Tropical Parasites Research Articles

Protective Role of the Neuropeptide Urocortin II against Experimental Sepsis and Leishmaniasis by Direct Killing of Pathogens

We currently face an alarming resurgence in infectious diseases characterized by antimicrobial resistance and therapeutic failure. This has generated the urgent need of developing new therapeutic approaches that include agents with nontraditional modes of action. A recent interest focused on approaches based on our natural immune defenses, especially on peptides that combine innate antimicrobial activity against diverse pathogens and immunoregulatory functions. In this study, to our knowledge, we describe for the first time the antimicrobial activity of the neuropeptide urocortin II (UCNII) against a panel of Gram-positive and Gram-negative bacteria and tropical parasites of the genus Leishmania. Importantly, this cytotoxicity was selective for pathogens, because UCNII did not affect mammalian cell viability. Structurally, UCNII has a cationic and amphipathic design that resembles antimicrobial peptides. Using mutants and UCNII fragments, we determined the structural requirements for the interaction between the peptide and the surface of pathogen. Following its binding to pathogen, UCNII caused cell death through different membrane-disrupting mechanisms that involve aggregation and membrane depolarization in bacteria and pore formation in Leishmania. Noteworthily, UCNII killed the infective form of Leishmania major even inside the infected macrophages. Consequently, UCNII prevented mortality caused by polymicrobial sepsis and ameliorated pathological signs of cutaneous leishmaniasis. Besides its presence in body physical and mucosal barriers, we found that innate immune cells produce UCNII in response to infections. Therefore, UCNII could be considered as an ancient highly-conserved host peptide involved in the natural antimicrobial defense and emerge as an attractive alternative to current treatments for microbial disorders with associated drug resistances.

Biogeography of tropical Indo-West Pacific parasites: A cryptic species of Transversotrema and evidence for rarity of Transversotrematidae (Trematoda) in French Polynesia

We sought transversotrematid trematodes from French Polynesian fishes by examining 304 individual scaled fishes of 53 species from seven families known to harbour the family elsewhere. A single species was found at two locations in the Tuamotus Archipelago on two species of Chaetodontidae (Chaetodon auriga and Chaetodon ephippium) and one species of Lutjanidae (Lutjanus gibbus). The species closely resembles Transversotrema borboleta Hunter & Cribb, 2012 from chaetodontids and lutjanids of the northern Great Barrier Reef (GBR) but differs from it consistently in 8 base positions of ITS2 rDNA. This level of variation exceeds that between some clearly morphologically distinct pairs of species of Transversotrema and the form from French Polynesia is thus interpreted as a distinct, though cryptic, species and named Transversotrema polynesiae n. sp. The new species forms part of a complex of species, here characterised as the T. borboleta complex, associated with chaetodontids and lutjanids in the tropical Indo-West Pacific. Most of the putative species within this complex are yet to be described. Comparison of identical numbers of matched samples of fishes from French Polynesia, Heron Island (southern GBR) and Lizard Island (northern GBR) revealed 1, 4 and 10 species of Transversotrema respectively suggesting that the French Polynesian fauna is depauperate for this family. In addition to those species apparently missing from suitable hosts in French Polynesia, several species from further west infect fishes (especially Nemipteridae) that are themselves absent from French Polynesia. This dramatic east–west decline in richness contrasts strongly with what is known for monogeneans, which appear to maintain their richness over the same scale, and is more precipitate than is known for other groups of trematodes. The decline might be explained in part by the absence of the as yet unknown first intermediate hosts in French Polynesia. However, we predict that it is explained by other life cycle traits. We hypothesise that the characters of large short-lived cercariae, short-lived miracidia, the absence in the life-cycle of second intermediate hosts that are capable of transporting the species, and definitive and first intermediate hosts that have limited vagility combine to give marine Transversotrematidae limited dispersal capacity and a propensity for localised speciation.

In silico methods to select biologically active anti-protozoan natural products

Neglected diseases (ND) caused by tropical protozoan parasites threaten millions of people in the world. Despite the efforts from academia, government authorities and pharma companies, the available marketed drugs are insufficient. Natural products (NP) comprise a rich source of compounds that may lead to new drugs against ND. In 2011, the Research Network Natural Products against Neglected Diseases (ResNet NPND)1 has been established as an international research initiative to make efforts against this global threat. In this work, we describe the use of in silico methods to find NP hits against protozoan parasites. A ResNet NPND data bank with ca. 1,000 chemical structures of anti-parasitic NP and their biological data has been created2. 2D/3D structure descriptors were calculated and non-relevant variables were eliminated by correlation matrix followed by linear forward selection. The in vitro activity data of 513 chemical structures was grouped into four different classes against the following parasites: Plasmodium falciparum (A; 291 structures), Trypanosoma brucei (B; 63), T. cruzi (C; 98) and Leishmania donovani (D; 61). Random Forest (RF) and k-Nearest Neighbors (k-NN), machine-learning tools used to classify objects according to their classes, were used for a multi-class classification of the 513 chemical structures of NP according to their biological activities (A-D). The cross-validated models using 2D descriptors showed an accuracy of 70 – 90% and good statistical significance (Kappa statistic and ROC area). Additional 2,948 chemical structures of NP from Analyticon Discovery GmbH (Germany) with unknown biological activities were used as external data set. The RF and k-NNN models were suitable to predict new NP hits against multiple targets that can be further investigated by docking and biological assays.

Triple worm infestation in an HIV-infected patient

A 32-year-old female African patient presented to the emergency department for abdominal pain. She had been diagnosed with HIV infection 3 years earlier. She was ART-naive with a CD4-T cell count of 456/ll and a viral load of 626 cp/ml. Her C-reactive protein level was elevated at 84.3 mg/l, and no other laboratory abnormality was noted. Surgery for suspected appendicitis was performed. Histopathological work-up revealed phlegmonous appendicitis with localized eosinophilic infiltration and necrotic epitheloid granulomas (Fig. 1a, b). Differential diagnoses included eosinophilic gastroenteritis, hematologic malignancy, and mycobacterial infection. Finally, three species of intestinal worms, Schistosoma mansoni (Fig. 1c), Strongyloides stercoralis (Fig. 1d), and Dicrocoelium dendriticum (Fig. 1e) were detected in a stool sample. Antihelminthic treatment with praziquantel (1,800 mg on days 1 and 8) and albendazole (800 mg qd on days 1–3 and 8–10) was administered. Further stool samples were negative, and the patient remained asymptomatic. The CD4-Tcell counts measured 1 and 4 months later were somewhat higher at 675 and 633/ll, respectively. More than two billion individuals are estimated to be infected with one or more helminth species [1, 2] and over 22 million are HIV-coinfected [3, 4], especially in sub-Saharan Africa. Typical clinical signs and symptoms or laboratory abnormalities are often absent, despite the frequency of typical histopathologic alterations such as eosinophilic granulomas in chronic schistosomiasis [5]. Helminthic infections are not considered to be opportunistic infections. However, helminth-induced immunomodulation may affect the CD4 count [3–6]. The benefit of deworming in helminth/HIV-coinfection is suggested by several studies, but its effect may vary by individual helminth species [4]. Routine screening for tropical parasites according to travel or origin is recommended by current HIV treatment guidelines [7], reflecting the traveland migration-related increasing overlap of tropical medicine and HIV care also in developed countries [8]. S. Sammet M. Huber U. Seybold (&) Sektion Klinische Infektiologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universitat, Ludwig-Maximilians-Universitat Munchen, Pettenkoferstr. 8a, 80336 Munchen, Germany e-mail: useybold@med.uni-muenchen.de

Natural Products as a Source for Treating Neglected Parasitic Diseases

Infectious diseases caused by parasites are a major threat for the entire mankind, especially in the tropics. More than 1 billion people world-wide are directly exposed to tropical parasites such as the causative agents of trypanosomiasis, leishmaniasis, schistosomiasis, lymphatic filariasis and onchocerciasis, which represent a major health problem, particularly in impecunious areas. Unlike most antibiotics, there is no “general” antiparasitic drug available. Here, the selection of antiparasitic drugs varies between different organisms. Some of the currently available drugs are chemically de novo synthesized, however, the majority of drugs are derived from natural sources such as plants which have subsequently been chemically modified to warrant higher potency against these human pathogens. In this review article we will provide an overview of the current status of plant derived pharmaceuticals and their chemical modifications to target parasite-specific peculiarities in order to interfere with their proliferation in the human host.

Hyperinfection with Strongyloides stercoralis in an Immunosuppressed Patient

Strongyloides stercoralis is a common intestinal parasite in tropics and subtropics. In Bangladesh, prevalence is likely to be high due to poor sanitation. Clinical presentations are frequently nonspecific. However, in immunosuppressed individuals, infection becomes overwhelming and may disseminate and results in high rates of mortality. Unless a high index of suspicion, this readily treatable disease may be missed. Here we report a case of hyperinfection with Strongyloides stercoralis in a patient who was on corticosteroid treatment. A 45 years old male was admitted in Gastroenterology department of Bangabandhu Sheikh Mujib Medical University (BSMMU) with the complaints of abdominal pain, vomiting and diarrhea for 2 weeks. He was on prednisolone 60 mg with omeprazole 40 mg daily for 4 weeks for his eyelid drooping prior to the development of abdominal symptoms. Physical examination revealed a severely malnourished, moderately anemic patient with muscle wasting, angular stomatitis, desquamated skins of feet and hands. Abdominal examination revealed generalized tenderness with moderate ascites. Investigations revealed Hb-7.4 gm/dl with normal WBC count (eosinophil-11% before steroid therapy), S.albumin-19gm/l with prolonged prothrombin time and hypokalemia. USG of abdomen revealed moderate ascites. Endoscopy of upper GIT showed congestion and multiple erosions in the stomach and also in the duodenum. Biopsy from the duodenum revealed adult Strongyloides stercoralis on the surface, larva and ova in the duodenal crypts. The patient was treated with 10 days of oral ivermectin along with blood transfusion, correction of nutritional status and electrolyte imbalance. Patient was discharged home after a total of 20 days of hospitalization DOI: http://dx.doi.org/10.3329/fmcj.v7i2.13526 Faridpur Med. Coll. J. 2012;7(2):98-101

Antiparasitic agents: new drugs on the horizon

The need for new drugs against tropical parasites such as Plasmodium falciparum and Trypanosoma brucei is persistent since problems with resistance and toxicity are jeopardizing the currently available medicines. Public-private partnerships aiming to develop new medicines for malaria and sleeping sickness have, over the past 12 years, brought forward several drug candidates that have entered clinical trials. These are the synthetic peroxide OZ439 and the spiroindolone NITD609 against P. falciparum, fexinidazole and the oxaborole SCYX-7158 against T. brucei. A further class of high chemotherapeutic potential are the diamidines, novel members of which may serve as back-up compounds against trypanosomes and other parasites. Thus, finally, new therapeutic agents against malaria and sleeping sickness are within reach.

Thromboembolic Stroke in a Young Woman with Chagas Cardiomyopathy (P06.247)

Objective: To report a case of acute ischemic stroke in a young woman originally from El Salvador, subsequently diagnosed with Chagas-associated cardiomyopathy. Background Chagas disease is an infectious disease caused by the tropical parasite Trypanosoma cruzi. The most frequent manifestation of the chronic form of Chagas disease is cardiomyopathy, associated with heart failure, arrhythmias, thromboembolism, and stroke. The incidence of chronic Chagas is estimated to be 8-14 million people world wide and is increasingly seen in the USA because of recent emigrations from endemic countries. Design/Methods: We describe the clinical course, investigations, and treatments of a 32 year old woman who presented with cardioembolic ischemic stroke secondary to Chagas cardiomyopathy. Results: A 32-year-old El Salvadorian woman presented with an acute episode of right-sided face/arm/leg tingling, weakness, confusion and inability to pronounce words. MRI/MRA demonstrated an acute left fronto-temporal infarct. Laboratory tests including hypercoagulable panel, toxicology, and lipids were unremarkable, but EKG and telemetry were notable for sinus bradycardia with sinus pause and junctional escape beats. TTE was concerning for a left ventricular thrombus. Cardiac MRI demonstrated fibrosis and a small mass within an akinetic apex, consistent with a cardiac thrombus. Further discussions with the patient elicited a history of symptomatic palpitations, difficulty swallowing solid foods and constipation, suggestive of chronic Chagas disease. The patient was started on a heparin bridge to warfarin and had an AICD placed. Chagas serologies sent to the CDC returned positive, and the patient was started on a course of Benznidazole to halt further progression of the disease. Conclusions: We report a case of a young El Salvadorian woman whose chronic Chagas disease was first diagnosed after presenting with a cardioembolic stroke. Given the increasing documentation of Chagas in the USA, Chagas-related cardiomyopathy should be considered in patients from endemic countries presenting with cardioembolic stroke. Disclosure: Dr. Busza has nothing to disclose. Dr. Cervantes-Arslanian has nothing to disclose. Dr. Kase has nothing to disclose.

The State of the American Journal of Tropical Medicine and Hygiene 2012

The State of the American Journal of Tropical Medicine and Hygiene 2012

Insect immune responses to nematode parasites

Host innate immunity plays a central role in detecting and eliminating microbial pathogenic infections in both vertebrate and invertebrate animals. Entomopathogenic or insect pathogenic nematodes are of particular importance for the control of insect pests and vectors of pathogens, while insect-borne nematodes cause serious diseases in humans. Recent work has begun to use the power of insect models to investigate host-nematode interactions and uncover host antiparasitic immune reactions. This review describes recent findings on innate immune evasion strategies of parasitic nematodes and host cellular and humoral responses to the infection. Such information can be used to model diseases caused by human parasitic nematodes and provide clues indicating directions for research into the interplay between vector insects and their invading tropical parasites.

Introduction of Bruce M. Christensen, Recipient of the 2011 Clark P. Read Mentor Award

Introduction of Bruce M. Christensen, Recipient of the 2011 Clark P. Read Mentor Award

Marinoquinolines A−F, Pyrroloquinolines from Ohtaekwangia kribbensis (Bacteroidetes)

Marinoquinoline A (1) was isolated from the gliding bacterium Ohtaekwangia kribbensis together with the novel marinoquinolines B-F (2-6). Their structures were elucidated from NMR and HRESIMS data. The pyrroloquinolines showed weak antibacterial and antifungal activities and moderate cytotoxicity against four growing mammalian cell lines with IC(50) values ranging from 0.3 to 8.0 μg/mL. In a screening against tropical parasites marinoquinolines A-F (1-6) showed activity against Plasmodium falciparum K1 with IC(50) values between 1.7 and 15 μM.

Particularités anatomopathologiques de la maladie rénale du sujet de l’Afrique sub-Saharienne : revue synthétique des données de la République démocratique du Congo

Chronic kidney disease (CKD) is a major global public health problem. But kidney involvement is more common and appears more severe in Africa than in developed countries. The likely causes of end stage renal disease (ESRD) or CKD stage 3 and above in developed countries are diabetes, hypertension and less frequently glomerular diseases. In contrast, in decreasing order in Africa are glomerulopathies, hypertension and diabetes. The reasons for this preponderance of glomerular diseases are not fully known but may be linked to the persistence or reemergence of tropical diseases. This study reviews the kidney involvements more associated with common tropical diseases including HIV/AIDS. The most common HIV/AIDS lesion is a specific focal and segmental glomerulosclerosis (FSGS) termed HIV-associated nephropathy (HIV-AN). Renal complications of tropical parasites are heterogenous. Various glomerulopathies like FSGS occur during various filariasis infections. Schistosoma mansoni is responsible for membranoproliferative glomerulonephritis and amyloidosis. Human African trypanosomiasis is associated with cryoglobulinemic membranoproliferative glomerulonephritis. The Plasmodium malariae is mainly responsible for membranoproliferative glomerulonephritis. Acute patterns (acute tubular necrosis or acute postinfectious glomerulonephritis) are observed during Plasmodium falciparum infection. Several other viral, bacterial or mycobacterial infections like leprosy and tuberculosis still prevalent in Africa can also affect the kidney. Sickle cell disease is responsible for a variety of renal injuries. In conclusion, kidney lesions linked to tropical diseases partly explain the peculiar pattern of CKD of the black race and play a significant role in the current outbreak of the CKD in Subsaharan Africa.

Curcuma as a Parasiticidal Agent: A Review

Members of the Curcuma plant species (Zingiberaceae) have been used for centuries in cooking, cosmetics, staining and in traditional medicine as "omnipotent" remedies. Herbal preparations made with, and molecules extracted from, Curcuma have been shown to possess a wide variety of pharmacological properties against malignant proliferation, hormonal disorders, inflammation, and parasitosis among other conditions. This review evaluates Curcuma and its associated bioactive compounds, particularly focusing on studies examining the parasiticidal activity of these components against the tropical parasites Plasmodium, leishmania, Trypanosoma, Schistosoma and more generally against other cosmopolitan parasites (nematodes, Babesia, Candida, Giardia, Coccidia and Sarcoptes).

Grain coatings: Diagenesis of Jurassic sandstones in south-central Utah and implications for targeting fossil microbes on Mars

Clusters of large-scale (decameters to > 100 m dia) fluidization pipes have been identified at several locations in Jurassic Navajo and Entrada sandstones in south-central Utah. These typically cut the cross-bedded aeolian-sabhka host rock at right angles. Similar pipe-like structures have been tentatively identified on Mars, and the question of the diagenesis of host rock has important implications for the genesis of pipe structures. Current thinking regarding the genesis of host rock structures is that the grains were derived from wet aeolian-sabkha environments. EDS of all samples indicates a Si:Al ratio of 2:1 suggesting smectite clay minerals are to be expected in a dry mid-latitude climatic zone, and unlike the pipe structures which contain hyphopodium-like structures (fungal filaments), similar in morphology to modern tropical leaf parasites, the host rock is relatively bereft of microbes entombed in grain coatings. Moreover, microtextural data from host rock grains in these wet aeolian (wet-sabkha) environments suggest a lack of volatility judging from infrequent observation of percussion crack evidence of grain collision presumably during the time of formation, a microfeature commonly found within the pipe structures. The diagenesis process can be reconstructed from the composition of the coatings on recovered grains of quartz, feldspar, mica, and occasional calcite as imaged with the SEM and studied by EDS. XRD of the coatings provides confirmation of the clay mineralogy, and INAA is used to cross check the chemistry obtained by EDS. If similar microfeatures exist on grains from both Earth and Mars, materials transported by similar aeolian processes, one would not expect to find fossil evidence of life on grains in host rocks. While martian pipe structures may be the optimum target for the astrobiological exploration of the red planet, host rock might be relatively devoid of fossil microbes if diagenesis of sandstones on Mars is anything like Earth.

Chagas’ disease: an update on immune mechanisms and therapeutic strategies

The final decade of the 20th century was marked by an alarming resurgence in infectious diseases caused by tropical parasites belonging to the kinetoplastid protozoan order. Among the pathogenic trypanosomatids, some species are of particular interest due to their medical importance. These species include the agent responsible for Chagas’ disease, Trypanosoma cruzi. Approximately 8 to 10 million people are infected in the Americas, and approximately 40 million are at risk. In the present review, we discuss in detail the immune mechanisms elicited during infection by T. cruzi and the effects of chemotherapy in controlling parasite proliferation and on the host immune system.

Almiramides A−C: Discovery and Development of a New Class of Leishmaniasis Lead Compounds

Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.

Rainfall induces time-lagged changes in the proportion of tropical aquatic hosts infected with metazoan parasites

Rainfall serves as a powerful driving force, shifting temporal abundance and prevalence patterns in parasites and free-living aquatic organisms in tropical environments. However, there is a lack of sound evidence showing the temporal scales at which rainfall influences infection parameters of parasites in the tropics either directly by affecting the parasite life cycle or indirectly by modifying host population abundance. In the present study, we demonstrate that changes in rainfall patterns lead to changes in the proportion of infected hosts with several parasite species, causing immediate or lagged favourable conditions for an increase in levels of infection. However, the temporal scale of the influence of rainfall varied depending on the ecological characteristics of aquatic ecosystems. Despite the environmental heterogeneity and stochastic events (storms and hurricanes) which affect the study sites, the proportion of infected hosts shows frequency cycles on a yearly scale, suggesting that environmental changes are within the range of variability that naturally occur at the study sites. We propose that the incorporation of stochastic events into long-term predictive models is crucial for understanding the potential effects of global climate change on infection parameters of tropical parasites.

A Protocol for HPLC-based Activity Profiling for Natural Products with Activities against Tropical Parasites

HPLC based activity profiling is an effective strategy to accelerate the discovery of new hits and leads from nature. It conveniently combines the superior separation power of HPLC micro scale compound separation with miniaturized biological screening methods, and on-line and off-line spectroscopy (PDA, MS(n), HR-MS, NMR) for structure elucidation. We here describe a protocol for the discovery of natural products with antimalarial, antileishmanial and antitrypanosomal activity, from extracts libraries in 96-well format. Analytical gradient HPLC on a 3 x 150 mm column of 350 microg of extract, and collection of one-minute fractions into 96 deep-well microtiter plates, parallel evaporation of the micro-fractions, and a suitable dilution scheme permitted parallel activity profiling against three parasites from a single HPLC injection. The protocol was validated with extracts and positive controls such as Artemisia annua.

The New Anthelmintic Tribendimidine is an L-type (Levamisole and Pyrantel) Nicotinic Acetylcholine Receptor Agonist

BackgroundIntestinal parasitic nematodes such as hookworms, Ascaris lumbricoides, and Trichuris trichiura are amongst most prevalent tropical parasites in the world today. Although these parasites cause a tremendous disease burden, we have very few anthelmintic drugs with which to treat them. In the past three decades only one new anthelmintic, tribendimidine, has been developed and taken into human clinical trials. Studies show that tribendimidine is safe and has good clinical activity against Ascaris and hookworms. However, little is known about its mechanism of action and potential resistance pathway(s). Such information is important for preventing, detecting, and managing resistance, for safety considerations, and for knowing how to combine tribendimidine with other anthelmintics.Methodology/Principal FindingsTo investigate how tribendimidine works and how resistance to it might develop, we turned to the genetically tractable nematode, Caenorhabditis elegans. When exposed to tribendimidine, C. elegans hermaphrodites undergo a near immediate loss of motility; longer exposure results in extensive body damage, developmental arrest, reductions in fecundity, and/or death. We performed a forward genetic screen for tribendimidine-resistant mutants and obtained ten resistant alleles that fall into four complementation groups. Intoxication assays, complementation tests, genetic mapping experiments, and sequencing of nucleic acids indicate tribendimidine-resistant mutants are resistant also to levamisole and pyrantel and alter the same genes that mutate to levamisole resistance. Furthermore, we demonstrate that eleven C. elegans mutants isolated based on their ability to resist levamisole are also resistant to tribendimidine.Conclusions/SignificanceOur results demonstrate that the mechanism of action of tribendimidine against nematodes is the same as levamisole and pyrantel, namely, tribendimidine is an L-subtype nAChR agonist. Thus, tribendimidine may not be a viable anthelmintic where resistance to levamisole or pyrantel already exists but could productively be used where resistance to benzimidazoles exists or could be combined with this class of anthelmintics.