Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice

Bhattacharya, Pinaki; Dey, Ranadhir; Dagur, Pradeep K.; Kruhlak, Michael J.; Ismail, Nevien; Debrabant, Alain; Joshi, Amritanshu B.; Akue, Adovi; KuKuruga, Mark; Takeda, Kazuyo; Selvapandiyan, Angamuthu; McCoy, J. Philip; Nakhasi, Hira L.

doi:10.1128/iai.00184-15

Cited by 60 publications

(64 citation statements)

References 72 publications

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“…Previous investigation shown that the proinflammatory cytokines like IL-12 and IFN-γ were upregulated upon in vitro infection of macrophages with live attenuated L . donovani parasites compared to that with wildtype [WT] parasites [ 26 ]. It is now well established that in leishmaniasis protective immunity is achieved when Th1 response, characterized by increased levels of IFN-γ and IL-12, dominates over Th2 response [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…donovani promastigote cell lines. Four weeks post infection, mice were sacrificed and the parasite burden in spleen was quantified and expressed as Leishman-Donovan units (LDU) using the formula: LDU = [(number of parasites/1000 host nuclei) x organ (spleen) weight in milligrams (mg) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…ASS was down regulated in the L . donovani amastigote stage when cell division is disrupted in centrin null mutant cell lines, which suggests that the increased expression of ASS in amastigotes is required to maintain virulence [ 26 , 27 ]. An earlier investigation in L .…”

Section: Introductionmentioning

confidence: 99%

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Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management

et al. 2016

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Reactive oxygen and nitrogen species (ROS and RNS) produced by the phagocytic cells are the most common arsenals used to kill the intracellular pathogens. However, Leishmania, an intracellular pathogen, has evolved mechanisms to survive by counterbalancing the toxic oxygen metabolites produced during infection. Polyamines, the major contributor in this anti-oxidant machinery, are largely dependent on the availability of L-arginine in the intracellular milieu. Argininosuccinate synthase (ASS) plays an important role as the rate-limiting step required for converting L-citrulline to argininosuccinate to provide arginine for an assortment of metabolic processes. Leishmania produce an active ASS enzyme, yet it has an incomplete urea cycle as it lacks an argininosuccinate lyase (ASL). There is no evidence for endogenous synthesis of L-arginine in Leishmania, which suggests that these parasites salvage L-arginine from extracellular milieu and makes the biological function of ASS and the production of argininosuccinate in Leishmania unclear. Our previous quantitative proteomic analysis of Leishmania promastigotes treated with sub-lethal doses of ROS, RNS, or a combination of both, led to the identification of several differentially expressed proteins which included ASS. To assess the involvement of ASS in stress management, a mutant cell line with greatly reduced ASS activity was created by a double-targeted gene replacement strategy in L. donovani promastigote. Interestingly, LdASS is encoded by three copies of allele, but Western blot analysis showed the third allele did not appear to express ASS. The free thiol levels in the mutant LdASS-/-/+ cell line were decreased. Furthermore, the cell viability in L-arginine depleted medium was greatly attenuated on exposure to different stress environments and was adversely impacted in its ability to infect mice. These findings suggest that ASS is important for Leishmania donovani to counterbalance the stressed environments encountered during infection and can be targeted for chemotherapeutic purpose to treat visceral leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management

et al. 2016

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“…tion(Rodríguez-Cortés et al, 2016). The authors believe that there are evidences suggesting that the innate immune system could have a relevant role by promoting the appropriate inflammatory response against the development of the disease(Bhattacharya et al, 2015). The authors found that dogs which had the disease had lower vitamin D levels than non-infected and asymptomatic animals.…”

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Vitamin D metabolism in dogs and cats and its relation to diseases not associated with bone metabolism

Zafalon

Risolia

Pedrinelli

et al. 2019

Animal Physiology Nutrition

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Due to the presence of receptors in the cells of numerous body tissues, vitamin D is associated with several physiological functions that go beyond calcium and phosphorus homoeostasis and control of bone metabolism in the body. In humans, several studies have associated lower vitamin D concentrations with numerous diseases, such as cancer, heart disease, autoimmune diseases and infectious diseases, and also with an increase in the total mortality rate of the population. Recently, this nutrient started to gain importance in veterinary medicine, and several articles have shown a correlation between low vitamin D status and diseases unrelated to bone metabolism. The present review aims to highlight the recent publications that investigated this relationship, bringing the evidence that exists so far in dogs and cats. K E Y W O R D S1,25(OH)2D, 25(OH)D, calcidiol, calcitriol, cholecalciferol, hypovitaminosis D

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“…O estudo desenvolvido porTEWARY et al, (2006) mostrou que a nistatina é capaz de inibir a ligação e entrada de L. donovani em macrófagos da linhagem J774. Além disso, verificou-se que a nistatina tem capacidade de aumentar os níveis de TNF-αem camundongos(SEMIS et al, 2012) que é uma importante citocina responsável por ativar macrófagos a um estado leishmanicida(BHATTACHARYA et al, 2015). As estruturas químicas desses fármacos podem ser observadas na Figura 9 abaixo.…”

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Avaliação do potencial leishmanicida de fármacos que atuam na rota bioquímica de esteróis

Yamamoto¹

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Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice

Cited by 60 publications

References 72 publications

Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management

Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management

Vitamin D metabolism in dogs and cats and its relation to diseases not associated with bone metabolism

Avaliação do potencial leishmanicida de fármacos que atuam na rota bioquímica de esteróis

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