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1.
J Proteomics ; : 104017, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33160910

RESUMO

Drug resistance and relapse after treatment of visceral leishmaniasis (VL) with the chemotherapeutic drugs has impeded the VL elimination programme especially, in the endemic region of Bihar, India. Currently, Antimonials (Sbv) have been rendered obsolete (Bihar) as frequent treatment failure and relapse in Sbv treated patient's warrants greater vigilance and attention to the limited drugs. A clinical isolate of L.donovani obtained from an Amphotericin B (AmB) relapse patient was evaluated for its susceptibility to AmB and a hyperlipidemic drug Guggul. The evaluation of susceptibility or resistance to any drug still relies on in vitro assay on promastigote and amastigote stages of Leishmania spp. as there are no validated markers which can ascertain drug resistance in Leishmania. The anti-promastigote effect of AmB and Guggul were demonstrated by significant cellular and morphological changes exhibiting apoptosis-mediated cell death. To further illustrate the molecular mechanism of the parasite's response upon exposure to either AmB and Guggul, sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics analysis was performed along with computational data analysis; revealing considerable differences in the proteome profiles which could be regarded as putative markers for resistance or drug targets for development of therapeutic antileishmanials.

2.
Front Cell Infect Microbiol ; 10: 570573, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178626

RESUMO

The design and development of new pharmaceutical formulations for the existing anti-leishmanial is a new strategic alternate to improve efficacy and safety rather than new drug discovery. Herein hybrid solid lipid nanoparticles (SLN) have been engineered to direct the oral delivery of two anti-leishmanial drugs amphotericin B (AmB) and paromomycin (PM). The combinatorial nanocarriers consist of conventional SLN, antileishmanial drugs (AmB and PM) which have been functionalized with chitosan (Cs) grafted onto the external surface. The Cs-SLN have the mean particle size of 373.9 ± 1.41 nm, polydispersity index (PDI) of 0.342 ± 0.02 and the entrapment efficiency for AmB and PM was found to be 95.20 ± 3.19% and 89.45 ± 6.86 %, respectively. Characterization of SLN was performed by scanning electron microscopy and transmission electron microscopy. Complete internalization of the formulation was observed in Caco-2 cells. Cs-SLN has shown a controlled and slow drug release profile over a period of 72 h and was stable at gastrointestinal fluids, confirmed by simulated gastro-intestinal fluids study. Cs coating enhanced the mucoadhesive property of Cs-SLN. The in-vitro anti-leishmanial activity of Cs-SLN (1 µg/ml) has shown a maximum percentage of inhibition (92.35%) on intra-cellular amastigote growth of L. donovani.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33142369

RESUMO

Visceral leishmaniasis (VL) is still a major public health concern in developing countries having the highest outbreak and mortality potential. While the treatment of VL has greatly improved in recent times, the current diagnostic tools are limited for use in the post-elimination setting. Although conventional serological methods of detection are rapid, they can only differentiate between active disease in strict combination with clinical criteria, and thus are not sufficient enough to diagnose relapse patients. Therefore, there is a dire need for a portable, authentic, and reliable assay that does not require large space, specialized instrument facilities, or highly trained laboratory personnel and can be carried out in primary health care settings. Advances in the nanodiagnostic approaches have led to the expansion of new frontiers in the concerned area. The nanosized particles are blessed with an ability to interact one-on-one with the biomolecules because of their unique optical and physicochemical properties and high surface area to volume ratio. Biomolecular detection systems based on nanoparticles (NPs) are cost-effective, rapid, nongel, non-PCR, and nonculture based that provide fast, one-step, and reliable results with acceptable sensitivity and specificity. In this review, we discuss different NPs that are being used for the identification of molecular markers and other biomarkers, such as toxins and antigens associated with leishmaniasis. The most promising diagnostic approaches have been included in the article, and the ability of biomolecular recognition, advantages, and disadvantages have been discussed in detail to showcase the enormous potential of nanodiagnostics in human and veterinary medicine. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Diagnostic Tools > Biosensing.

4.
Front Cell Infect Microbiol ; 10: 595415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240825

RESUMO

Previously we have shown that long term oral treatment of tricyclic-antidepressant-drug, imipramine, against experimental visceral leishmaniasis, results in clearance of organ parasites, regardless of input infection, either with antimony-sensitive (SbS) or antimony-resistant (SbR) Leishmania donovani (LD) clinical isolates. Although continuous imipramine monotherapy for 28 days (5 mg/kg) results in significant clearance of organ parasites in both SbR and SbSLD infected hamsters, the dose for the sterile parasite clearance from visceral organ is comparatively higher (10 mg/kg) and shows signs of toxicity. Hence, to reduce the toxicity, we encapsulated imipramine in squalene-phosphatidylcholine (SP) liposome (Lip-Imi) and tested its efficacy for a short-course treatment (10 days) in the animal model of visceral leishmaniasis. We observed a significant reduction of hepatic toxicity coupled with sterile parasite clearance in case of this short-course treatment of Lip-Imi, which is absent with free Imi treatment. This also correlates with significant increase in serum availability of imipramine in case of Lip-Imi treatment due to sustained release. Clearance of parasite was coupled with the polarization of antileishmanial immune repertoire from Th2 to Th1 after treatment with Lip-Imi in both SbRLD and SbSLD infected mouse models of LD infection. This study showed that imipramine is effective against both SbSLD and SbRLD at a significantly lower dose with reduced time course of treatment without any toxic side effects, when encapsulated in SP-liposome. Thus, the drug has the potential to be repurposed for the treatment of Kala-azar.

5.
Cytokine ; : 155300, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32978033

RESUMO

The protozoan parasite L. donovani resides inside macrophages as amastigotes and inflicts a potentially lethal disease visceral leishmaniasis (VL). Due to absence of a vaccine, chemotherapy with antimonials, amphotericin B, miltefosine or paromomycin remains the only option for treating VL. Prolonged treatment with a single drug resulted in parasite strains resistant to each of these drugs. As immuno-suppression characterizes the disease, we examined whether eliciting immunosuppressive cytokines is a mechanism of manifestation of drug-resistance. We infected BALB/c mice with the clinical isolates of L. donovani- BHU1066 (sensitive), NS2 (antimony-resistant), BHU1064 (miltefosine-resistant), BHU919 (Amphotericin B-resistant) and BHU1020 (paromomycin-resistant)- from the respective drug-unresponsive patients and assessed splenic parasite load and production of pro-inflammatory and anti-inflammatory cytokines. Although the splenic parasite loads in the drug-resistant L. donovani-infected BALB/c mice were higher than that observed in the drug-sensitive parasites-infected mice, the cytokine profiles were not significantly different between these two sets of mice. The drug-resistance in L. donovani results from innate drug modulation but perhaps not from host immune-suppressive cytokines.

6.
PLoS One ; 15(9): e0238840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925980

RESUMO

Diagnosis of visceral leishmaniasis (VL) relies on invasive and risky aspirate procedures, and confirmation of cure after treatment is unreliable. Detection of Leishmania donovani antigens in urine has the potential to provide both a non-invasive diagnostic and a test of cure. We searched for L. donovani antigens in urine of VL patients from India and Sudan to contribute to the development of urine antigen capture immunoassays. VL urine samples were incubated with immobilised anti-L. donovani polyclonal antibodies and captured material was eluted. Sudanese eluted material and concentrated VL urine were analysed by western blot. Immunocaptured and immunoreactive material from Indian and Sudanese urine was submitted to mass spectrometry for protein identification. We identified six L. donovani proteins from VL urine. Named proteins were 40S ribosomal protein S9, kinases, and others were hypothetical. Thirty-three epitope regions were predicted with high specificity in the 6 proteins. Of these, 20 were highly specific to Leishmania spp. and are highly suitable for raising antibodies for the subsequent development of an antigen capture assay. We present all the identified proteins and analysed epitope regions in full so that they may contribute to the development of non-invasive immunoassays for this deadly disease.


Assuntos
Anticorpos Antiprotozoários/urina , Antígenos de Protozoários/urina , Leishmania donovani/imunologia , Leishmaniose Visceral/diagnóstico , Proteínas de Protozoários/urina , Adulto , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/isolamento & purificação , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/isolamento & purificação , Estudos de Casos e Controles , Humanos , Índia/epidemiologia , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/urina , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/isolamento & purificação
7.
Mater Sci Eng C Mater Biol Appl ; 117: 111279, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32919641

RESUMO

Despite the advancement of new anti-leishmanials, amphotericin B (AmB) prevails as one of the most potent agent in the treatment of visceral leishmaniasis (VL), a neglected tropical disease affecting mostly poverty ridden and underdeveloped regions of the globe. Nonetheless, many patients display intolerance to parenteral AmB, notably at higher dosages. Also, conventional AmB presents an apparently poor absorption. Therefore, to improve AmB bioavailability and overcome multiple barriers for oral delivery of AmB, we fabricated a promising vitamin B12-stearic acid (VBS) conjugate coated solid lipid nanoparticles (SLNs) encapsulated with AmB (VBS-AmB-SLNs) by a combination of double emulsion solvent evaporation and thermal sensitive hydrogel techniques. VBS-AmB-SLNs showed a particle size of 306.66 ± 3.35 nm with polydispersity index of 0.335 ± 0.08 while the encapsulation efficiency and drug loading was observed to be 97.99 ± 1.6% and 38.5 ± 5.6% respectively. In vitro drug release showed a biphasic release pattern and chemical stability of AmB was ensured against simulated gastrointestinal fluids. Cellular uptake studies confirmed complete internalization of the formulation. Anti-leishmanial evaluation against intramacrophage amastigotes showed an enhanced efficacy of 94% which was significantly (P < 0.01) higher than conventional AmB without showing any toxic effects on J774A.1 cells. VBS-AmB-SLNs could serve as a potential therapeutic strategy against VL.

8.
Nat Immunol ; 21(10): 1205-1218, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32839608

RESUMO

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.

9.
Clin Infect Dis ; 2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32827255

RESUMO

BACKGROUND: Antimonial drugs have long been the mainstay to treat visceral leishmaniasis. Their use has been discontinued in the Indian subcontinent because of drug resistance, but they are still clinically useful elsewhere. The goal of this study was to find markers of antimony resistance in Leishmania donovani clinical isolates and validate experimentally their role in resistance. METHODS: The genomes of sensitive and antimony resistant clinical isolates were sequenced. The role of a specific gene in contributing to resistance was studied by CRISPR Cas9-mediated gene editing and intracellular drug sensitivity assays. RESULTS: Both gene copy number variations and single nucleotide variants were associated with antimony resistance. A homozygous insertion of two nucleotides was found in the gene coding for the aquaglyceroporin AQP1 in both resistant isolates. Restoring the wildtype AQP1 open reading frame re-sensitized the two independent resistant isolates to antimonials. Alternatively, editing the genome of a sensitive isolate by incorporating the two-nucleotide insertion in its AQP1 gene led to antimony resistant parasites. CONCLUSIONS: Through genomic analysis and CRISPR-Cas9 mediated genome editing we have proven the role of the AQP1 mutations in antimony clinical resistance in L. donovani.

10.
PLoS Negl Trop Dis ; 14(8): e0008363, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790716

RESUMO

Visceral leishmaniasis (VL) remains an important public health issue worldwide causing substantial morbidity and mortality. The Indian subcontinent accounted for up to 90% of the global VL burden in the past but made significant progress during recent years and is now moving towards elimination. However, to achieve and sustain elimination of VL, knowledge gaps on infection reservoirs and transmission need to be addressed urgently. Xenodiagnosis is the most direct way for testing the infectiousness of hosts to the vectors and can be used to investigate the dynamics and epidemiology of Leishmania donovani transmission. There are, however, several logistic and ethical issues with xenodiagnosis that need to be addressed before its application on human subjects. In the current Review, we discuss the critical knowledge gaps in VL transmission and the role of xenodiagnosis in disease transmission dynamics along with its technical challenges. Establishment of state of the art xenodiagnosis facilities is essential for the generation of much needed evidence in the VL elimination initiative.


Assuntos
Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/transmissão , Phlebotomus/parasitologia , Xenodiagnóstico , Animais , Ásia , Doenças Assintomáticas , Reservatórios de Doenças/parasitologia , Humanos , Leishmania donovani/fisiologia
11.
Front Chem ; 8: 510, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719770

RESUMO

Visceral leishmaniasis (VL) has been a major health concern in the developing world, primarily affecting impoverished people. It is caused by a protozoan parasite Leishmania donovani and is characterized by immune dysfunction that can lead to deadly secondary infections. Several adverse side effects limit the existing treatment options; hence, the need of the hour is some drug option with high efficacy and no toxicity. To make targeted delivery of Amphotericin B (AmB), we have used amine-functionalized versions of carbon nanostructures, namely f-CNT and f-Graphene (f-Grap). The results with f-Grap-AmB, because of a much larger surface area, were expected to be better. However, the results obtained by us showed only marginal improvement (IC50 f-Grap-AmB; 0.0038 ± 0.00119 µg/mL). This is, in all likelihood, due to the agglomeration effect of f-Grap-AmB, which is invariably obtained with graphene. To resolve this issue, we have synthesized a graphene-CNT composite (graphene 70% and CNT 30% by weight). Because CNT is dispersed in between graphene sheets, the agglomeration effect is avoided, and our study suggests that the f-Composite-AmB (f-Comp-AmB) showed no toxicity against the murine J774A.1 macrophage cell line and did not induce any hepatic or renal toxicity in Swiss albino mice. The f-Comp-AmB also showed a remarkable elevation in the in vitro and in vivo antileishmanial efficacy in comparison to AmB and f-CNT-AmB or f-Grap-AmB in J774A.1 and Golden Syrian hamsters, respectively. Additionally, we have also observed that the percentage suppression of parasite replication in the spleen of the hamster was significantly higher in the f-Comp-AmB (97.79 ± 0.2375) treated group in comparison with the AmB (85.66 ± 1.164) treated group of hamsters. To conclude, f-Comp-AmB could be a safe and reliable therapeutic option over the other carbon-based nanoparticles (NPs), i.e., f-CNT-AmB, f-Grap-AmB, and conventional AmB.

12.
J Infect Dis ; 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32614452

RESUMO

Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γ and tumour necrosis factor in response to soluble leishmanial antigen (SLA) in whole blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL10), a cytokine implicated in VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 in a single network with TNF as hub. SLA plus anti-IL10 produced 454 DEGs, 292 in a single network with TNF, IFNG, NFKBIA, IL6 and IL1B as hubs in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular effect of IL10 as a potent immune modulator in VL.

13.
PLoS Negl Trop Dis ; 14(7): e0008221, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614818

RESUMO

Leishmaniasis remains a public health concern around the world that primarily affects poor folks of the developing world spanning across 98 countries with mortality of 0.2 million to 0.4 million annually. Post kala-azar dermal leishmaniasis (PKDL) is the late skin manifestation of visceral leishmaniasis (VL). It has been reported that about 2.5% to 20% of patients recovered from VL develop PKDL having stilted macular or nodular lesions with parasites. In the Indian subcontinent (ISC), it manifests a few months after recovery from VL, though in Africa it can occur simultaneously with VL or a little later. New cases of PKDL are also observed without prior VL in the ISC. These individuals with PKDL represent an important but largely neglected reservoir of infection that perpetuates anthroponotic Leishmania donovani transmission in the ISC and can jeopardize the VL elimination program as these cases can infect the sand flies and spread the endemic. Therefore, it becomes imperative to eradicate PKDL as a part of the VL elimination program. With the limited treatment options besides little knowledge on PKDL, this review stands out in focusing on different aspects that should be dealt for sustained VL elimination.


Assuntos
Leishmaniose Cutânea/etiologia , Leishmaniose Visceral/complicações , Gluconato de Antimônio e Sódio/efeitos adversos , Biomarcadores , Predisposição Genética para Doença , Humanos , Memória Imunológica , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/prevenção & controle , Leishmaniose Visceral/tratamento farmacológico
14.
Chem Phys Lipids ; 231: 104946, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32621810

RESUMO

In the current study, we have focused on the design, development and in-vitro evaluation of d-α-tocopheryl polyethylene glycol 1000 succinate modified amphotericin B (AmB) and paromomycin (PM) loaded solid lipid nanoparticles (TPGS-SLNPs) by emulsion-solvent evaporation method. The optimized TPGS-SLNPs had a mean particle size of 199.4 ± 18.9 nm with a polydispersity index of 0.22 ± 0.14 and entrapment efficiency for AmB and PM was found to be 94 ± 1.5 % and 89 ± 0.50 % respectively. The prepared lipid nanoparticles were characterized by Powdered X-ray diffraction study, Fourier transform infrared spectroscopy, Nuclear magnetic resonance spectroscopy to confirm the absence of any interaction between lipids and drugs. The developed formulation showed a sustained drug release over a period of 48 h and were stable at different temperatures. Finally, TPGS-SLNPs (1 µg/mL) was found to significantly (P < 0.001) mitigate the intra-cellular amastigote growth compared to free AmB. The results obtained suggest TPGS-SLNPs could be an efficient carrier for delivering poorly water-soluble drugs and efficiently enhance its therapeutic potential.

15.
Sci Rep ; 10(1): 12243, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699361

RESUMO

The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of 2-hydroxypropyl-ß-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of L. donovani. m-DDSLNs (20 mg/kg × 5 days, p.o.) has significantly (P < 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days, p.o.) in L. donovani-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs.


Assuntos
Anfotericina B/química , Anfotericina B/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Nanopartículas/química , Paromomicina/química , Paromomicina/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular , Emulsões/química , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão/métodos , Tamanho da Partícula , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacologia
16.
J Proteomics ; 223: 103800, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32380292

RESUMO

The present study provides comprehensive proteomics analyses of the response of L. donovani parasite to pharamacological stress in vitro. Identification of differentially expressed proteins with associated molecular functions and metabolic pathways, clearly provides an insight into the potential mechanism of the antileishmanial effects as well as a comparative response of the parasite to Guggul and AmB. Treatment of parasite with AmB results in an enhanced modulatory mechanism to counteract the drug induced stress which may have contributed to relapse. In the case of Guggul treatment, an effective antipromastigote activity was observed, which is being reported for the first time. Thus, a deeper understanding of the molecular pathways in the Leishmania parasite in response to pharmacological stress would help in designing novel and effective strategies in targeting the key molecules essential for parasite survival. It will also help in screening of new lead molecules targeting these vital pathways which could be used as an adjunct therapy along with the limited repertoire of antileishmanial drugs.

17.
EMBO Mol Med ; 12(3): e11011, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32031337

RESUMO

HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles-mediated export of miRNAs, ensures robust derepression of miRNA-repressed cytokines essential for strong pro-inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti-inflammatory response essential for the survival of the parasite. We have found that during Leishmania infection, the pathogen targets HuR to promote onset of anti-inflammatory response in mammalian macrophages. In infected macrophages, Leishmania also upregulate protein phosphatase 2A that acts on Ago2 protein to keep it in dephosphorylated and miRNA-associated form. This causes robust repression of the miRNA-targeted pro-inflammatory cytokines to establish an anti-inflammatory response in infected macrophages. HuR has an inhibitory effect on protein phosphatase 2A expression, and mathematical modelling of macrophage activation process supports antagonistic miRNA-modulatory roles of HuR and protein phosphatase 2A which mutually balances immune response in macrophage by targeting miRNA function. Supporting this model, ectopic expression of the protein HuR and simultaneous inhibition of protein phosphatase 2A induce strong pro-inflammatory response in the host macrophage to prevent the virulent antimonial drug-sensitive or drug-resistant form of L. donovani infection. Thus, HuR can act as a balancing factor of immune responses to curtail the macrophage infection process by the protozoan parasite.

18.
Cell Rep ; 30(8): 2512-2525.e9, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101732

RESUMO

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.

19.
PLoS Negl Trop Dis ; 14(1): e0007995, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995564

RESUMO

BACKGROUND: Bangladesh, India, and Nepal aim for the elimination of Visceral Leishmaniasis (VL), a systemic parasitic infectious disease, as a public health problem by 2020. For decades, male patients have comprised the majority of reported VL cases in this region. By comparing this reported VL sex ratio to the one observed in population-based studies conducted in the Indian subcontinent, we tested the working hypothesis that mainly socio-cultural gender differences in healthcare-seeking behavior explain this gender imbalance. METHODOLOGY/PRINCIPAL FINDINGS: We compared the observed sex ratio of male versus female among all VL cases reported by the health system in Nepal and in the two most endemic states in India with that observed in population-based cohort studies in India and Nepal. Also, we assessed male sex as a potential risk factor for seroprevalence at baseline, seroconversion, and VL incidence in the same population-based data. The male/female ratio among VL cases reported by the health systems was 1.40 (95% CI 1.37-1.43). In the population cohort data, the age- and study site-adjusted male to female risk ratio was 1.27 (95% CI 1.08-1.51). Also, males had a 19% higher chance of being seropositive at baseline in the population surveys (RR 1.19; 95% CI 1.11-1.27), while we observed no significant difference in seroconversion rate between both sexes at the DAT cut-off titer defined as the primary endpoint. CONCLUSIONS/SIGNIFICANCE: Our population-based data show that male sex is a risk factor for VL, and not only as a socio-cultural determinant. Biological sex-related differences likely play an important role in the pathogenesis of this disease.


Assuntos
Notificação de Doenças/estatística & dados numéricos , Leishmaniose Visceral/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Instalações de Saúde , Humanos , Incidência , Lactente , Leishmaniose Visceral/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Razão de Masculinidade , Adulto Jovem
20.
ACS Infect Dis ; 6(1): 3-13, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31808676

RESUMO

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

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