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Immunomodulatory dynamics of Excretory and Secretory products on Th9 immune response during <i>Haemonchus contortus</i> infection in goat

PLoS Neglected Tropical Diseases News - 3 April 2020 - 9:00pm

by Muhammad Ali Memon, Muhammad Ali-ul-Husnain Naqvi, Huang Xin, Liang Meng, Muhammad Waqqas Hasan, Muhammad Haseeb, Shakeel Ahmed Lakho, Kalilixiati Aimulajiang, Yongqian Bu, Lixin Xu, Xiaokai Song, Xiangrui Li, Ruofeng Yan

CD4+ T cells play critical roles in mediating adaptive immunity to a variety of pathogens. Recently, new subset of CD4+T named as T helper 9 cells that express the prototypical interleukin-9 (IL-9) cytokine have been recognized in human and mice models during different parasitic infections. Haemonchus contortus is a gastrointestinal nematode of small ruminants which cause high mortality in young animals. During infection, Excretory and Secretary Products (ESPs) are released in the host body. No other study has reported yet on immunomodulatory dynamics of H. contortus ESPs on Th9 immune response in vitro or in vivo. In this study, immunomodulatory effects of ESPs (5, 10, 20, 40, 80; μg/mL) incubated with goat PBMCs on Th9 cells, IL-9 immune response and TGF-β/Smad signaling regulator were evaluated in vitro. Moreover, for in vivo study, goats were infected with different doses (P-800, P-2400, and P-8000) of H. contortus infective larva (L3) and immunomodulatory effects on Th9 cells, IL-9 immune response and TGF-β/Smad signaling regulator were evaluated at 7, 10, 14, 18, 21, 28 Days Post Infection (DPI). Flow cytometry was performed to evaluate the effects on Th9 cells and quantitative real time polymerase chain reaction was performed to evaluate the IL-9 cytokine transcription level. Additionally, fecal egg counting was also performed in parallel to confirm the infection. All goats were dewormed at 29 DPI and all experiments were also performed at 35 DPI, one week post deworming. The finding indicated that 10, 20, 40, 80 μg/mL concentration of ESPs incubated with goat PBMCs showed significant increase in the production of Th9 cells, signature cytokine IL-9 and expression of TGF-β/Smad signaling regulator as compared to control group in vitro.All infected groups showed significant increase in production of Th9 cells and IL-9 cytokine and expression of TGF-β/Smad key genes at 18, 21, and 28 DPI as compared to control group. Likewise, at 14 DPI, P-2400 and P-8000 groups showed significant increase in production of Th9 cells, IL-9 cytokine and expression of TGF-β/Smad key genes. While at 10 DPI, production of Th9 cells and IL-9 was significantly increased in P-2400 & P-8000 groups, and at 7 DPI only P-8000 showed significantly increase in IL-9 production. No immunomodulatory effects were observed at 0 and 3 DPI. Additionally, significant gradually up-regulated key genes expression of TGF-β/Smad signaling regulator in all infected groups confirmed the above results. After deworming, production of Th9 cells, associated immune response and expression of signaling regulator in each group were significantly decreased. Based on this study, it is concluded that Th9 immune response was induced during H. contortus infection in goat by up-regulation of TGF-β/Smad signaling key genes.

Persistent deleterious effects of a deleterious <i>Wolbachia</i> infection

PLoS Neglected Tropical Diseases News - 3 April 2020 - 9:00pm

by Perran A. Ross, Jason K. Axford, Ashley G. Callahan, Kelly M. Richardson, Ary A. Hoffmann

Wolbachia are being used to reduce dengue transmission by Aedes aegypti mosquitoes around the world. To date releases have mostly involved Wolbachia strains with limited fitness effects but strains with larger fitness costs could be used to suppress mosquito populations. However, such infections are expected to evolve towards decreased deleterious effects. Here we investigate potential evolutionary changes in the wMelPop infection transferred from Drosophila melanogaster to Aedes aegypti more than ten years (~120 generations) ago. We show that most deleterious effects of this infection have persisted despite strong selection to ameliorate them. The wMelPop-PGYP infection is difficult to maintain in laboratory colonies, likely due to the persistent deleterious effects coupled with occasional maternal transmission leakage. Furthermore, female mosquitoes can be scored incorrectly as infected due to transmission of Wolbachia through mating. Infection loss in colonies was not associated with evolutionary changes in the nuclear background. These findings suggest that Wolbachia transinfections with deleterious effects may have stable phenotypes which could ensure their long-term effectiveness if released in natural populations to reduce population size.

<i>In vivo</i> imaging of transgenic <i>Brugia malayi</i>

PLoS Neglected Tropical Diseases News - 3 April 2020 - 9:00pm

by Canhui Liu, Sai Lata De, Kristi Miley, Thomas R. Unnasch

Background

Studies of the human filarial parasite have been hampered by the fact that they are obligate parasites with long life cycles. In other pathogenic infections, in vivo imaging systems (IVIS) have proven extremely useful in studying pathogenesis, tissue tropism and in vivo drug efficacy. IVIS requires the use of transgenic parasites expressing a florescent reporter. Developing a method to produce transgenic filarial parasites expressing a florescent reporter would permit IVIS to be applied to the study of tissue tropism and provide a non-invasive way to screen for in vivo drug efficacy against these parasites.

Methodology/Principal findings

We report the development of a dual luciferase reporter construct in a piggyBac backbone that may be used to stably transfect Brugia malayi, a causative agent of human filariasis. Parasites transfected with this construct were visible in IVIS images obtained from infected gerbils. The signal in these infected animals increased dramatically when the transgenic parasites matured to the adult stage and began to produce transgenic progeny microfilaria. We demonstrate that the IVIS system can be used to develop an effective method for cryopreservation of transgenic parasites, to non-invasively monitor the effect of treatment with anti-filarial drugs, and to rapidly identify transgenic F1 microfilariae.

Conclusions

To our knowledge, this represents the first application of IVIS to the study of a human filarial parasite. This method should prove useful in studies of tissue tropism and as an efficient in vivo assay for candidate anti-filarial drugs.

Urticaria and silent parasitism by Ascaridoidea: Component-resolved diagnosis reinforces the significance of this association

PLoS Neglected Tropical Diseases News - 3 April 2020 - 9:00pm

by Marta Viñas, Idoia Postigo, Ester Suñén, Jorge Martínez

Urticaria remains a major problem in terms of aetiology, investigation, and management, and although parasitic diseases are considered potential causes, the absence of a consistent link between parasitic infections and skin allergy symptoms leads to the need for a deeper study of parameters that support this association. The objectives of this study were to analyse a possible relationship between parasitism by Ascarididae (Toxocara canis and Anisakis simplex) and the clinical expression of urticaria and to identify possible parasitic molecular markers for improving the diagnosis of unknown urticaria aetiology. The prevalence of Toxocara and Anisakis infestations was evaluated by measuring the levels of specific IgG (sIgG) and IgE (sIgE) antibodies against crude extracts and isolated components from whole larvae of Anisakis simplex (Ani s 1, Ani s 3 and Ani s 7) and Toxocara canis (TES-120, TES-70, TES-32 and TES-26) using immunologic and molecular diagnostic methods. A cross-sectional study was performed in a group of 400 individuals. The study group consisted of 95 patients diagnosed with urticaria (55 with chronic urticaria and 40 with acute urticaria). A control group consisted of 305 subjects without urticaria (182 diagnosed with respiratory allergy and 123 without allergy). Statistically significant differences were demonstrated in the seroprevalence of specific IgG and IgE antibodies between the urticaria patients and the healthy general population when isolated ascarid antigens were evaluated. The prevalence of IgG antibodies against Ani s 1, IgE antibodies against TES-120 and IgE antibodies against TES-70 were significantly different between the control individuals (healthy general population) and patients with urticaria. Moreover, the urticaria patient group demonstrated a higher seroprevalence of antibodies (sIgE and sIgG) against Anisakis simplex larva whole extract than the control group but just with statistically diferences when sIgE was evaluated. The presence of IgE and/or IgG antibodies against Ani s 3 (tropomyosin) can help to discriminate between patients with and without urticaria. Both ascarids seem to be associated with urticaria, although in our region, Anisakis seems to have greater involvement than Toxocara in this relationship. Molecular diagnostics can be used to associate urticaria with parasite infestations. Tropomyosin and Ani s 1 were the most relevant markers to demonstrate the association between urticaria and the most relevant Ascarididae parasites in our region.

Non-typhoidal <i>Salmonella</i> bloodstream infections in Kisantu, DR Congo: Emergence of O5-negative <i>Salmonella</i> Typhimurium and extensive drug resistance

PLoS Neglected Tropical Diseases News - 2 April 2020 - 9:00pm

by Bieke Tack, Marie-France Phoba, Barbara Barbé, Lisette M. Kalonji, Liselotte Hardy, Sandra Van Puyvelde, Brecht Ingelbeen, Dadi Falay, Dauly Ngbonda, Marianne A. B. van der Sande, Stijn Deborggraeve, Jan Jacobs, Octavie Lunguya

Background

Non-typhoidal Salmonella (NTS) are a major cause of bloodstream infection (BSI) in sub-Saharan Africa. This study aimed to assess its longitudinal evolution as cause of BSI, its serotype distribution and its antibiotic resistance pattern in Kisantu, DR Congo.

Methods

As part of a national surveillance network, blood cultures were sampled in patients with suspected BSI admitted to Kisantu referral hospital from 2015–2017. Blood cultures were worked-up according to international standards. Results were compared to similar data from 2007 onwards.

Results

In 2015–2017, NTS (n = 896) represented the primary cause of BSI. NTS were isolated from 7.6% of 11,764 suspected and 65.4% of 1371 confirmed BSI. In children <5 years, NTS accounted for 9.6% of suspected BSI. These data were in line with data from previous surveillance periods, except for the proportion of confirmed BSI, which was lower in previous surveillance periods. Salmonella Typhimurium accounted for 63.1% of NTS BSI and Salmonella Enteritidis for 36.4%. Of all Salmonella Typhimurium, 36.9% did not express the O5-antigen (i.e. variant Copenhagen). O5-negative Salmonella Typhimurium were rare before 2013, but increased gradually from then onwards. Multidrug resistance was observed in 87.4% of 864 NTS isolates, decreased ciprofloxacin susceptibility in 7.3%, ceftriaxone resistance in 15.7% and azithromycin resistance in 14.9%. A total of 14.2% of NTS isolates, that were all Salmonella Typhimurium, were multidrug resistant and ceftriaxone and azithromycin co-resistant. These Salmonella isolates were called extensively drug resistant. Compared to previous surveillance periods, proportions of NTS isolates with resistance to ceftriaxone and azithromycin and decreased ciprofloxacin susceptibility increased.

Conclusion

As in previous surveillance periods, NTS ranked first as the cause of BSI in children. The emergence of O5-negative Salmonella Typhimurium needs to be considered in the light of vaccine development. The high proportions of antibiotic resistance are worrisome.

Schistosome migration in the definitive host

PLoS Neglected Tropical Diseases News - 2 April 2020 - 9:00pm

by Catherine S. Nation, Akram A. Da’dara, Jeffrey K. Marchant, Patrick J. Skelly

Schistosomes are parasitic blood flukes that infect >200 million people around the world. Free-swimming larval stages penetrate the skin, invade a blood vessel, and migrate through the heart and lungs to the vasculature of the liver, where maturation and mating occurs. From here, the parasite couples migrate to their preferred egg laying sites. Here, we compare and contrast what is known about the migration patterns within the definitive host of the three major species of human schistosome: Schistosoma mansoni, S. japonicum, and S. haematobium. We conclude that intravascular schistosomes are inexorable colonizers whose migration and egg laying strategy is profligate; all three species (and their eggs) can be found throughout the mesenteric venules, the rectal venous plexus, and, to a greater or lesser extent, the urogenital venous plexuses. In addition, it is common for parasite eggs to be deposited in locations that lack easy access to the exterior, further demonstrating the relentless exploratory nature of these intravascular worms.

Adding <i>MASP1</i> to the lectin pathway—Leprosy association puzzle: Hints from gene polymorphisms and protein levels

PLoS Neglected Tropical Diseases News - 2 April 2020 - 9:00pm

by Hellen Weinschutz Mendes, Angelica Winter Boldt, Ewalda Stahlke, Jens Christian Jensenius, Steffen Thiel, Iara J. Taborda Messias-Reason

Background

Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease.

Methodology

We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3’-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls.

Principal findings

Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR = 0.5–0.6, Pcorr = 0.01–0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding.

Conclusion

Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.

A novel cystatin derived from <i>Trichinella spiralis</i> suppresses macrophage-mediated inflammatory responses

PLoS Neglected Tropical Diseases News - 1 April 2020 - 9:00pm

by Porntida Kobpornchai, Robin J. Flynn, Onrapak Reamtong, Nonglucksanawan Rittisoonthorn, Nathamon Kosoltanapiwat, Kobporn Boonnak, Usa Boonyuen, Sumate Ampawong, Montakan Jiratanh, Muncharee Tattiyapong, Poom Adisakwattana

Trichinella spiralis can modulate host immune responses to retain a suitable environment for its long-term survival. Incidentally, the parasite elicits regulatory effects through immunomodulatory molecule release, which can suppress host inflammation and may be used for the treatment of unrelated inflammatory diseases in someday. Here we identified and characterized a novel T. spiralis cystatin (TsCstN), which inhibits inflammation mediated by LPS-treated macrophages.Proteins contained in the excretory–secretory (ES) product of muscle-stage T. spiralis (ES-L1) were fractionated, and each was treated with mouse bone marrow-derived macrophages (mBMDMs) before LPS stimulation. The fractions that exhibited high immunomodulatory property by decreasing pro-inflammatory cytokines or increasing anti-inflammatory cytokines were identified by mass spectrometry. Incidentally, the conserved hypothetical protein (Tsp_04814) was selected for further characterization as it presented the most significant MS score. An annotation of Tsp_04814 using protein structural homology comparison suggested that it has high structural similarity to human cystatin E/M (TM score 0.690). The recombinant T. spiralis novel cystatin (rTsCstN) was expressed in Escherichia coli at a molecular weight of approximately 13 kDa. Mouse anti-rTsCstN polyclonal antibody (pAb) could detect native TsCstN in crude worm antigens (CWA) and ES-L1 and be predominantly localized in the stichosome and subcuticular cells. rTsCstN inhibited cysteine proteases in vitro, especially cathepsin L, at an optimal pH of 6. Besides, rTsCstN could be internalized into mBMDMs, which were mostly distributed in the cytoplasm and lysosome both before and after LPS stimulation. To evaluate the rTsCstN immunomodulatory properties on mBMDMs, rTsCstN was incubated with mBMDM before LPS stimulation; this demonstrated that rTsCstN suppressed pro-inflammatory cytokine production and MHC class II expression.T. spiralis L1-derived TsCstN was characterized as a novel cysteine protease inhibitor. The protein elicits an anti-inflammatory property by suppressing pro-inflammatory cytokines and interfering with the antigen presentation process through depletion of MHC class II expression.

Deciphering the possible role of <i>ctxB7</i> allele on higher production of cholera toxin by Haitian variant <i>Vibrio cholerae</i> O1

PLoS Neglected Tropical Diseases News - 1 April 2020 - 9:00pm

by Arindam Naha, Rahul Shubhra Mandal, Prosenjit Samanta, Rudra Narayan Saha, Sreeja Shaw, Amit Ghosh, Nabendu Sekhar Chatterjee, Pujarini Dutta, Keinosuke Okamoto, Shanta Dutta, Asish Kumar Mukhopadhyay

Cholera continues to be an important public health concern in developing countries where proper hygiene and sanitation are compromised. This severe diarrheal disease is caused by the Gram-negative pathogen Vibrio cholerae belonging to serogroups O1 and O139. Cholera toxin (CT) is the prime virulence factor and is directly responsible for the disease manifestation. The ctxB gene encodes cholera toxin B subunit (CTB) whereas the A subunit (CTA) is the product of ctxA gene. Enzymatic action of CT depends on binding of B pentamers to the lipid-based receptor ganglioside GM1. In recent years, emergence of V. cholerae Haitian variant strains with ctxB7 allele and their rapid spread throughout the globe has been linked to various cholera outbreaks in Africa and Asia. These strains produce classical type (WT) CTB except for an additional mutation in the signal sequence region where an asparagine (N) residue replaces a histidine (H) at the 20th amino acid position (H20N) of CTB precursor (pre-CTB). Here we report that Haitian variant V. cholerae O1 strains isolated in Kolkata produced higher amount of CT compared to contemporary O1 El Tor variant strains under in vitro virulence inducing conditions. We observed that the ctxB7 allele, itself plays a pivotal role in higher CT production. Based on our in silico analysis, we hypothesized that higher accumulation of toxin subunits from ctxB7 allele might be attributed to the structural alteration at the CTB signal peptide region of pre-H20N CTB. Overall, this study provides plausible explanation regarding the hypertoxigenic phenotype of the Haitian variant strains which have spread globally, possibly through positive selection for increased pathogenic traits.

Risk factors for acute human brucellosis in Ijara, north-eastern Kenya

PLoS Neglected Tropical Diseases News - 1 April 2020 - 9:00pm

by Stella G. Kiambi, Eric M. Fèvre, Jared Omolo, Joseph Oundo, William A. de Glanville

Brucellosis is an important zoonotic disease globally, with particularly high burdens in pastoral settings. While the zoonotic transmission routes for Brucella spp. are well known, the relative importance of animal contact, food-handling and consumption practices can vary. Understanding the local epidemiology of human brucellosis is important for directing veterinary and public health interventions, as well as for informing clinical diagnostic decision making. We conducted a cross-sectional study in Ijara District Hospital, north-eastern Kenya. A total of 386 individuals seeking care and reporting symptoms of febrile illness were recruited in 2011. Samples were tested for the presence of Brucella spp. using a real-time PCR (RT-PCR) and results compared to those from the test for brucellosis used at Ijara District Hospital, the febrile Brucella plate agglutination test (FBAT). A questionnaire was administered to all participants and risk factors for brucellosis identified using logistic regression with an information theoretic (IT) approach and least absolute shrinkage and selection (LASSO). Sixty individuals were RT-PCR positive, resulting in a prevalence of probable brucellosis of 15.4% (95% CI 12.0–19.5). The IT and LASSO approaches both identified consuming purchased milk as strongly associated with elevated risk and boiling milk before consumption strongly associated with reduced risk. There was no evidence that livestock keepers were at different risk of brucellosis than non-livestock keepers. The FBAT had poor diagnostic performance when compared to RT-PCR, with an estimated sensitivity of 36.6% (95% CI 24.6–50.1) and specificity of 69.3% (95% CI 64.0–74.3). Brucellosis is an important cause of febrile illness in north-eastern Kenya. Promotion of pasteurisation of milk in the marketing chain and health messages encouraging the boiling of raw milk before consumption could be expected to lead to large reductions in the incidence of brucellosis in Ijara. This study supports the growing evidence that the FBAT performs very poorly in the diagnosis of brucellosis.

High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

PLoS Neglected Tropical Diseases News - 1 April 2020 - 9:00pm

by Julien Slagboom, Marija Mladić, Chunfang Xie, Taline D. Kazandjian, Freek Vonk, Govert W. Somsen, Nicholas R. Casewell, Jeroen Kool

Snakebite is a neglected tropical disease that results in a variety of systemic and local pathologies in envenomed victims and is responsible for around 138,000 deaths every year. Many snake venoms cause severe coagulopathy that makes victims vulnerable to suffering life-threating haemorrhage. The mechanisms of action of coagulopathic snake venom toxins are diverse and can result in both anticoagulant and procoagulant effects. However, because snake venoms consist of a mixture of numerous protein and peptide components, high throughput characterizations of specific target bioactives is challenging. In this study, we applied a combination of analytical and pharmacological methods to identify snake venom toxins from a wide diversity of snake species that perturb coagulation. To do so, we used a high-throughput screening approach consisting of a miniaturised plasma coagulation assay in combination with a venom nanofractionation approach. Twenty snake venoms were first separated using reversed-phase liquid chromatography, and a post-column split allowed a small fraction to be analyzed with mass spectrometry, while the larger fraction was collected and dispensed onto 384-well plates. After fraction collection, any solvent present in the wells was removed by means of freeze-drying, after which it was possible to perform a plasma coagulation assay in order to detect coagulopathic activity. Our results demonstrate that many snake venoms simultaneously contain both procoagulant and anticoagulant bioactives that contribute to coagulopathy. In-depth identification analysis from seven medically-important venoms, via mass spectrometry and nanoLC-MS/MS, revealed that phospholipase A2 toxins are frequently identified in anticoagulant venom fractions, while serine protease and metalloproteinase toxins are often associated with procoagulant bioactivities. The nanofractionation and proteomics approach applied herein seems likely to be a valuable tool for the rational development of next-generation snakebite treatments by facilitating the rapid identification and fractionation of coagulopathic toxins, thereby enabling specific targeting of these toxins by new therapeutics such as monoclonal antibodies and small molecule inhibitors.

Decreasing fluconazole susceptibility of clinical South African <i>Cryptococcus neoformans</i> isolates over a decade

PLoS Neglected Tropical Diseases News - 31 March 2020 - 9:00pm

by Serisha D. Naicker, Ruth S. Mpembe, Tsidiso G. Maphanga, Thokozile G. Zulu, Daniel Desanto, Jeannette Wadula, Nomonde Mvelase, Caroline Maluleka, Kessendri Reddy, Halima Dawood, Motlatji Maloba, Nelesh P. Govender, for GERMS-SA

Background

Fluconazole is used in combination with amphotericin B for induction treatment of cryptococcal meningitis and as monotherapy for consolidation and maintenance treatment. More than 90% of isolates from first episodes of cryptococcal disease had a fluconazole minimum inhibitory concentration (MIC) ≤4 μg/ml in a Gauteng population-based surveillance study of Cryptococcus neoformans in 2007–2008. We assessed whether fluconazole resistance had emerged in clinical cryptococcal isolates over a decade.

Methodology and principal findings

We prospectively collected C. neoformans isolates from 1 January through 31 March 2017 from persons with a first episode of culture-confirmed cryptococcal disease at 37 South African hospitals. Isolates were phenotypically confirmed to C. neoformans species-complex level. We determined fluconazole MICs (range: 0.125 μg/ml to 64 μg/ml) of 229 C. neoformans isolates using custom-made broth microdilution panels prepared, inoculated and read according to Clinical and Laboratory Standards Institute M27-A3 and M60 recommendations. These MIC values were compared to MICs of 249 isolates from earlier surveillance (2007–2008). Clinical data were collected from patients during both surveillance periods. There were more males (61% vs 39%) and more participants on combination induction antifungal treatment (92% vs 32%) in 2017 compared to 2007–2008. The fluconazole MIC50, MIC90 and geometric mean MIC was 4 μg/ml, 8 μg/ml and 4.11 μg/ml in 2017 (n = 229) compared to 1 μg/ml, 2 μg/ml and 2.08 μg/ml in 2007–2008 (n = 249) respectively. Voriconazole, itraconazole and posaconazole Etests were performed on 16 of 229 (7%) C. neoformans isolates with a fluconazole MIC value of ≥16 μg/ml; only one had MIC values of >32 μg/ml for these three antifungal agents.

Conclusions and significance

Fluconazole MIC50 and MIC90 values were two-fold higher in 2017 compared to 2007–2008. Although there are no breakpoints, higher fluconazole doses may be required to maintain efficacy of standard treatment regimens for cryptococcal meningitis.

Dopaminergic antagonists inhibit bile chemotaxis of adult <i>Clonorchis sinensis</i> and its egg production

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Fuhong Dai, Jin-Ho Song, Yeon Pyo Hong, Xuelian Bai, Woon-Mok Sohn, Sung-Jong Hong

Human clonorchiasis, caused by Clonorchis sinensis, is endemic in East Asian countries. C. sinensis metacercariae excyst in the duodenum of mammalian hosts, migrate to the intrahepatic bile duct, and mature into adults in the milieu of bile. We have previously shown that newly excysted juvenile C. sinensis move chemotactically toward bile and bile acids. Here, the chemotactic behavior of adult C. sinensis (CsAd) toward bile and bile acids was investigated. CsAds moved toward 0.05–5% bile and were most attracted to 0.5% bile but moved away from 10% bile. Upon exposure to 1–10% bile, CsAds eventually stopped moving and then died quickly. Among bile acids, CsAds showed strong chemotaxis toward cholic acid (CA) and deoxycholic acid. On the contrary, CsAds repelled from lithocholic acid (LCA). Moreover, at higher than 10 mM LCA, CsAds became sluggish and eventually died. Dopamine D1 receptor antagonists (LE-300 and SKF-83566), D2/3 receptor antagonists (raclopride and its derivative CS-49612), and a dopamine re-uptake inhibitor inhibited CA-induced chemotaxis of CsAds almost completely. Clinically used antipsychotic drugs, namely chlorpromazine, haloperidol, and clozapine, are dopaminergic antagonists and are secreted into bile. They completely inhibited chemotaxis of CsAds toward CA. At the maximum doses used to treat patients, the three tested medicines only expelled 2–12% of CsAds from the experimentally infected rabbits, but reduced egg production by 64–79%. Thus, antipsychotic medicines with dopaminergic antagonism could be considered as new anthelmintic candidates for human C. sinensis infections.

Comprehensive response to Usutu virus following first isolation in blood donors in the Friuli Venezia Giulia Region of Italy: Development of recombinant NS1-based serology and sensitivity to antiviral drugs

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Ilaria Caracciolo, Erick Mora Cardenas, Chiara Aloise, Tea Carletti, Ludovica Segat, Maria Sole Burali, Alexsia Chiarvesio, Vivianna Totis, Tatjana Avšič–Županc, Eloise Mastrangelo, Giuseppe Manfroni, Pierlanfranco D’Agaro, Alessandro Marcello

Surveillance of Usutu virus is crucial to prevent future outbreaks both in Europe and in other countries currently naïve to the infection, such as the Americas. This goal remains difficult to achieve, notably because of the lack of large-scale cohort studies and the absence of commercially available diagnostic reagents for USUV. This work started with the first identification of USUV in a blood donor in the Friuli Venezia Giulia (FVG) Region in Northern-Eastern Italy, which is endemic for West Nile virus. Considering that only one IgG ELISA is commercially available, but none for IgM, a novel NS1 antigen based IgG/M ELISA has been developed. This assay tested successfully for the detection of Usutu virus in blood donors with the identification of a second case of transmission and high levels of exposure. Furthermore, two pan-flavivirus antiviral drugs, that we previously characterized to be inhibitors of other flavivirus infectivity, were successfully tested for inhibition of Usutu virus with inhibitory concentrations in the low micromolar range. To conclude, this work identifies North-Eastern Italy as endemic for Usutu virus with implications for the screening of transfusion blood. A novel NS1-based ELISA test has been implemented for the detection of IgM/G that will be of importance as a tool for the diagnosis and surveillance of Usutu virus infection. Finally, Usutu virus is shown to be sensitive to a class of promising pan-flavivirus drugs.

Is <i>Sporothrix chilensis</i> circulating outside Chile?

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Carlos Alberto Tiburcio Valeriano, Reginaldo Gonçalves de Lima-Neto, Cícero Pinheiro Inácio, Vanessa Brito de Souza Rabello, Ertênia Paiva Oliveira, Rosely Maria Zancopé-Oliveira, Rodrigo Almeida-Paes, Rejane Pereira Neves, Manoel Marques Evangelista de Oliveira

Sporothrix chilensis is a mild-pathogenical specie of Sporothrix pallida complex, until now, known as restrict to Chile. Herein, we describe the first clinical isolates identified as S. chilensis in Brazil, preserved in the URM Culture Collection, by polyphasic taxonomy, and their respective antifungal profile of this emergent fungus.

A retrospective epidemiological analysis of human <i>Cryptosporidium</i> infection in China during the past three decades (1987-2018)

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Aiqin Liu, Baiyan Gong, Xiaohua Liu, Yujuan Shen, Yanchen Wu, Weizhe Zhang, Jianping Cao

Background

Cryptosporidiosis is an emerging infectious disease of public health significance worldwide. The burden of disease caused by Cryptosporidium varies between and within countries/areas. To have a comprehensive understanding of epidemiological status and characteristics of human Cryptosporidium infection in China since the first report in 1987, a retrospective epidemiological analysis was conducted by presenting differences in the prevalence of Cryptosporidium by province, year, population, living environment and season and possible transmission routes and risk factors as well as genetic characteristics of Cryptosporidium in humans.

Methodology/Principal findings

A systematic search was conducted to obtain epidemiological papers of human Cryptosporidium infection/cryptosporidiosis from PubMed and Chinese databases. Finally, 164 papers were included in our analysis. At least 200,054 people from 27 provinces were involved in investigational studies of Cryptosporidium, with an average prevalence of 2.97%. The prevalence changed slightly over time. Variable prevalences were observed: 0.65–11.15% by province, 1.89–47.79% by population, 1.77–12.87% and 0–3.70% in rural and urban areas, respectively. The prevalence peak occurred in summer or autumn. Indirect person-to-person transmission was documented in one outbreak of cryptosporidiosis in a pediatric hospital. 263 Cryptosporidium isolates were obtained, and seven Cryptosporidium species were identified: C. hominis (48.3%), C. andersoni (22.43%), C. parvum (16.7%), C. meleagridis (8.36%), C. felis (3.04%), C. canis (0.76%) and C. suis (0.38%).

Conclusions/Significances

This systematic review reflects current epidemiological status and characteristics of Cryptosporidium in humans in China. These data will be helpful to develop efficient control strategies to intervene with and prevent occurrence of human Cryptosporidium infection/cryptosporidiosis in China as well as have a reference effect to other countries. Further studies should focus on addressing a high frequency of C. andersoni in humans and a new challenge with respect to cryptosporidiosis with an increasing population of elderly people and patients with immunosuppressive diseases.

Altered composition and functional profile of high-density lipoprotein in leprosy patients

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Robertha Mariana R. Lemes, Carlos Adriano de M. e Silva, Maria Ângela de M. Marques, Georgia C. Atella, José Augusto da C. Nery, Maria Renata S. Nogueira, Patricia S. Rosa, Cléverson T. Soares, Prithwiraj De, Delphi Chatterjee, Maria Cristina V. Pessolani, Cristiana S. de Macedo

The changes in host lipid metabolism during leprosy have been correlated to fatty acid alterations in serum and with high-density lipoprotein (HDL) dysfunctionality. This is most evident in multibacillary leprosy patients (Mb), who present an accumulation of host lipids in Schwann cells and macrophages. This accumulation in host peripheral tissues should be withdrawn by HDL, but it is unclear why this lipoprotein from Mb patients loses this function. To investigate HDL metabolism changes during the course of leprosy, HDL composition and functionality of Mb, Pb patients (paucibacillary) pre- or post-multidrug therapy (MDT) and HC (healthy controls) were analyzed. Mb pre-MDT patients presented lower levels of HDL-cholesterol compared to HC. Moreover, Ultra Performance Liquid Chromatography-Mass Spectrometry lipidomics of HDL showed an altered lipid profile of Mb pre-MDT compared to HC and Pb patients. In functional tests, HDL from Mb pre-MDT patients showed impaired anti-inflammatory and anti-oxidative stress activities and a lower cholesterol acceptor capacity compared to other groups. Mb pre-MDT showed lower concentrations of ApoA-I (apolipoprotein A-I), the major HDL protein, when compared to HC, with a post-MDT recovery. Changes in ApoA-I expression could also be observed in M. leprae-infected hepatic cells. The presence of bacilli in the liver of a Mb patient, along with cell damage, indicated hepatic involvement during leprosy, which may reflect on ApoA-I expression. Together, altered compositional and functional profiles observed on HDL of Mb patients can explain metabolic and physiological changes observed in Mb leprosy, contributing to a better understanding of its pathogenesis.

Cost of interventions to control schistosomiasis: A systematic review of the literature

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Paola Salari, Thomas Fürst, Stefanie Knopp, Jürg Utzinger, Fabrizio Tediosi

Background

Schistosomiasis, a disease caused by blood flukes of the genus Schistosoma, belongs to the neglected tropical diseases. Left untreated, schistosomiasis can lead to severe health problems and even death. An estimated 800 million people are at risk of schistosomiasis and 250 million people are infected. The global strategy to control and eliminate schistosomiasis emphasizes large-scale preventive chemotherapy with praziquantel targeting school-age children. Other tools are available, such as information, education, and communication (IEC), improved access to water, sanitation, and hygiene (WASH), and snail control. Despite available evidence of the effectiveness of these control measures, analyses estimating the most cost-effective control or elimination strategies are scarce, inaccurate, and lack standardization. We systematically reviewed the literature on costs related to public health interventions against schistosomiasis to strengthen the current evidence-base.

Methodology

In adherence to the PRISMA guidelines, we systematically searched three readily available electronic databases (i.e., PubMed, WHOLIS, and ISI Web of Science) from inception to April 2019 with no language restrictions. Relevant documents were screened, duplicates eliminated, specific rules on studies to consider were defined, and the eligible studies fully reviewed. Costs of schistosomiasis interventions were classified in three groups: (i) preventive chemotherapy; (ii) preventive chemotherapy plus an individual diagnostic test to identify at-risk population; and (iii) test-and-treat interventions.

Principal findings

Fifteen articles met our inclusion criteria. In general, it was hard to compare the reported costs from the different studies due to different approaches used to estimate and classify the costs of the intervention assessed. Costs varied considerably from one study to another, ranging from US$ 0.06 to US$ 4.46 per person treated. The difference between financial and opportunity costs only played a minimal role in the explanation of the costs’ variation, even if delivery costs were two times higher in the analyses including economic costs. Most of the studies identified in our systematic review focused on sub-Saharan African countries.

Conclusions/Significance

The degree of transparency of most of the costing studies of schistosomiasis interventions found in the current review was limited. Hence, there is a pressing need for strategies to improve the quality of cost analyses, and higher reporting standards and transparency that should be fostered by peer-review journal policies. Cost information on these interventions is crucial to inform resource allocation decisions and those regarding the affordability of scaling-up interventions.

Risk practices for bovine tuberculosis transmission to cattle and livestock farming communities living at wildlife-livestock-human interface in northern KwaZulu Natal, South Africa

PLoS Neglected Tropical Diseases News - 30 March 2020 - 9:00pm

by Petronillah Rudo Sichewo, Catiane Vander Kelen, Séverine Thys, Anita Luise Michel

Bovine tuberculosis (bTB) is a disease of cattle that is transmitted through direct contact with an infected animal or ingestion of contaminated food or water. This study seeks to explore the local knowledge on bTB, obtain information on social and cultural practices regarding risk of bTB transmission to cattle and humans (zoonotic TB) in a traditional livestock farming community with a history of bTB diagnosis in cattle and wildlife. Information was collected using a qualitative approach of Focus Group Discussions (FGDs) targeting household members of livestock farmers that owned bTB tested herds. We conducted fourteen FGDs (150 individuals) across four dip tanks that included the following categories of participants from cattle owning households: head of households, herdsmen, dip tank committee members and women. The qualitative data was managed using NVivo Version 12 Pro software. Social and cultural practices were identified as major risky practices for bTB transmission to people, such as the consumption of undercooked meat, consumption of soured /raw milk and lack of protective measures during slaughtering of cattle. The acceptance of animals into a herd without bTB pre-movement testing following traditional practices (e.g. lobola, ‘bride price’, the temporary introduction of a bull for ‘breeding’), the sharing of grazing and watering points amongst the herds and with wildlife were identified as risky practices for M. bovis infection transmission to cattle. Overall, knowledge of bTB in cattle and modes of transmission to people and livestock was found to be high. However, the community was still involved in risky practices that expose people and cattle to bovine TB. An inter-disciplinary ‘One Health’ approach that engages the community is recommended, to provide locally relevant interventions that allows the community to keep their traditional practices and socio-economic systems whilst avoiding disease transmission to cattle and people.

Assessment of control strategies against <i>Clonorchis sinensis</i> infection based on a multi-group dynamic transmission model

PLoS Neglected Tropical Diseases News - 27 March 2020 - 9:00pm

by Xiao-Hong Huang, Men-Bao Qian, Guang-Hu Zhu, Yue-Yi Fang, Yuan-Tao Hao, Ying-Si Lai

Clonorchiasis is one of the most important food-borne trematodiases affecting millions of people. Strategies were recommended by different organizations and control programmes were implemented but mostly in short-time periods. It’s important to assess the long-term benefits and sustainability of possible control strategies on morbidity control of the disease. We developed a multi-group transmission model to describe the dynamics of C. sinensis transmission among different groups of people with different raw-fish-consumption behaviors, based on which, a full model with interventions was proposed and three common control measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental modification) and their possible combinations were considered. Under a typical setting of C. sinensis transmission, we simulated interventions according to different strategies and with a series of values of intervention parameters. We found that combinations of measures were much beneficial than those singly applied; higher coverages of measures had better effects; and strategies targeted on whole population performed better than that on at-risk population with raw-fish-consumption behaviors. The strategy recommended by the government of Guangdong Province, China shows good and sustainable effects, under which, the infection control (with human prevalence <5%) could be achieved within 7.84 years (95% CI: 5.78–12.16 years) in our study setting (with original observed prevalence 33.67%). Several sustainable strategies were provided, which could lead to infection control within 10 years. This study makes the effort to quantitatively assess the long-term effects of possible control strategies against C. sinensis infection under a typical transmission setting, with application of a multi-group dynamic transmission model. The proposed model is easily facilitated with other transmission settings and the simulation outputs provide useful information to support the decision-making of control strategies on clonorchiasis.

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