Jenni A. Hayward

Australian National University

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Giel G. van Dooren

Australian National University

Anukriti Mathur

Australian National University

Soraya M. Zwahlen

Australian National University

Si Ming Man

Australian National University

Esther Rajendran

Australian National University

Chinh Ngo

Australian National University

Fadzai Victor Makota

Australian National University

Shouya Feng

Hudson Institute of Medical Research

Daniel Fox

Australian Regenerative Medicine Institute

Daniela Cihalova

Australian National University

Cooperative Institutions

Australian National University

Monash University

University of Melbourne

Australian Regenerative Medicine Institute

Walter and Eliza Hall Institute of Medical Research

University of Michigan–Ann Arbor

University of California, San Francisco

Centre National de la Recherche Scientifique

National Institutes of Health

Wuhan University

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Correction: Ticks from diverse genera encode chemokine-inhibitory evasin proteins.

Journal of Biological Chemistry (2018)

Jenni A. Hayward Julie Sanchez Andrew Perry Cheng Huang M. Rodriguez-Valle

VOLUME 292 (2017) PAGES 15670–15680 The primary institutional affiliation of author Manuel Rodriguez Valle should have been the Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, 306 Carmody Rd., Bldg. 80, Level 3, St. Lucia QLD 4072, Australia. The grant footnote should have stated that the Ixodes holocyclus transcriptome database was an outcome of the Australian Research Council Linkage project LP120200836 and collaboration with Elanco Animal Health at The University of Queensland. Several GenBankTM accession numbers were inadvertently omitted for the sequences from the Ixodes holocyclus and Rhipicephalus microplus transcriptomes in Table S1. This error has now been corrected online.

ENCODE

10.1074/jbc.aac118.005871

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Mechanisms of Regulation of the Chemokine-Receptor Network

International Journal of Molecular Sciences (2017)

Martin J. Stone Jenni A. Hayward Cheng Huang Zil E Huma Julie Sanchez

The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms by which the interactions of chemokines with chemokine receptors are regulated, including: selective and competitive binding interactions; genetic polymorphisms; mRNA splice variation; variation of expression, degradation and localization; down-regulation by atypical (decoy) receptors; interactions with cell-surface glycosaminoglycans; post-translational modifications; oligomerization; alternative signaling responses; and binding to natural or pharmacological inhibitors.

CCR1

Decoy

10.3390/ijms18020342

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Citations (250)

Correction: A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

PLoS Pathogens (2024)

Jenni A. Hayward Fadzai Victor Makota Daniela Cihalova Rachel Leonard Esther Rajendran

In the Abstract, one of the compounds referenced is incorrectly named MMV024937.The correct compound is MMV024397.Also, in Fig 9, the x axis of panel H is incorrectly labelled as MMV024937.

Chain (unit)

10.1371/journal.ppat.1011987

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Citations (1)

A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites

Open Biology (2024)

Soraya M. Zwahlen Jenni A. Hayward Capella S. Maguire Alex R. Qin Giel G. van Dooren

Succinate dehydrogenase (SDH) is a protein complex that functions in the tricarboxylic acid cycle and the electron transport chain of mitochondria. In most eukaryotes, SDH is highly conserved and comprises the following four subunits: SdhA and SdhB form the catalytic core of the complex, while SdhC and SdhD anchor the complex in the membrane. Toxoplasma gondii is an apicomplexan parasite that infects one-third of humans worldwide. The genome of T. gondii encodes homologues of the catalytic subunits SdhA and SdhB, although the physiological role of the SDH complex in the parasite and the identity of the membrane-anchoring subunits are poorly understood. Here, we show that the SDH complex contributes to optimal proliferation and O 2 consumption in the disease-causing tachyzoite stage of the T. gondii life cycle. We characterize a small membrane-bound subunit of the SDH complex called mitochondrial protein ookinete developmental defect (MPODD), which is conserved among myzozoans, a phylogenetic grouping that incorporates apicomplexan parasites and their closest free-living relatives. We demonstrate that Tg MPODD is essential for SDH activity and plays a key role in attaching the Tg SdhA and Tg SdhB proteins to the membrane anchor of the complex. Our findings highlight a unique and important feature of mitochondrial energy metabolism in apicomplexan parasites and their relatives.

SDHB

SDHA

SDHD

10.1098/rsob.230463

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Citations (1)

Ticks from diverse genera encode chemokine-inhibitory evasin proteins

Journal of Biological Chemistry (2017)

Jenni A. Hayward Julie Sanchez Andrew Perry Cheng Huang M. Rodriguez-Valle

Rhipicephalus sanguineus

10.1074/jbc.m117.807255

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Citations (51)

Control of human toxoplasmosis

International Journal for Parasitology (2020)

Nicholas C. Smith Cibelly Goulart Jenni A. Hayward Andreas Kupz Catherine Miller

Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal. Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world. Toxoplasmosis is a disease with multiple manifestations: it can cause a fatal encephalitis in immunosuppressed people; if first contracted during pregnancy, it can cause miscarriage or congenital defects in the neonate; and it can cause serious ocular disease, even in immunocompetent people. The disease has a complex epidemiology, being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts. In this review we examine current and future approaches to control toxoplasmosis, which encompass a variety of measures that target different components of the life cycle of T. gondii. These include: education programs about the parasite and avoidance of contact with infectious stages; biosecurity and sanitation to ensure food and water safety; chemo- and immunotherapeutics to control active infections and disease; prophylactic options to prevent acquisition of infection by livestock and cyst formation in meat; and vaccines to prevent shedding of oocysts by definitive feline hosts.

Toxoplasmosis

Zoonosis

Paratenic

Ascaris suum

Parasitic Disease

10.1016/j.ijpara.2020.11.001

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Citations (200)

Real-Time Analysis of Mitochondrial Electron Transport Chain Function in Toxoplasma gondii Parasites Using a Seahorse XFe96 Extracellular Flux Analyzer

BIO-PROTOCOL (2022)

Jenni A. Hayward Esther Rajendran Fadzai Victor Makota Brad Bassett Michael Devoy

The mitochondrial electron transport chain (ETC) performs several critical biological functions, including maintaining mitochondrial membrane potential, serving as an electron sink for important metabolic pathways, and contributing to the generation of ATP via oxidative phosphorylation. The ETC is important for the survival of many eukaryotic organisms, including intracellular parasites such as the apicomplexan Toxoplasma gondii. The ETC of T. gondii and related parasites differs in several ways from the ETC of the mammalian host cells they infect, and can be targeted by anti-parasitic drugs, including the clinically used compound atovaquone. To characterize the function of novel ETC proteins found in the parasite and to identify new ETC inhibitors, a scalable assay that assesses both ETC function and non-mitochondrial parasite metabolism (e.g., glycolysis) is desirable. Here, we describe methods to measure the oxygen consumption rate (OCR) of intact T. gondii parasites and thereby assess ETC function, while simultaneously measuring the extracellular acidification rate (ECAR) as a measure of general parasite metabolism, using a Seahorse XFe96 extracellular flux analyzer. We also describe a method to pinpoint the location of ETC defects and/or the targets of inhibitors, using permeabilized T. gondii parasites. We have successfully used these methods to investigate the function of T. gondii proteins, including the apicomplexan parasite-specific protein subunit TgQCR11 of the coenzyme Q:cytochrome c oxidoreductase complex (ETC Complex III). We note that these methods are also amenable to screening compound libraries to identify candidate ETC inhibitors.

10.21769/bioprotoc.4288

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Citations (13)

Divergent features of the coenzyme Q:cytochromecoxidoreductase complex inToxoplasma gondiiparasites

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Jenni A. Hayward Esther Rajendran Soraya M. Zwahlen Pierre Faou Giel G. van Dooren

Abstract The mitochondrion is critical for the survival of apicomplexan parasites. Several major anti-parasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase complex (Complex III). Despite being an important drug target, the protein composition of Complex III of apicomplexan parasites has not been elucidated. Here, we undertake a mass spectrometry-based proteomic analysis of Complex III in the apicomplexan Toxoplasma gondii . Along with canonical subunits that are conserved across eukaryotic evolution, we identify several novel or highly divergent Complex III components that are conserved within the apicomplexan lineage. We demonstrate that one such subunit, which we term Tg QCR11, is critical for parasite proliferation, mitochondrial oxygen consumption and Complex III activity, and establish that loss of this protein leads to defects in Complex III integrity. We conclude that the protein composition of Complex III in apicomplexans differs from that of the mammalian hosts that these parasites infect. Author summary Apicomplexan parasites cause numerous diseases in humans and animals, including malaria ( Plasmodium species) and toxoplasmosis ( Toxoplasma gondii ). The coenzyme Q:cytochrome c oxidoreductase protein complex (Complex III) performs a central role in the mitochondrial electron transport chain of many eukaryotes. Despite being the target of several major anti-apicomplexan drugs, the protein composition of Complex III in apicomplexans was previously unknown. Our work identifies novel proteins in Complex III of apicomplexans, one of which is critical for complex function and integrity. Our study highlights divergent features of Complex III in apicomplexans, and provides a broader understanding of Complex III evolution in eukaryotes. Our study also provides important insights into what sets this major drug target apart from the equivalent complex in host species.

Atovaquone

10.1101/2020.08.18.253468

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A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

PLoS Pathogens (2023)

Jenni A. Hayward Fadzai Victor Makota Daniela Cihalova Rachel Leonard Esther Rajendran

Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.

Chain (unit)

10.1371/journal.ppat.1011517

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Citations (13)

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Microbiology and Molecular Biology Reviews (2018)

Jenni A. Hayward Anukriti Mathur Chinh Ngo Si Ming Man

Infection is a dynamic biological process underpinned by a complex interplay between the pathogen and the host. Microbes from all domains of life, including bacteria, viruses, fungi, and protozoan parasites, have the capacity to cause infection. Infection is sensed by the host, which often leads to activation of the inflammasome, a cytosolic macromolecular signaling platform that mediates the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and cleavage of the pore-forming protein gasdermin D, leading to pyroptosis. Host-mediated sensing of the infection occurs when pathogens inject or carry pathogen-associated molecular patterns (PAMPs) into the cytoplasm or induce damage that causes cytosolic liberation of danger-associated molecular patterns (DAMPs) in the host cell. Recognition of PAMPs and DAMPs by inflammasome sensors, including NLRP1, NLRP3, NLRC4, NAIP, AIM2, and Pyrin, initiates a cascade of events that culminate in inflammation and cell death. However, pathogens can deploy virulence factors capable of minimizing or evading host detection. This review presents a comprehensive overview of the mechanisms of microbe-induced activation of the inflammasome and the functional consequences of inflammasome activation in infectious diseases. We also explore the microbial strategies used in the evasion of inflammasome sensing at the host-microbe interaction interface.

Pyroptosis

AIM2

NLRC4

Pyrin domain

Proinflammatory cytokine

10.1128/mmbr.00015-18

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Citations (141)