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Category: publications

Age influences the thermal suitability of Plasmodium falciparum transmission in the Asian malaria vector Anopheles stephensi

Donna Huber on July 22, 2020

Models predicting disease transmission are vital tools for long-term planning of malaria reduction efforts, particularly for mitigating impacts of climate change. We compared temperature-dependent malaria transmission models when mosquito life-history traits were estimated from a truncated portion of the lifespan (a common practice) versus traits measured across the full lifespan. We conducted an experiment on adult female Anopheles stephensi, the Asian urban malaria mosquito, to generate daily per capita values for mortality, egg production and biting rate at six constant temperatures. Both temperature and age significantly affected trait values. Further, we found quantitative and qualitative differences between temperature–trait relationships estimated from truncated data versus observed lifetime values. Incorporating these temperature–trait relationships into an expression governing the thermal suitability of transmission, relative R0(T), resulted in minor differences in the breadth of suitable temperatures for Plasmodium falciparum transmission between the two models constructed from only An. stephensi trait data. However, we found a substantial increase in thermal niche breadth compared with a previously published model consisting of trait data from multiple Anopheles mosquito species. Overall, this work highlights the importance of considering how mosquito trait values vary with mosquito age and mosquito species when generating temperature-based suitability predictions of transmission.

K. L. Miazgowicz, M. S. Shocket, S. J. Ryan, O. C. Villena, R. J. Hall, J. Owen, T. Adanlawo, K. Balaji, L. R. Johnson, E. A. Mordecai and C. C. Murdock. Proc Biol Sci. 2020 Jul 29;287(1931):20201093. doi: 10.1098/rspb.2020.1093.

Pre-Erythrocytic Vaccines against Malaria

Donna Huber on July 21, 2020

Malaria, caused by the protozoan Plasmodium, is a devastating disease with over 200 million new cases reported globally every year. Although immunization is arguably the best strategy to eliminate malaria, despite decades of research in this area we do not have an effective, clinically approved antimalarial vaccine. The current impetus in the field is to develop vaccines directed at the pre-erythrocytic developmental stages of Plasmodium, utilizing novel vaccination platforms. We here review the most promising pre-erythrocytic stage antimalarial vaccine candidates.

Camila Marques-da-Silva, Kristen Peissig, and Samarchith P. Kurup. Pre-Erythrocytic Vaccines against Malaria. Vaccines 2020, 8, 400. https://doi.org/10.3390/vaccines8030400

Test, Treat, Track, Test, and Treat Active Surveillance toward Elimination of Schistosomiasis: A Feasibility Study

Donna Huber on July 13, 2020

We assessed the feasibility of using a test, treat, track, test, and treat (5T) active surveillance strategy to identify and treat individuals with schistosomiasis in three very low-prevalence villages in Kafr El Sheikh Governorate, Egypt. Primary index cases (PICs) were identified using the point-of-care circulating cathodic antigen (POC-CCA) assay in schools, in rural health units (retesting individuals with positive Kato-Katz examinations over the previous 6 months), and at potential water transmission sites identified by PICs and field observations. Primary cases identified potential second-generation cases-people with whom they shared water activities-who were then tracked, tested, and treated if infected. Those sharing water activities with second-generation cases were also tested. The yield of PICs from the three venues were 128 of 3,576 schoolchildren (3.6%), 42 of 696 in rural health units (6.0%), and 83 of 1,156 at water contact sites (7.2%). There were 118 second- and 19 third-generation cases identified. Persons testing positive were treated with praziquantel. Of 388 persons treated, 368 (94.8%) had posttreatment POC-CCA tests 3-4 weeks after treatment, and 81.8% (301) became negative. The 67 persons remaining positive had negative results after a second treatment. Therefore, all those found positive, treated, and followed up were negative following one or two treatments. Analysis of efforts as expressed in person-hours indicates that 4,459 person-hours were required for these 5T activities, with nearly 65% of that time spent carrying out interviews, treatments, and evaluations following treatment. The 5T strategy appears feasible and acceptable as programs move toward elimination.

Reda M R Ramzy, Amal Rabiee, Khaled M Abd Elaziz, Carl H Campbell, Nupur Kittur, Daniel G Colley, Ayat A Haggag. Am J Trop Med Hyg. 2020 Jul 13. doi: 10.4269/ajtmh.20-0156.

Flavanones From the Twigs and Barks of Artocarpus Lakoocha Having Antiplasmodial and Anti-TB Activities

Donna Huber on July 1, 2020

Chromatographic separation of the acetone extracts from the twigs and barks of Artocarpus lakoocha led to the isolation of the one new flavanone, lakoochanone (1), together with eleven known compounds (2-12). Lakoochanone (1) and moracin C (4) exhibited weak antiplasmodial activity against Plasmodium falciparum Dd2 with IC50 values of 36.7 and 33.9 µM, respectively. Moreover, moracin C (4) and sanggenofuran B (5) showed cytotoxic activity against A2780 cell line with the respective IC50 values of 15.0 and 57.1 µM. In addition, cyclocommunin (7) displayed strong antimycobacterial activity against Mycobacterium tuberculosis H37Ra with the minimum inhibitory concentration (MIC) value of 12.3 µM.

Sirada Boonyaketgoson, Yongle Du, Ana L. Valenciano Murillo, Maria B. Cassera, David G. I. Kingston, Kongkiat Trisuwan. Chem Pharm Bull (Tokyo). 2020;68(7):671-674. doi: 10.1248/cpb.c20-00080.

Lathosterol Oxidase (Sterol C-5 Desaturase) Deletion Confers Resistance to Amphotericin B and Sensitivity to Acidic Stress in Leishmania Major

Donna Huber on July 1, 2020

Lathosterol oxidase (LSO) catalyzes the formation of the C-5–C-6 double bond in the synthesis of various types of sterols in mammals, fungi, plants, and protozoa. In Leishmania parasites, mutations in LSO or other sterol biosynthetic genes are associated with amphotericin B resistance. To investigate the biological roles of sterol C-5–C-6 desaturation, we generated an LSO-null mutant line (lso−) in Leishmania major, the causative agent for cutaneous leishmaniasis. lso− parasites lacked the ergostane-based sterols commonly found in wild-type L. major and instead accumulated equivalent sterol species without the C-5–C-6 double bond. These mutant parasites were replicative in culture and displayed heightened resistance to amphotericin B. However, they survived poorly after reaching the maximal density and were highly vulnerable to the membrane-disrupting detergent Triton X-100. In addition, lso− mutants showed defects in regulating intracellular pH and were hypersensitive to acidic conditions. They also had potential alterations in the carbohydrate composition of lipophosphoglycan, a membrane-bound virulence factor in Leishmania. All these defects in lso− were corrected upon the restoration of LSO expression. Together, these findings suggest that the C-5–C-6 double bond is vital for the structure of the sterol core, and while the loss of LSO can lead to amphotericin B resistance, it also makes Leishmania parasites vulnerable to biologically relevant stress.

IMPORTANCE Sterols are essential membrane components in eukaryotes, and sterol synthesis inhibitors can have potent effects against pathogenic fungi and trypanosomatids. Understanding the roles of sterols will facilitate the development of new drugs and counter drug resistance. LSO is required for the formation of the C-5–C-6 double bond in the sterol core structure in mammals, fungi, protozoans, plants, and algae. Functions of this C-5–C-6 double bond are not well understood. In this study, we generated and characterized a lathosterol oxidase-null mutant in Leishmania major. Our data suggest that LSO is vital for the structure and membrane-stabilizing functions of leishmanial sterols. In addition, our results imply that while mutations in lathosterol oxidase can confer resistance to amphotericin B, an important antifungal and antiprotozoal agent, the alteration in sterol structure leads to significant defects in stress response that could be exploited for drug development.

Yu Ning, Cheryl Frankfater, Fong-Fu Hsu, Rodrigo P Soares, Camila A Cardoso, Paula M Nogueira, Noelia Marina Lander, Roberto Docampo, Kai Zhang. mSphere. 2020 Jul 1;5(4):e00380-20. doi: 10.1128/mSphere.00380-20.

Cutting Edge: Augmenting Muscle MHC Expression Enhances Systemic Pathogen Control at the Expense of T Cell Exhaustion

Donna Huber on June 26, 2020

Myocytes express low levels of MHC class I (MHC I), perhaps influencing the ability of CD8+ T cells to efficiently detect and destroy pathogens that invade muscle. Trypanosoma cruzi infects many cell types but preferentially persists in muscle, and we asked if this tissue-dependent persistence was linked to MHC expression. Inducible enhancement of skeletal muscle MHC I in mice during the first 20 d of T. cruzi infection resulted in enhanced CD8-dependent reduction of parasite load. However, continued overexpression of MHC I beyond 30 d ultimately led to a collapse of systemic parasite control associated with immune exhaustion, which was reversible in part by blocking PD-1:PD-L1 interactions. These studies demonstrate a surprisingly strong and systemically dominant effect of skeletal muscle MHC expression on maintaining T cell function and pathogen control and argue that the normally low MHC I expression in skeletal muscle is host protective by allowing for pathogen control while preventing immune exhaustion.

Angela D. Pack and Rick L. Tarleton. J Immunol. 2020 Jun 26;ji2000218. doi: 10.4049/jimmunol.2000218.

Bioactivity of Spongian Diterpenoid Scaffolds From the Antarctic Sponge Dendrilla antarctica

Donna Huber on June 23, 2020

The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B-D (10–12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13–15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.

Alexandre Bory, Andrew J Shilling, Jessie Allen, Ala Azhari, Alison Roth, Lindsey N Shaw, Dennis E Kyle, John H Adams, Charles D Amsler, James B McClintock, Bill J Baker. Mar Drugs. 2020 Jun 23;18(6):E327. doi: 10.3390/md18060327.

New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected With Trypanosoma cruzi: Clinical, Parasitological and Serological Assessment After Three Years of Follow-Up

Donna Huber on June 22, 2020

Introduction. In a pilot study, we showed that intermittent administration of benznidazole in chronic Chagas disease patients resulted in a low rate of treatment suspension and therapeutic failure, as assessed by qPCR at the end of treatment. Herein, a three-year post-treatment follow-up study of the same cohort of patients is presented.

Methods. The treatment scheme consisted of 12 doses of benznidazole at 5 mg/kg/day in two daily doses every 5 days. Parasite load, T. cruzi-specific antibodies and serum chemokine levels were measured prior to treatment and after a median follow-up of 36 months post-treatment by kDNA and SatDNA qPCR methods, conventional serological techniques and a Luminex-based assay with recombinant T. cruzi protein, and a cytometric bead array, respectively.

Results. At the end of follow-up, 14 of 17 (82%) patients had negative qPCR findings, whereas three of 17 (18%) had detectable nonquantifiable findings by at least one of the qPCR techniques. A decline in parasite-specific antibodies at 12 months post-treatment was confirmed by conventional serological tests and the Luminex assays. Monocyte chemoattractant protein-1 (MCP-1) levels increased after treatment, whereas monokine induced by gamma interferon (MIG) levels decreased. New post-treatment electrocardiographic abnormalities were observed in only one patient who had cardiomyopathy prior to treatment.

Conclusions. Altogether, these data strengthen our previous findings by showing that the intermittent administration of benznidazole results in a low rate of treatment suspension, with comparable treatment efficacy to that of a daily dose of 5mg/kg for 60 days.

María Gabriela Álvarez, Juan Carlos Ramírez, Graciela Bertocchi, Marisa Fernández, Yolanda Hernández, Bruno Lococo, Constanza Lopez-Albizu, Alejandro Schijman, Carolina Cura, Marcelo Abril, Susana Laucella, Rick L Tarleton, María Ailen Natale, Melisa Castro Eiro, Sergio Sosa-Estani, Rodolfo Viotti. Antimicrob Agents Chemother. 2020 Jun 22;AAC.00439-20. doi: 10.1128/AAC.00439-20.

Dynamics of Infection and Pathology Induced by the Aporocotylid, Cardicola Laruei, in Spotted Seatrout, Cynoscion Nebulosus (Sciaenidae)

Donna Huber on June 19, 2020

 

The sciaenid Spotted Seatrout (Cynoscion nebulosus) are infected by blood flukes (Cardicola spp.). A 2 year survey in estuaries of South Carolina, USA, showed that adult flukes and granulomas occurred throughout the year but their prevalence was highest in summer (61% and 84%, respectively), indicating an unusually high level of infection for wild fish. Granulomas remained after adult flukes could no longer be found. PCR-Restriction Fragment Length Polymorphism (RFLP) of a subsample of specimens allowed identification of Cardicola laruei as the only species infecting these seatrout during the period of study. Mean intensity of infection by flukes was higher in female seatrout, suggesting endocrine and/or immune system involvement. The prevalence of granulomas declined sharply in winter, indicating possible mortality of infected seatrout as this species is known to be cold-sensitive. Granulomas were studied using histology, immunohistochemistry, and transmission electron microscopy. Eggs were encapsulated by an inner core of dark epithelioid cells, and an outer core of large epithelioid cells undergoing epithelialization. Fibrosis was observed around granulomas and some granulomas detached from the surrounding damaged myocardium. Numerous inflammatory cells appeared mobilized around granulomas and pathology could be severe, in some cases showing grossly visible blister-like extrusions scattered in the damaged epicardium. At the gross level, some granulomas possessing eggs with live miracidia were observed at the surface of the epicardium. These findings suggest that granulomas carrying both dead and live eggs can clear the fish heart by host-mediated transport through the myocardium, as is known to occur in related human Schistosoma infections.

Eric J. McElroy, Barbara Nowak, Kristina M. Hill-Spanik, Willard O. Granath, Vincent A. Connors, Jim Driver, C. Jonathan Tucker, Dennis E. Kyle, Isaurede Buron. Int J Parasitol. 2020 Jun 19;S0020-7519(20)30148-X. doi: 10.1016/j.ijpara.2020.03.016.

Regional Survey of Diamondback Moth (Lepidoptera: Plutellidae) Response to Maximum Dosages of Insecticides in Georgia and Florida

Donna Huber on June 19, 2020

We conducted maximum dose bioassays of insecticide for the control of diamondback moth (DBM), Plutella xylostella (Linnaeus), in cole crops, from 2016 to 2019 at several commercial locations in Georgia and Florida. The nominal maximum dose was defined as the highest labeled rate of an insecticide at the beginning of the survey in the equivalent of 935 liters/ha dilution. The results indicated low insecticide efficacy for high labeled rates of the following insecticides by common name (Insecticide Resistance Action Committee group number in parentheses). Our 4-yr survey identified very low levels of DBM larval control (<47%) by lambda-cyhalothrin (3), methoxyfenozide (18), pyriproxyfen (7C), novaluron (15), bifenthrin (3), chlorantraniliprole (28), indoxacarb (22A), and methomyl (1A). The best products for DBM control (>74%) listed in decreasing average levels of efficacy were naled (1B), cyclaniliprole (28), tolfenpyrad (21A), emamectin benzoate (6), and cyantraniliprole (28). Intermediate levels of control (61-71%) were obtained with Bacillus thuringiensis subspecies aizawai (11A), Bacillus thuringiensis, subsp. kurstaki, strain ABTS-351 (11A), and spinetoram (5). This rapid bioassay provided the grower with a ranking of insecticide efficacy for the control the DBM population for that farm site. These data allowed growers to make an informed decision on control quickly and plan for resistance management rotations for DBM that season.

David Riley, Hugh Smith, John Bennett, Philip Torrance, Evan Huffman, Alton Sparks, Jr, Charles Gruver, Thomas Dunn, Donald Champagne. J Econ Entomol. 2020 Jun 19;toaa125. doi: 10.1093/jee/toaa125.