Donna Huber, Author at Center for Tropical and Emerging Global Diseases

Chet Joyner receives $1.1 million grant to study malaria vaccine

Donna Huber on March 28, 2023

RESEARCH WILL BE IN COLLABORATION WITH YALE UNIVERSITY

Chet Joyner, PhD, a faculty member in the Center for Vaccines and Immunology and the Center for Tropical and Emerging Diseases in the College of Veterinary Medicine (CVM) at the University of Georgia, is the recipient of a $1.1 million grant from Open Philanthropy to perform preclinical testing of a vaccine designed to prevent reinfection from malaria.

“A vaccine that lessens the impact of this disease will have incalculable value in terms of lives saved and the quality of life of those in the affected areas,” said Lisa K. Nolan, DVM, PhD, dean of the CVM. “We are proud of Dr. Joyner’s work and that he has chosen to do it in the College of Veterinary Medicine at the University of Georgia.”

Joyner is collaborating with Dr. Richard Bucala, MD, PhD, of Yale University to test the vaccine that targets Plasmodium-encoded Macrophage Migration Inhibitory Factor (pMIF), a protein secreted by Plasmodium falciparum, a pathogen that causes malaria.

The science team for Open Philanthropy, which recommended grants to Joyner and Bucala for the three-year study, believes that vaccinating against pMIF may provide an important boost to the efficacy of existing malaria vaccines, according to a statement on its website, openphilanthropy.org.

Open Philanthropy is a Silicon Valley-based nonprofit which aims to use its resources to help others as much as possible. They fund work in many areas, including global health.

Joyner, who was recruited from Emory University to join the CVM in January of 2020, said the college is uniquely positioned to test the efficacy of the vaccine developed by Bucala at Yale.

“We are a strong malaria group with unique infrastructure and facilities that can support this necessary research within the CVM,” Joyner said.

Immunity to malaria is acquired naturally after exposure, but the disease can be fatal to children younger than five and debilitating up to age 10 because malaria parasites disrupt the immune system’s response with their own proteins that mimic the human Macrophage Migration Inhibitory Factor (MIF).

Not only does the resulting illness cause children to miss school, but it also leads to long-term cognitive decline due to nutritional deficiencies. Parents miss work to care for children and the economic impacts compound.

According to the World Health Organization’s 2022 World Malaria report, an estimated 247 million cases of malaria occurred worldwide in 2021 and 619,000 people died, mostly children under the age of five in sub-Saharan Africa.

This story was originally published at https://vet.uga.edu/cvm-researcher-wins-1-1-million-grant-to-study-malaria-vaccine/

Cripowellins Pause Plasmodium falciparum Intraerythrocytic Development at the Ring Stage

Donna Huber on March 13, 2023

Cripowellins from Crinum erubescens are known pesticidal and have potent antiplasmodial activity. To gain mechanistic insights to this class of natural products, studies to determine the timing of action of cripowellins within the asexual intraerythrocytic cycle of Plasmodium falciparum were performed and led to the observation that this class of natural products induced reversible cytostasis in the ring stage within the first 24 h of treatment. The transcriptional program necessary for P. falciparum to progress through the asexual intraerythrocytic life cycle is well characterized. Whole transcriptome abundance analysis showed that cripowellin B “pauses” the transcriptional program necessary to progress through the intraerythrocytic life cycle coinciding with the lack of morphological progression of drug treated parasites. In addition, cripowellin B-treated parasites re-enter transcriptional progression after treatment was removed. This study highlights the use of cripowellins as chemical probes to reveal new aspects of cell cycle progression of the asexual ring stage of P. falciparum which could be leveraged for the generation of future antimalarial therapeutics.

Joshua H Butler, Heather J Painter, Emily K Bremers, Priscilla Krai, Manuel Llinás, Maria B Cassera. Molecules. 2023 Mar 13;28(6):2600. doi: 10.3390/molecules28062600.

Analysis of the Interactome of the Toxoplasma gondii Tgj1 HSP40 Chaperone

Donna Huber on March 1, 2023

Toxoplasma gondii is an obligate intracellular apicomplexan that causes toxoplasmosis in humans and animals. Central to its dissemination and pathogenicity is the ability to rapidly divide in the tachyzoite stage and infect any type of nucleated cell. Adaptation to different cell contexts requires high plasticity in which heat shock proteins (Hsps) could play a fundamental role. Tgj1 is a type I Hsp40 of T. gondii, an ortholog of the DNAJA1 group, which is essential during the tachyzoite lytic cycle. Tgj1 consists of a J-domain, ZFD, and DNAJ_C domains with a CRQQ C-terminal motif, which is usually prone to lipidation. Tgj1 presented a mostly cytosolic subcellular localization overlapping partially with endoplasmic reticulum. Protein-protein Interaction (PPI) analysis showed that Tgj1 could be implicated in various biological pathways, mainly translation, protein folding, energy metabolism, membrane transport and protein translocation, invasion/pathogenesis, cell signaling, chromatin and transcription regulation, and cell redox homeostasis among others. The combination of Tgj1 and Hsp90 PPIs retrieved only 70 interactors linked to the Tgj1-Hsp90 axis, suggesting that Tgj1 would present specific functions in addition to those of the Hsp70/Hsp90 cycle, standing out invasion/pathogenesis, cell shape motility, and energy pathway. Within the Hsp70/Hsp90 cycle, translation-associated pathways, cell redox homeostasis, and protein folding were highly enriched in the Tgj1-Hsp90 axis. In conclusion, Tgj1 would interact with a wide range of proteins from different biological pathways, which could suggest a relevant role in them.

Jonathan Munera López, Andrés Mariano Alonso, Maria Julia Figueras, Ana María Saldarriaga Cartagena, Miryam A Hortua Triana, Luis Diambra, Laura Vanagas, Bin Deng, Silvia N J Moreno, Sergio Oscar Angel. Proteomes. 2023 Mar 1;11(1):9. doi: 10.3390/proteomes11010009.

An X-Domain Phosphoinositide Phospholipase C (PI-PLC-like) of Trypanosoma brucei Has a Surface Localization and Is Essential for Proliferation

Donna Huber on February 28, 2023

Trypanosoma brucei is the causative agent of African trypanosomiasis, a deadly disease that affects humans and cattle. There are very few drugs to treat it, and there is evidence of mounting resistance, raising the need for new drug development. Here, we report the presence of a phosphoinositide phospholipase C (TbPI-PLC-like), containing an X and a PDZ domain, that is similar to the previously characterized TbPI-PLC1. TbPI-PLC-like only possesses the X catalytic domain and does not have the EF-hand, Y, and C2 domains, having instead a PDZ domain. Recombinant TbPI-PLC-like does not hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) and does not modulate TbPI-PLC1 activity in vitro. TbPI-PLC-like shows a plasma membrane and intracellular localization in permeabilized cells and a surface localization in non-permeabilized cells. Surprisingly, knockdown of TbPI-PLC-like expression by RNAi significantly affected proliferation of both procyclic and bloodstream trypomastigotes. This is in contrast with the lack of effect of downregulation of expression of TbPI-PLC1.

Núria W Negrão, Logan P Crowe, Brian S Mantilla, Rodrigo P Baptista, Sharon King-Keller, Guozhong Huang, Roberto Docampo. Pathogens. 2023 Feb 28;12(3):386. doi: 10.3390/pathogens12030386.

First bovine vaccine to prevent human schistosomiasis – a cluster randomised Phase 3 clinical trial

Donna Huber on February 21, 2023

Objective

Schistosomiasis is a neglected tropical parasitic disease caused by blood flukes of the genus Schistosoma. Schistosoma japonicum is zoonotic in China, the Philippines, and Indonesia, with bovines acting as major reservoirs of human infection. The primary objective of the trial was to examine the impact of a combination of human mass chemotherapy, snail control through mollusciciding, and SjCTPI bovine vaccination on the rate of human infection.

Methods

A 5-year phase IIIa cluster randomized control trial was conducted among 18 schistosomiasis-endemic villages comprising 18,221 residents in Northern Samar, The Philippines.

Results

Overall, bovine vaccination resulted in a statistically significant decrease in human infection (relative risk [RR] = 0.75; 95% confidence interval [CI] = 0.69 to 0.82) across all trial follow-ups. The best outcome of the trial was when bovine vaccination was combined with snail mollusciciding. This combination resulted in a 31% reduction (RR = 0.69; 95% CI = 0.61 to 0.78) in human infection.

Conclusion

This is the first trial to demonstrate the effectiveness of a bovine vaccine for schistosomiasis in reducing human schistosome infection. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001048178).

Allen G. Ross, Donald A. Harn, Delia Chy, Marianette Inobaya, Jerric R. Guevarra, Lisa Shollenberger, Yuesheng Li, Donald P. McManus, Darren J. Gray and Gail M. Williams. 2023. International Journal of Infectious Diseases. S1201-9712(23)00038-3. doi: 10.1016/j.ijid.2023.01.037. Online ahead of print.

Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery

Donna Huber on January 25, 2023

The carbazole CBL0137 (1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices (5j, 5t, 5v, 5w, 5y, 8d, 13i, and 22e). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse model of HAT; while 5v demonstrated a lead-like profile for HAT drug development, 5w showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.

Baljinder Singh, Amrita Sharma, Naresh Gunaganti, Mitch Rivers, Pradip K Gadekar, Brady Greene, Michael Chichioco, Carlos E Sanz-Rodriguez, Courtney Fu, Catherine LeBlanc, Erin Burchfield, Nyle Sharif, Benjamin Hoffman, Gaurav Kumar, Andrei Purmal, Kojo Mensa-Wilmot, Michael P Pollastri. J Med Chem. 2023 Jan 25. doi: 10.1021/acs.jmedchem.2c01767.

Delayed Activation of T Cells at the Site of Infection Facilitates the Establishment of Trypanosoma cruzi in Both Naive and Immune Hosts

Donna Huber on January 25, 2023

Although parasite entry through breaks in the skin or mucosa is one of the main routes of natural transmission of Trypanosoma cruzi, little is known about the host cell types initially invaded nor the ability of those host cells to initiate immune responses at the site of infection. To gain insights into these early events, we studied the fate of fluorescently tagged T. cruzi delivered subcutaneously in mouse footpads or ears. We demonstrate that the majority of parasites introduced into the skin initially proliferate there until 8 to 10 days postinfection, when the parasite load decreases. This decline in parasite numbers is dependent on the presence of an intact T cell compartment and on the ability of hosts to produce gamma interferon (IFN-γ). Many of the parasite-containing cells at the initial infection site display a macrophage/monocyte phenotype but with low expression of activation markers, suggesting that these cells provide an early niche for T. cruzi proliferation, rather than being active in parasite control. It is only after the first round of T. cruzi replication and release from host cells that signs of immune activation and control of parasites become apparent. The delay in the activation and failure to rapidly control parasite replication are observed even when T. cruzi-primed T cells are present, such as in chronically infected mice. This failure of a primed immune system to recognize and react prior to extensive parasite expansion at the infection site likely poses a significant challenge for the development of vaccines aiming to prevent T. cruzi infection. IMPORTANCE Trypanosoma cruzi, the parasite causing Chagas disease, usually infects through the mucosa or breaks in the skin, but little is known about the parasite’s fate at the site of entry or the early events involving immune control there. Here, we track the local proliferation and subsequent dissemination of fluorescently tagged T. cruzi and the initial immune response at the point of entry. We show that T. cruzi preferentially infects innate immune cells in the skin and that the stimulation of an adaptive T cell response does not occur until after the release of parasites from this first round of infected host cells. This first immunologically “silent” proliferation occurs even in the presence of a strong immune T cell memory generated by previous infection. This capacity of T. cruzi to establish infections while avoiding initial immune recognition has important implications for the potential to develop vaccines to prevent T. cruzi infection.

Angel M Padilla, Charles Rosenberg, Peter Cook, Fernando Sanchez-Valdez, Caroline McElhannon, Rick L Tarleton. mSphere. 2023 Jan 25;e0060122. doi: 10.1128/msphere.00601-22.

TriTrypDB: An integrated functional genomics resource for kinetoplastida

Donna Huber on January 19, 2023

Parasitic diseases caused by kinetoplastid parasites are a burden to public health throughout tropical and subtropical regions of the world. TriTrypDB (https://tritrypdb.org) is a free online resource for data mining of genomic and functional data from these kinetoplastid parasites and is part of the VEuPathDB Bioinformatics Resource Center (https://veupathdb.org). As of release 59, TriTrypDB hosts 83 kinetoplastid genomes, nine of which, including Trypanosoma brucei brucei TREU927, Trypanosoma cruzi CL Brener and Leishmania major Friedlin, undergo manual curation by integrating information from scientific publications, high-throughput assays and user submitted comments. TriTrypDB also integrates transcriptomic, proteomic, epigenomic, population-level and isolate data, functional information from genome-wide RNAi knock-down and fluorescent tagging, and results from automated bioinformatics analysis pipelines. TriTrypDB offers a user-friendly web interface embedded with a genome browser, search strategy system and bioinformatics tools to support custom in silico experiments that leverage integrated data. A Galaxy workspace enables users to analyze their private data (e.g., RNA-sequencing, variant calling, etc.) and explore their results privately in the context of publicly available information in the database. The recent addition of an annotation platform based on Apollo enables users to provide both functional and structural changes that will appear as ‘community annotations’ immediately and, pending curatorial review, will be integrated into the official genome annotation.

Achchuthan Shanmugasundram, David Starns, Ulrike Böhme, Beatrice Amos, Paul A Wilkinson, Omar S Harb, Susanne Warrenfeltz, Jessica C Kissinger, Mary Ann McDowell, David S Roos, Kathryn Crouch, Andrew R Jones. PLoS Negl Trop Dis. 2023 Jan 19;17(1):e0011058. doi: 10.1371/journal.pntd.0011058.

Praziquantel target validation of a Ca2+ permeable channel in schistosomes

Donna Huber on January 18, 2023

Highlights

Schistosomiasis is a devastating neglected helminthic disease.
Praziquantel (PZQ) is the most important drug against schistosomiasis.
Previous work identified a TRP channel of the melastatin type as a PZQ target.
Molecular studies now reveal the basis for varied PZQ sensitivity of different helminths.

Roberto Docampo. Cell Calcium. 2023 Jan 18;110:102698. doi: 10.1016/j.ceca.2023.102698

Malaria disrupts the rhesus macaque gut microbiome

Donna Huber on January 13, 2023

Previous studies have suggested that a relationship exists between severity and transmissibility of malaria and variations in the gut microbiome, yet only limited information exists on the temporal dynamics of the gut microbial community during a malarial infection. Here, using a rhesus macaque model of relapsing malaria, we investigate how malaria affects the gut microbiome. In this study, we performed 16S sequencing on DNA isolated from rectal swabs of rhesus macaques over the course of an experimental malarial infection with Plasmodium cynomolgi and analyzed gut bacterial taxa abundance across primary and relapsing infections. We also performed metabolomics on blood plasma from the animals at the same timepoints and investigated changes in metabolic pathways over time. Members of Proteobacteria (family Helicobacteraceae) increased dramatically in relative abundance in the animal’s gut microbiome during peak infection while Firmicutes (family Lactobacillaceae and Ruminococcaceae), Bacteroidetes (family Prevotellaceae) and Spirochaetes amongst others decreased compared to baseline levels. Alpha diversity metrics indicated decreased microbiome diversity at the peak of parasitemia, followed by restoration of diversity post-treatment. Comparison with healthy subjects suggested that the rectal microbiome during acute malaria is enriched with commensal bacteria typically found in the healthy animal’s mucosa. Significant changes in the tryptophan-kynurenine immunomodulatory pathway were detected at peak infection with P. cynomolgi, a finding that has been described previously in the context of P. vivax infections in humans. During relapses, which have been shown to be associated with less inflammation and clinical severity, we observed minimal disruption to the gut microbiome, despite parasites being present. Altogether, these data suggest that the metabolic shift occurring during acute infection is associated with a concomitant shift in the gut microbiome, which is reversed post-treatment.

Danielle N Farinella, Sukhpreet Kaur, ViLinh Tran, Monica Cabrera-Mora, Chester J Joyner, Stacey A Lapp, Suman B Pakala, Mustafa V Nural, Jeremy D DeBarry, Jessica C Kissinger, Dean P Jones, Alberto Moreno, Mary R Galinski, Regina Joice Cordy. Front Cell Infect Microbiol. 2023 Jan 13;12:1058926. doi: 10.3389/fcimb.2022.1058926. eCollection 2022.

Author: Donna Huber