Jonathan Marchant

Medical College of Wisconsin | MCW · Department of Cell Biology, Neurobiology & Anatomy

Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni sample...

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases—for example, the parasitic blood fluke infection schistosomiasis—are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid chan...

The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resis...

Lysosomes and the endoplasmic reticulum (ER) are Ca²⁺ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca²⁺ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca²⁺. Cell-wide Ca²⁺ signals evoked by activation of endogenous NAADP-sensitive channels on...

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently need...

Introduction Praziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms – rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target medi...

The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPMPZQ, has recently been identified. Intriguingly, certain praziquantel d...

Membrane contact sites (MCSs) between endosomes and the endoplasmic reticulum (ER) are thought to act as specialized trigger zones for Ca²⁺ signaling, where local Ca²⁺ released via endolysosomal ion channels is amplified by ER Ca²⁺-sensitive Ca²⁺ channels into global Ca²⁺ signals. Such amplification is integral to the action of the second messenger...

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases — for example, the parasitic blood fluke infection, schistosomiasis — are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola. This is due to a single amino...

Praziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms – rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target mediating these e...

The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) evokes calcium ion (Ca2+) release from endosomes and lysosomes by activating two-pore channels (TPCs) on these organelles. Rather than directly binding to TPCs, NAADP associates with proteins that indirectly confer NAADP sensitivity to the TPC complex. We investigated whethe...

TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P2 and indirectly by the calcium ion (Ca2+)-mobilizing molecule NAADP through accessory proteins that associate with the channel. TPC2 toggles between PI(3,5)P2-induced, sodium ion (Na+)-selective and NAADP-induced, Ca2+-permeable...

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ, as well as servin...

The human sodium-dependent vitamin C transporter-1 (hSVCT1) is localized at the apical membrane domain of polarized intestinal and renal epithelial cells to mediate ascorbic acid (AA) uptake. Currently, little is known about the array of interacting proteins that aid hSVCT1 trafficking and functional expression at the cell surface. Here we used an...

The anthelmintic drug praziquantel (PZQ) causes contraction of parasitic schistosomes, as well as constriction of blood vessels within the mesenteric vasculature of the host where the adult blood flukes reside. The contractile action of PZQ on the vasculature is mediated by activation of host serotonergic 5-HT2B receptors. However, and the molecula...

Ion channels have proved to be productive targets for anthelmintic chemotherapy. One example is the recent discovery of a parasitic flatworm ion channel targeted by praziquantel (PZQ), the main clinical therapy used for treatment of schistosomiasis. The ion channel activated by PZQ - a transient receptor potential ion channel of the melastatin subf...

The parasitic flatworm ion channel, TRPMPZQ, is a non-selective cation channel that mediates Ca2+ entry and membrane depolarization when activated by the anthelmintic drug, praziquantel (PZQ). TRPMPZQ is conserved in all platyhelminth genomes scrutinized to date, with the sensitivity of TRPMPZQ in any particular flatworm correlating with the overal...

The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified— a transient receptor potential ion channel in the melastatin subfamily (TRPM PZQ )—however, little is known about the properties of TRPM PZQ in other parasitic...

A photo-clickable analog of adenosine was devised and synthesized in which the photoactive functional group (8-azidoadenosine) and the click moiety (2ʹ-O-propargyl-ether) were compactly combined within the structure of the adenosine nucleoside itself. We synthesized 8-N3-2ʹ-O-propargyl adenosine in four steps starting from adenosine. This photo-cli...

Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by t...

Two-pore channels are ion channels expressed on acidic organelles such as the various vesicles that constitute the endo-lysosomal system. They are permeable to Ca2+ and Na+ and activated by the second messenger NAADP as well as the phosphoinositide, PI(3,5)P2 and/or voltage. Here, we review the proteins that interact with these channels including r...

Vitamin C is an antioxidant that acts as a free radical scavenger and cofactor for many important biological reactions. It plays an important role in stem cell homeostasis, proliferation and differentiation. However, the role of vitamin C transporters in the neuronal differentiation of human induced pluripotent stem cells (hiPSCs) has not yet been...

Two-pore channels are ancient members of the voltage-gated ion channel superfamily that are expressed predominantly on acidic organelles such as endosomes and lysosomes. Here we review recent advances in understanding how TPCs are activated by their ligands and identify five salient features: (1) TPCs are Ca²⁺-permeable non-selective cation channel...

Many viruses exploit host-cell Ca²⁺ signaling processes throughout their life cycle. This is especially relevant for viruses that translocate through the endolysosomal system, where cellular infection is keyed to the microenvironment of these acidic Ca²⁺ stores and Ca²⁺-dependent trafficking pathways. As regulators of the endolysosomal ionic milieu...

Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against liver flukes of the Fasciola genus. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here,...

Mass drug administration with praziquantel (PZQ) monotherapy is considered the mainstay for control and elimination of the parasites causing schistosomiasis in humans. This drug shows imperfect cure rates in the field, and parasites showing reduced PZQ response can be selected in the laboratory, but the extent of resistance in Schistosoma mansoni p...

Single-domain Variable New Antigen Receptors (VNARs) from the immune system of sharks are the smallest naturally occurring binding domains found in nature. Possessing flexible paratopes that can recognize protein motifs inaccessible to classical antibodies, VNARs have yet to be exploited for the development of SARS-CoV-2 therapeutics. Here, we deta...

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca²⁺ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer’s disease. Therefore, there is considerable interest in therapeutically...

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected diseases. Neurotransmitter signaling is of critical importance for these parasites which lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode motilit...

Given the worldwide burden of neglected tropical diseases, there is ongoing need to develop novel anthelmintic agents to strengthen the pipeline of drugs to combat these burdensome infections. Many diseases caused by parasitic flatworms are treated using the anthelmintic drug praziquantel (PZQ), employed for decades as the key clinical agent to tre...

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca²⁺ from endosomes and lysosomes by activating ion channels called two-pore channels (TPCs). However, no NAADP-binding site has been identified on TPCs. Rather, NAADP activates TPCs indirectly by engaging NAADP-binding proteins (NAADP-BPs) that form part of t...

Ascorbic acid (AA) uptake in neurons occurs via a Na⁺-dependent carrier-mediated process mediated by the sodium-dependent vitamin C transporter-2 (SVCT2). Relatively little information is available concerning the network of interacting proteins that support human (h)SVCT2 trafficking and cell surface expression in neuronal cells. Here we identified...

Intestinal absorption of vitamin C in humans is mediated via the sodium-dependent vitamin C transporters (hSVCT1 and hSVCT2). hSVCT1 and hSVCT2 are localized at the apical and basolateral membranes, respectively, of polarized intestinal epithelia. Studies have identified low plasma levels of vitamin C and decreased expression of hSVCT1 in patients...

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and...

Background Enteropathogenic Escherichia coli (EPEC) infection causes prolonged, watery diarrhea leading to morbidity and mortality. Although EPEC infection impacts nutrient transporter function and expression in intestinal epithelial cells, the effects of EPEC infection on intestinal absorption of ascorbic acid (AA) have not yet been investigated.A...

Mass treatment with praziquantel (PZQ) monotherapy is the mainstay for schistosome treatment. This drug shows imperfect cure rates in the field and parasites showing reduced response to PZQ can be selected in the laboratory, but the extent of resistance in Schistosoma mansoni populations is unknown. We examined the genetic basis of variation in PZQ...

The endoplasmic reticulum (ER) Ca²⁺ store contains many rapidly differentiable subdomains with specialized signaling properties. Recent work highlights how an integral ER membrane protein - the sigma 1 receptor (S1R) - nucleates local formation of cholesterol-rich ER subdomains. Biophysical approaches cast new light on S1Rs and how their dynamics i...

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca ²⁺ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a “click...

Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against the liver fluke Fasciola . The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we show...

The process of obtaining ascorbic acid (AA) via intestinal absorption and blood circulation is carrier-mediated utilizing the AA transporters SVCT1 and SVCT2, which are expressed in the intestine and brain (SVCT2 in abundance). AA concentration is decreased in Alzheimer’s disease (AD), but information regarding the status of intestinal AA uptake in...

Nicotinamide adenine dinucleotide phosphate (NADP) is an indispensable metabolic co-substrate and nicotinic acid adenine dinucleotide phosphate (NAADP) is an important Ca²⁺ releasing intracellular second messenger. Exploration of the NADP and NAADP interactome often requires the synthesis of NADP derivatives substituted on the adenosine nucleoside....

Enteropathogenic Escherichia coli (EPEC) is a food‐borne pathogen and causes enteric illnesses in children. EPEC infection is often associated with malnutrition of the host, especially in individuals experiencing severe and prolonged infection, and/or in those who are nutritionally compromised. While EPEC infection impacts nutrient transporter func...

Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic blood flukes. Treatment of schistosomiasis has relied on a single drug - praziquantel (PZQ) - for decades. The utility of PZQ as an essential medication is, however, intertwined with a s...

The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca2+ influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use....

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+ mobilizing second messenger which triggers Ca2+ release in both sea urchin egg homogenates and in mammalian cells. The NAADP binding protein has not been identified and the regulation of NAADP mediated Ca2+ release remains controversial. To address this issue, we have synthesize...

Regeneration is the process by which lost or damaged tissue is replaced in adult organisms. Some organisms exhibit robust regenerative capabilities, while others, including humans, do not. Understanding the molecular principles governing the regenerative malleability of different organisms is of fundamental biological interest. Further, this proble...

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Conseque...

The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people. The target of PZQ in the blood fluke responsible for this disease is unknown. Here, we demonstrate that PZQ activates a transient receptor potential (TRP) channel found in parasitic schistosomes and other PZQ...

Ascorbic acid (AA; vitamin C) is essential for normal human health and well‐being. Vitamin C acts as a cofactor for many important enzymatic reactions and is a potent antioxidant. Humans cannot synthesize vitamin C endogenously and obtain the vitamin from dietary sources via intestinal absorption, a process that involves the human sodium‐dependent...

Sea urchin eggs have been extensively used to study Ca 2 + release through intracellular Ca 2 + -permeable channels. Their amenability to homogenization yields a robust, cell-free preparation that was central to establishing the Ca 2 + mobilizing actions of cyclic ADP-ribose and NAADP. Egg homogenates have continued to provide insight into the basi...

Nicotinic acid adenine dinucleotide phosphate is an evolutionarily conserved second messenger, which mobilizes Ca²⁺ from acidic stores. The molecular identity of the NAADP receptor has yet to be defined. In pursuit of isolating and identifying NAADP-binding proteins, we synthesized and characterized a bifunctional probe that incorporates both a pho...

Intestinal absorption of ascorbic acid (AA) occurs via a Na⁺-dependent carrier-mediated process facilitated through the human sodium-dependent vitamin C transporters-1 &-2 (hSVCT1 and hSVCT2). Many studies have shown that hSVCT1 (product of the SLC23A1 gene) is expressed on the apical membrane of polarized enterocytes where it mediates AA absorptio...

Vitamin C is an antioxidant and acts as a cofactor for many enzymatic reactions. Humans obtain vitamin C from dietary sources via intestinal absorption, a process that involves the sodium-dependent vitamin C transporters-1 and -2 (SVCT1 and SVCT2). Enterotoxigenic Escherichia coli (ETEC) infection impacts intestinal absorption/secretory functions,...

Parasitic blood flukes ( Schistosoma species of flatworms) infect over 200 million people worldwide, making them the second most costly parasite behind malaria. Despite this, the disease is currently treated with one broad spectrum drug, praziquantel, which has been in use for nearly 40 years. Concerns over reports of resistance in the field and th...

Counter-screen of Sm.5HTRLhits for action on endogenous mammalian GPCRs and toxicity. (A) Activity of tryptamine Sm.5HTRL agonists (gray symbols, 10 μM) against the parental GloSensor-22F cell line. Forskolin (FSK, open symbol, 25 μM) serves as a positive control for cAMP production. (B) Effect of benzylisoquinoline Sm.5HTRL antagonists (black symb...

Structures and screening data for all compounds tested on Sm.5HTRL. Sheet 1. All 13 tryptamine derivatives screened, with Emax (mean ± standard deviation for, normalized to maximal 5-HT response) and EC50 values (±95% confidence intervals) provided for agonist hits. Sheet 2. All 89 aporphines tested, with pKi values provided for antagonist hits. Sh...

Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscular function to sexual maturation and egg laying. In the parasitic blood fluke Schistosoma mansoni, 5-HT targets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement....

Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections are associated with a significant mortality rate, and existing drugs show poor efficacy. Identifying novel targets/pathways required for MERS infectivity is therefore important for developing novel therapeutics. As an enveloped virus, translocation through the endolysosomal system p...

The Ca2+ mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. Targeting NAADP-evoked Ca2+ signaling may therefore be an effective strategy for discovering novel antivirals as well as therape...

ELife digest More than 200 million people worldwide are infected with parasitic worms that cause the disease schistosomiasis. Most cases occur in sub-Saharan Africa. Long-term infections can damage organs, and children who are affected may suffer delayed growth and learning difficulties. Despite its significant health and economic impact, schistoso...

Natural product library screening data. (Sheet 1) Vendor, chemical identification (SMILES) and primary screening data for all natural product compounds screened against Sm.5HTRL. (Sheet 2) Counter screening data for agonist primary hits in cells expressing the 22F cAMP GloSensor and lacking Sm.5HTRL. (Sheet 3) Counter screening data for antagonist...

RNA-Seq data of drug treated and control infected mouse livers. Read counts for uninfected control, infected control, infected ergotamine-treated and infected praziquantel treated liver samples.

RNA-Seq data of drug treated and control infected mouse spleens. Read counts for uninfected control, infected control, infected ergotamine-treated and infected praziquantel treated spleen samples.

Signaling pathways enriched in drug treated livers relative to control infections. Ingenuity Pathway Analysis (IPA) of transcripts differentially expressed in livers of PZQ (Sheet 1) and ergotamine (Sheet 2) treated mice relative to control infections. IPA generated activation Z-scores are shown if magnitude ≥2. KEGG pathway analysis of transcripts...

The anthelmintic praziquantel (±PZQ) serves as a highly effective antischistosomal therapy. ±PZQ causes a rapid paralysis of adult schistosome worms and deleterious effects on the worm tegument. In addition to these activities against the parasite, ±PZQ also modulates host vascular tone in blood vessels where the adult worms reside. In resting mese...

Heterologously expressed TRPM8 mediates Ca2+ influx. Addition of menthol (300μM, first arrow) to TRPM8-expressing HEK293 cells does not cause a Ca2+ signal in Ca2+-free media, only when extracellular media is replaced with Ca2+-containing media. Traces represent fluorescence profiles from individual cells from a representative experiment. (TIF)

Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with an increased serum and intestinal mucosa levels of TNF-α, which also exerts profound effects on intestinal absorption process. Elevated levels of TNF-α have been linked...

Intestinal inflammation and systemic bacterial infection are associated with an increase in the level of proinflammatory cytokines like tumor necrosis factor alpha (TNFα) in the intestinal mucosa and blood. Though important for intestinal immunity, TNFα also exerts profound effects on intestinal absorptive and secretory functions through specific i...

Background Cestodes are a diverse group of parasites, some of them being agents of neglected diseases. In cestodes, little is known about the functional properties of G protein coupled receptors (GPCRs) which have proved to be highly druggable targets in other organisms. Notably, serotoninergic G-protein coupled receptors (5-HT GPCRs) play major ro...