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Author: Donna Huber

Modeling approaches to predicting persistent hotspots in SCORE studies for gaining control of schistosomiasis mansoni in Kenya and Tanzania

BACKGROUND:

Some villages, labeled “persistent hotspots (PHS),” fail to respond adequately in regard to prevalence and intensity of infection to mass drug administration (MDA) for schistosomiasis. Early identification of PHS, for example, before initiating or after a year or two of MDA could help guide programmatic decision-making.

METHODS:

In a study with multiple rounds of MDA, data collected prior to the third MDA were used to predict PHS. We assessed six predictive approaches using data from before MDA and after 2 rounds of annual MDA from Kenya and Tanzania.

RESULTS:

Generalized linear models with variable selection possessed relatively stable performance compared to tree-based methods. Models applied to Kenya data alone or combined data from Kenya and Tanzania could reach over 80% predictive accuracy, while predicting PHS for Tanzania was challenging. Models developed from one country and validated in another failed to achieve satisfactory performance. Several Year 3 variables were identified as key predictors.

CONCLUSIONS:

Statistical models applied to Year 3 data could help predict PHS and guide program decisions, with infection intensity, prevalence of heavy infections (≥400 eggs/gram of feces), and total prevalence being particularly important factors. Additional studies including more variables and locations could help in developing generalizable models.

Ye Shen, Meng-Hsuan Sung, Charles H King, Sue Binder, Nupur Kittur, Christopher C Whalen, Daniel G Colley. J Infect Dis. 2019 Oct 17. pii: jiz529. doi: 10.1093/infdis/jiz529

Comparison of transcriptomes of an orthotospovirus vector and non-vector thrips species

Thrips transmit one of the most devastating plant viruses worldwide–tomato spotted wilt tospovirus (TSWV). Tomato spotted wilt tospovirus is a type species in the genus Orthotospovirus and family Tospoviridae. Although there are more than 7,000 thrips species, only nine thrips species are known to transmit TSWV. In this study, we investigated the molecular factors that could affect thrips ability to transmit TSWV. We assembled transcriptomes of a vector, Frankliniella fusca [Hinds], and a non-vector, Frankliniella tritici [Fitch], and performed qualitative comparisons of contigs associated with virus reception, virus infection, and innate immunity. Annotations of Ffusca and Ftritici contigs revealed slight differences across biological process and molecular functional groups. Comparison of virus cell surface receptors revealed that homologs of integrin were present in both species. However, homologs of another receptor, heperan sulfate, were present in Ffusca alone. Contigs associated with virus replication were identified in both species, but a contig involved in inhibition of virus replication (radical s-adenosylmethionine) was only present in the non-vector, Ftritici. Additionally, some differences in immune signaling pathways were identified between vector and non-vector thrips. Detailed investigations are necessary to functionally characterize these differences between vector and non-vector thrips and assess their relevance in orthotospovirus transmission.

Shrestha A, Champagne DE, Culbreath AK, Abney MR, Srinivasan R (2019) Comparison of transcriptomes of an orthotospovirus vector and non-vector thrips species. PLoS ONE 14(10): e0223438. https://doi.org/10.1371/journal.pone.0223438

Anibamine and Its Analogues: Potent Antiplasmodial Agents from Aniba citrifolia

In our continuing search for novel natural products with antiplasmodial activity, an extract of Aniba citrifolia was found to have good activity, with an IC50 value less than 1.25 μg/mL. After bioassay-directed fractionation, the known indolizinium alkaloid anibamine (1) and the new indolizinium alkaloid anibamine B (2) were isolated as the major bioactive constituents, with antiplasmodial IC50 values of 0.170 and 0.244 μM against the drug-resistant Dd2 strain of Plasmodium falciparum. The new coumarin anibomarin A (3), the new norneolignan anibignan A (5), and six known neolignans (712) were also obtained. The structures of all the isolated compounds were determined based on analyses of 1D and 2D NMR spectroscopic and mass spectrometric data, and the absolute configuration of anibignan A (5) was assigned from its ECD spectrum. Evaluation of a library of 28 anibamine analogues (1340) indicated that quaternary charged analogues had IC50 values as low as 58 nM, while uncharged analogues were inactive or significantly less active. Assessment of the potential effects of anibamine and its analogues on the intraerythrocytic stages and morphological development of P. falciparum revealed substantial activity against ring stages for compounds with two C-10 side chains, while those with only one C-10 side chain exhibited substantial activity against trophozoite stages, suggesting different mechanisms of action.

Yongle Du, Ana Lisa Valenciano, Yumin Dai, Yi Zheng, Feng Zhang, Yan Zhang, Jason Clement, Michael Goetz, David G. I. Kingston, Maria B. Cassera. 2019. J Nat Prod. doi: 10.1021/acs.jnatprod.9b00724.

Sylvatic cycles of arboviruses in non-human primates

Arboviruses infecting people primarily exist in urban transmission cycles involving urban mosquitoes in densely populated tropical regions. For dengue, chikungunya, Zika and yellow fever viruses, sylvatic (forest) transmission cycles also exist in some regions and involve non-human primates and forest-dwelling mosquitoes. Here we review the investigation methods and available data on sylvatic cycles involving non-human primates and dengue, chikungunya, Zika and yellow fever viruses in Africa, dengue viruses in Asia and yellow fever virus in the Americas. We also present current putative data that Mayaro, o’nyong’nyong, Oropouche, Spondweni and Lumbo viruses exist in sylvatic cycles.

Matthew John Valentine, Courtney Cuin Murdock & Patrick John Kelly. 2019. Parasit Vectors.;12(1):463. doi: 10.1186/s13071-019-3732-0

Mapping Schistosoma mansoni endemicity in Rwanda: a critical assessment of geographical disparities arising from circulating cathodic antigen versus Kato-Katz diagnostics

Background

Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Intervention relies on identifying high-risk regions, yet rapid Schistosoma diagnostics (Kato-Katz stool assays (KK) and circulating cathodic antigen urine assays (CCA)) yield different prevalence estimates. We mapped Smansoni prevalence and delineated at-risk regions using a survey of schoolchildren in Rwanda, where Schistosoma mansoni is an endemic parasite. We asked if different diagnostics resulted in disparities in projected infection risk.

 

Methods

Infection data was obtained from a 2014 Rwandan school-based survey that used KK and CCA diagnostics. Across 386 schools screened by CCA (N = 19,217). To allow for uncertainty when interpreting ambiguous CCA trace readings, which accounted for 28.8% of total test results, we generated two presence-absence datasets: CCA trace as positive and CCA trace as negative. Samples (N = 9,175) from 185 schools were also screened by KK. We included land surface temperature (LST) and the Normalized Difference Vegetation and Normalized Difference Water Indices (NDVI, NDWI) as predictors in geostatistical regressions.

 

Findings

Across 8,647 children tested by both methods, prevalence was 35.93% for CCA trace as positive, 7.21% for CCA trace as negative and 1.95% for KK. LST was identified as a risk factor using KK, whereas NDVI was a risk factor for CCA models. Models predicted high endemicity in Northern and Western regions of Rwanda, though the CCA trace as positive model identified additional high-risk areas that were overlooked by the other methods. Estimates of current burden for children at highest risk (boys aged 5–9 years) varied by an order of magnitude, with 671,856 boys projected to be infected by CCA trace as positive and only 60,453 projected by CCA trace as negative results.

 

Conclusions

Our findings show that people in Rwanda’s Northern, Western and capital regions are at high risk of Smansoni infection. However, variation in identification of environmental risk factors and delineation of at-risk regions using different diagnostics likely provides confusing messages to disease intervention managers. Further research and statistical analyses, such as latent class analysis, can be used to improve CCA result classification and assess its use in guiding treatment regimes.

 

Clark NJ, Umulisa I, Ruberanziza E, Owada K, Colley DG, Ortu G, et al. (2019) Mapping Schistosoma mansoni endemicity in Rwanda: a critical assessment of geographical disparities arising from circulating cathodic antigen versus Kato-Katz diagnostics. PLoS Negl Trop Dis 13(9): e0007723. https://doi.org/10.1371/journal.pntd.0007723

Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

The shikimate pathway, a metabolic pathway absent in humans, is responsible for the production of chorismate, a branch point metabolite. In the malaria parasite, chorismate is postulated to be a direct precursor in the synthesis of p-aminobenzoic acid (folate biosynthesis), p-hydroxybenzoic acid (ubiquinone biosynthesis), menaquinone, and aromatic amino acids. While the potential value of the shikimate pathway as a drug target is debatable, the metabolic dependency of chorismate in P. falciparum remains unclear. Current evidence suggests that the main role of chorismate is folate biosynthesis despite ubiquinone biosynthesis being active and essential in the malaria parasite. Our goal in the present work was to expand our knowledge of the ubiquinone head group biosynthesis and its potential metabolic dependency on chorismate in P. falciparum. We systematically assessed the development of both asexual and sexual stages of P. falciparum in a defined medium in the absence of an exogenous supply of chorismate end-products and present biochemical evidence suggesting that the benzoquinone ring of ubiquinones in this parasite may be synthesized through a yet unidentified route.

Ana Lisa Valenciano, Maria L. Fernández-Murga, Emilio F. Merino, Nicole R. Holderman, Grant J. Butschek, Karl J. Shaffer, Peter C. Tyler & Maria Belen Cassera. 2019. Sci Rep.;9(1):13936. doi: 10.1038/s41598-019-50319-5.

Clinically silent relapsing malaria may still pose a threat

The immune system can control a relapsing form of malaria enough to avoid clinical signs of disease, but it doesn’t eliminate transmissible parasites from the body that may still be infectious to mosquitoes. That’s the conclusion of a study on a nonhuman primate model of Plasmodium vivax infection, which has implications relevant to malaria elimination strategies.

Keep reading about the MaPHIC study at Technology.org

Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes

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 Pvivax and Povale, 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 Pcynomolgi–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, Pcynomolgi-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 Pcynomolgi 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