Bioluminescent Imaging Identifies Thymus, As Overlooked Colonized Organ, in a Chronic Model of <i>Leishmania donovani</i> Mouse Visceral Leishmaniasis

Domínguez-Asenjo, Bárbara; Gutiérrez-Corbo, Camino; Pérez-Pertejo, Yolanda; Iborra, Salvador; Balaña‐Fouce, Rafael; Reguera, Rosa M.

doi:10.1021/acsinfecdis.0c00864

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…At 8 weeks post infection, when the chronic phase of the infection is established, groups of 5 mice were administered intraperitoneally with Salinomycin (SAL) (MedChemTronica) in 25% of DMSO at 5 mg/kg body weight (bw); paclitaxel (PXT) (Teva) in 0.154 M NaCl at 22.5 mg/kg bw or docetaxel (DXT) (Taxotere, Sanofi) in 0.9% NaCl at 6 mg/kg bw once a day for 10 days. − Nifuratel (NFT) (MedChemTronica), diluted in 0.75% carboxymethyl cellulose (Sigma-Aldrich), was administered by oral gavage at 50 mg/kg bw once or twice a day for 10 days . Oral miltefosine (Sigma-Aldrich) at 40 mg/kg bw once a day for 5 days, was used as control.…”

Section: Methodsmentioning

confidence: 99%

Ex Vivo Phenotypic Screening of Two Small Repurposing Drug Collections Identifies Nifuratel as a Potential New Treatment against Visceral and Cutaneous Leishmaniasis

et al. 2021

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Leishmaniases are vector-borne neglected diseases caused by single-celled parasites. The search for new antileishmanial drugs has experienced a strong boost thanks to the application of bioimaging to phenotypic screenings based on intracellular amastigotes. Mouse splenic explants infected with fluorescent strains of Leishmania are proven tools of drug discovery, where hits can be easily transferred to preclinical in vivo models. We have developed a two-staged platform for antileishmanial drugs. First, we screened two commercial collections of repurposing drugs with a total of 1769 compounds in ex vivo mouse splenocytes infected with an infrared emitting Leishmania infantum strain. The most active and safest compounds were scaled-up to in vivo models of chronic Leishmania donovani visceral leishmaniasis and Leishmania major cutaneous leishmaniasis. From the total of 1769 compounds, 12 hits with selective indices >35 were identified, and 4 of them were tested in vivo in a model of L. donovani visceral leishmaniasis. Nifuratel, a repurposed synthetic nitrofuran, when administered orally at 50 mg/kg bw once or twice a day for 10 days, caused >80% reduction in the parasitic load. Furthermore, the intralesional administration of nifuratel in a model of cutaneous leishmaniasis by L. major produced the parasitological cure. From the previous results we have deduced the great capacity of mouse splenic explants to identify new hits, a model which could be easily transferred to in vivo models, as well as the potential use of nifuratel as an alternative to the current treatment of cutaneous leishmaniasis.

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Section: Methodsmentioning

confidence: 99%

Ex Vivo Phenotypic Screening of Two Small Repurposing Drug Collections Identifies Nifuratel as a Potential New Treatment against Visceral and Cutaneous Leishmaniasis

et al. 2021

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“…With the introduction of bioluminescent mouse models of visceral leishmaniasis, it has become easier to track infection; this could potentially be used longitudinally to track the location of parasites as the disease develops. For example, in a recent study 46 it was reported that the thymus, a lymphatic organ, seems to be infected from the beginning until the late phases of the infection.…”

Section: Improved Understanding Of Parasite Biologymentioning

confidence: 99%

Anti-trypanosomatid drug discovery: progress and challenges

et al. 2022

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Leishmaniasis (visceral and cutaneous), Chagas disease and human African trypanosomiasis cause substantial death and morbidity, particularly in low- and middle-income countries. Although the situation has improved for human African trypanosomiasis, there remains an urgent need for new medicines to treat leishmaniasis and Chagas disease; the clinical development pipeline is particularly sparse for Chagas disease. In this Review, we describe recent advances in our understanding of the biology of the causative pathogens, particularly from the drug discovery perspective, and we explore the progress that has been made in the development of new drug candidates and the identification of promising molecular targets. We also explore the challenges in developing new clinical candidates and discuss potential solutions to overcome such hurdles.

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“…Interestingly, it was possible to observe many more intact amastigotes in the undernourished animals than in the well-nourished ones ( 70 ). Recent reports have confirmed, using bioluminescence, the presence of the parasite in the thymus of well-nourished BALB/c mice infected with L. donovani ( 71 ). These observations demonstrate that the thymus is a target organ during infection by viscerotropic species of Leishmania , including L. infantum and L. donovani .…”

Section: Undernutrition Yields a Further Negative Impact Of Acute Inf...mentioning

confidence: 78%

Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

et al. 2022

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Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus—a primary lymphoid organ responsible for the generation of T lymphocytes—is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected with Leishmania infantum (that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection.

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Bioluminescent Imaging Identifies Thymus, As Overlooked Colonized Organ, in a Chronic Model of Leishmania donovani Mouse Visceral Leishmaniasis

Cited by 10 publications

References 45 publications

Ex Vivo Phenotypic Screening of Two Small Repurposing Drug Collections Identifies Nifuratel as a Potential New Treatment against Visceral and Cutaneous Leishmaniasis

Ex Vivo Phenotypic Screening of Two Small Repurposing Drug Collections Identifies Nifuratel as a Potential New Treatment against Visceral and Cutaneous Leishmaniasis

Anti-trypanosomatid drug discovery: progress and challenges

Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

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