Molecular crosstalks in<i>Leishmania</i>-sandfly-host relationships

Volf, Petr; Hostomská, Jitka; Rohoušová, Iva

doi:10.1051/parasite/2008153237

Cited by 26 publications

(20 citation statements)

References 64 publications

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“…Rapida men te os promas tigotas diferenciam-se em amastigotas e multi pli cam-se no inte rior destes vacúolos, até que o macrófago se rompe, liberando amastigotas no tecido, sendo novamente fagocitadas, ini ci ando no local um novo ciclo intracelular e causando, assim, as leishmanioses. 16 …”

Section: A Leishmaniaunclassified

Proteases de Leishmania: novos alvos para o desenvolvimento racional de fármacos

Silva-López¹

2010

Quím. Nova

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Recebido em 7/6/09; aceito em 22/3/10; publicado na web em 29/6/10 Leishmania PROTEASES: NEW TARGETS FOR RATIONAL DRUG DEVELOPMENT. Leishmania causes tegumental and visceral diseases called leishmaniasis. Disease control is possible interrupting the transmission cycle, but HIV co-infection, chemotheraphy toxicity and lack of a vaccine are paramount difficulties. So, is necessary to study new Leishmania molecules and investigate the possibility to develop rational drugs using these molecules as targets. Leishmania express many peptidases during their life, and cysteine are the most abundant protease and many inhibitors were developed but failed to kill parasites. On the other hand, inhibitors of serine proteases killed promastigotes, indicating the possibility of these enzymes to be important targets in the development of anti-Leishmania drugs.Keywords: proteases; Leishmania; chemotheraphy. INTRODUÇÃOProtozoários do gênero Leishmania são responsáveis por um amplo espectro de doenças tropicais e subtropicais do homem e de outros animais nas regiões quentes do Velho e do Novo Mundo. As leishmanioses são endêmicas em 88 países com estimativa de 12 milhões de casos no mundo.1 Em teoria, seu controle é possível pela interrupção do ciclo de transmissão da Leishmania. A utilização de inseticidas, a proteção individual, a eliminação de animais domésticos infectados, a detecção e o tratamento precoce de casos humanos representam algumas das estratégias usadas para prevenir a transmissão. Entretanto, as dificuldades no controle se devem à grande diversida de biológi ca dos parasitos; à existência de muitas espécies de vetores e de mamíferos que po dem atuar como fontes de infecção; aos fatores sócio-econômicos das populações afetadas; às diferentes formas clíni cas da doença, incluindo aquelas formas graves e resistentes à quimioterapia; medicamentos de alto custo e com grande toxicidade para o hospedeiro e, ainda, à inexistência de uma vacina eficaz.2 As investiga ções sobre controle e tratamento das leishmanioses devem ser metas prioritárias na saúde pública, pois tem sido observado o aumento do número de casos da doença, a disseminação do parasito em bancos de sangue e sua coinfecção em pacientes com HIV.3 Logo, é necessário que sejam identificadas novas moléculas na Leishmania para melhor compreender sua interação com os hospedeiros, e investigar a possibilidade do emprego destas moléculas como alvos para o desenvolvimento racional de fármacos. As proteases de parasitos têm sido bastante estudadas, pois participam da invasão ao hospedeiro, da assimilação dos ami no ácidos como fonte nutricional ou para síntese de substâncias orgânicas, no metabolismo de proteínas ou peptídeos biologicamente ativos, na dife ren ciação e no escape ao sistema imune do hospedeiro, ou ainda, na resistência do parasito à terapia medicamentosa. 4 ENZIMAS PROTEOLÍTICASTradicionalmente as proteases ou peptidases são enzimas que catalisam a hidrólise de ligações peptídicas em proteínas ou peptídeos, liberando peptídeos de tamanho variável ou ami...

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Section: A Leishmaniaunclassified

Proteases de Leishmania: novos alvos para o desenvolvimento racional de fármacos

Silva-López¹

2010

Quím. Nova

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“…However, all species have a similar life cycle involving a motile, flagellated stage in the midgut of vector (promastigote) and an intracellular non-motile stage (amastigote) in host macrophages. 4 Macrophages are the most important effector cells in Leishmania infection, and their appropriate activation is required to eliminate the parasite. The destruction of the parasite by macrophages depends on the production of nitric oxide (NO), tumor necrosis factor (TNF), interleukin (IL)-1 among other mediators, and is negatively affected by a variety of factors including IL-10.…”

Section: Introductionmentioning

confidence: 99%

Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles

et al. 2016

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Influence of various structural patterns in a series of novel bi- and tricyclic N-heterocycles on the activity against Leishmania major and Leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. Both quinolines and tetrahydrooxazinoindoles (TOI) proved to have significant antileishmanial activities, while substituted indoles were inactive. We have also showed that a chloroquine analogue induces Leishmania killing by modulating macrophage activation.

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“…While feeding on an infected host, phlebotomine females ingest the amastigote form of the parasite, which, differentiates into the flagellated promastigotes in the sand fly gut lumen. Different forms of the promastigote appear during parasite development inside the gut lumen culminating with the appearance of the metacyclic promastigote, the form that infects the vertebrate host [1]–[3].…”

Section: Introductionmentioning

confidence: 99%

Host Modulation by a Parasite: How Leishmania infantum Modifies the Intestinal Environment of Lutzomyia longipalpis to Favor Its Development

et al. 2014

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Some reports have described the interference of Leishmania on sand flies physiology, and such behavior most likely evolved to favor the development and transmission of the parasite. Most of these studies showed that Leishmania could modulate the level of proteases in the midgut after an infective blood meal, and decreased proteolytic activity is indeed beneficial for the development of promastigotes in the gut of sand flies. In the present study, we performed a detailed investigation of the intestinal pH in Lutzomyia longipalpis females naturally infected with Leishmania infantum and investigated the production of trypsin by these insects using different approaches. Our results allowed us to propose a mechanism by which these parasites interfere with the physiology of L. longipalpis to decrease the production of proteolytic enzymes. According to our hypothesis L. infantum promastigotes indirectly interfere with the production of trypsin by modulating the mechanism that controls the intestinal pH via the action of a yet non-identified substance released by promastigote forms inside the midgut. This substance is not an acid, whose action would be restrict on to release H+ to the medium, but is a substance that is able to interfere with midgut physiology through a mechanism involving pH control. According to our hypothesis, as the pH decreases, the proteolytic enzymes efficiency is also reduced, leading to a decline in the supply of amino acids to the enterocytes: this decline reduces the stimulus for protease production because it is regulated by the supply of amino acids, thus leading to a delay in digestion.

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Molecular crosstalks inLeishmania-sandfly-host relationships

Cited by 26 publications

References 64 publications

Proteases de Leishmania: novos alvos para o desenvolvimento racional de fármacos

Proteases de Leishmania: novos alvos para o desenvolvimento racional de fármacos

Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles

Host Modulation by a Parasite: How Leishmania infantum Modifies the Intestinal Environment of Lutzomyia longipalpis to Favor Its Development

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