages receiving four years of annual community-wide treatment (CWT) and those who received biennial SBT over 4 years. These regimens were also associated with reduced odds of undernutrition and reduced odds of portal vein dilation at follow-up. However, neither hemoglobin levels nor the prevalence of the rare abnormal pattern C liver scores on ultrasound improved. For the combined cohorts, growth stunting worsened in the areas receiving biennial SBT, and maximal oxygen uptake as estimated by fitness testing scores declined under both regimens. After adjusting for imbalance in starting prevalence between study arms, children in villages receiving annual CWT had significantly greater decreases in infection prevalence and intensity than those villages receiving biennial SBT. Although health-related quality-of-life scores improved in both study arms, children in the CWT villages gained significantly more. We conclude that programs using annual CWT are likely to achieve better overall S. mansoni morbidity control than those implementing only biennial SBT.

Ye Shen, Ryan E. Wiegand, Annette Olsen, Charles H. King, Nupur Kittur, Sue Binder, Feng Zhang, Christopher C. Whalen, William Evan Secor, Susan P. Montgomery, Pauline N. M. Mwinzi, Pascal Magnussen, Safari Kinung’hi, Carl H. Campbell Jr. and Daniel G. Colley. Am J Trop Med Hyg. 2019 Aug 12. doi: 10.4269/ajtmh.19-0273.

Robust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages

Donna Huber on August 12, 2019

The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts.

Chua ACY, Ong JJY, Malleret B, Suwanarusk R, Kosaisavee V, Zeeman AM, Cooper CA, Tan KSW, Zhang R, Tan BH, Abas SN, Yip A, Elliot A, Joyner CJ, Cho JS, Breyer K, Baran S, Lange A, Maher SP, Nosten F, Bodenreider C, Yeung BKS, Mazier D, Galinski MR, Dereuddre-Bosquet N, Le Grand R, Kocken CHM, Rénia L, Kyle DE, Diagana TT, Snounou G, Russell B, Bifani P. Nat Commun. 2019 Aug 12;10(1):3635. doi: 10.1038/s41467-019-11332-4.

Isolation and characterization of antiplasmodial constituents from the marine sponge Coscinoderma sp.

Donna Huber on August 6, 2019

Six known compounds, namely two halisulfates 1 and 2 and four epidioxy sterols 3–6, were isolated from the marine sponge Coscinoderma sp. The structures of these compounds were confirmed by nuclear magnetic resonance (¹H and ¹³C NMR) spectroscopy, and their antiplasmodial activities were determined against the chloroquine-resistant Dd2 strain of Plasmodium falciparum. The epidioxy steroids 3–6 all showed moderate to weak antiplasmodial activity, with IC₅₀ values of 2.7 μM for (24S)-5α,8α-epidioxy-24-methylcholesta-6-en-3β-ol (3), 11.6 μM for 5α,8α-epidioxycholesta-6,24(28)-dien-3β-o1 (4), 2.33 μM for 5α,8α-epidioxy-24-methylcholesta-6,9(11)-24(28)-trien-3β-ol (5), and between 12 and 24 μM for 5α,8α-epidioxycholesta-6-en-3β-ol (6). In contrast, halisulfate 2 (1) was inactive, and halisulfate 1 (2) had an of IC₅₀ value of about 24 μM.

Jeong H, Latif A, Kong CS, Seo Y, Lee YJ, Dalal SR, Cassera MB, Kingston DGI. Z Naturforsch C. 2019 Aug 6. pii: /j/znc.ahead-of-print/znc-2019-0039/znc-2019-0039.xml. doi: 10.1515/znc-2019-0039.

Toxoplasma F-box protein 1 is required for daughter cell scaffold function during parasite replication

Donna Huber on July 26, 2019

By binding to the adaptor protein SKP1 and serving as substrate receptors for the Skp1, Cullin, F-box E3 ubiquitin ligase complex, F-box proteins regulate critical cellular processes including cell cycle progression and membrane trafficking. While F-box proteins are conserved throughout eukaryotes and are well studied in yeast, plants, and animals, studies in parasitic protozoa are lagging. We have identified eighteen putative F-box proteins in the Toxoplasmagenome of which four have predicted homologs in Plasmodium. Two of the conserved F-box proteins were demonstrated to be important for Toxoplasma fitness and here we focus on an F-box protein, named TgFBXO1, because it is the most highly expressed by replicative tachyzoites and was also identified in an interactome screen as a Toxoplasma SKP1 binding protein. TgFBXO1 interacts with Toxoplasma SKP1 confirming it as a bona fide F-box protein. In interphase parasites, TgFBXO1 is a component of the Inner Membrane Complex (IMC), which is an organelle that underlies the plasma membrane. Early during replication, TgFBXO1 localizes to the developing daughter cell scaffold, which is the site where the daughter cell IMC and microtubules form and extend from. TgFBXO1 localization to the daughter cell scaffold required centrosome duplication but before kinetochore separation was completed. Daughter cell scaffold localization required TgFBXO1 N-myristoylation and was dependent on the small molecular weight GTPase, TgRab11b. Finally, we demonstrate that TgFBXO1 is required for parasite growth due to its function as a daughter cell scaffold effector. TgFBXO1 is the first F-box protein to be studied in apicomplexan parasites and represents the first protein demonstrated to be important for daughter cell scaffold function.

Carlos Gustavo Baptista, Agnieszka Lis, Bowen Deng, Elisabet Gas-Pascual, Ashley Dittmar, Wade Sigurdson, Christopher M. West, Ira J. Blader. PLoS Pathog. 2019 Jul 26;15(7):e1007946. doi: 10.1371/journal.ppat.1007946.

Elimination of onchocerciasis in Africa by 2025: the need for a broad perspective

Donna Huber on July 15, 2019

In response to the recent publication “Is onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes” by Dadzie et al., it is important to clarify and highlight the positive and unequivocal research and operational contributions from the American experience towards the worldwide elimination of human onchocerciasis (river blindness).

Main text

The strategies of twice or more rounds of mass drug administration (MDA) of ivermectin per year, as well as the use of OV-16 serology have allowed four American countries to be verified by World Health Organization to have eliminated transmission of Onchocerca volvulus, the etiological agent. These advances were also implemented in Sudan and Uganda; currently, both are the only African countries where ivermectin MDA was safely stopped in several transmission zones.

Conclusions

Programmatic treatment and evaluation approaches, pioneered in the Americas, are the most efficient among the existing tools for elimination, and their broader use could catalyze the successful elimination of this disease in Africa.

Ed Cupp, Mauricio Sauerbrey, Vitaliano Cama, Mark Eberhard, Patrick J. Lammie and Thomas R. Unnasch. Infect Dis Poverty. 2019 Jul 15;8(1):50. doi: 10.1186/s40249-019-0557-1.

Category: publications