phenanthrenes and Leishmaniasis--Cutaneous

Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome-scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both Leishmania major targets (e.g. in silico gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.. This metabolic network-driven approach identified 15 L. major genes as high-priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high-throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated in vitro against L. major promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated in vitro against L. major and four combinations involving the drug disulfiram that showed superadditivity are presented.. A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority L. major targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis.

Topics: Antimalarials; Drug Delivery Systems; Humans; Leishmania major; Leishmaniasis, Cutaneous; Metabolic Networks and Pathways; Neglected Diseases; Phenanthrenes; United States; United States Food and Drug Administration

The macrophage-expressed CD40 regulates immune responses to Leishmania major infection by reciprocal signaling through p38 MAPK and ERK1/2. CD40-induced IL-10 or IL-12 plays crucial roles in the promotion or protection from L. major infection, respectively. Because p38 MAPK and ERK1/2 are dephosphorylated by dual-specificity MAPK phosphatases (MKPs), we tested the role of CD40 in the regulation of MKPs in L. major infection. MKP-1 expression and activity increased whereas MKP-3 expression and activity decreased in virulent L. major-infected macrophages. CD40 differentially regulated the expression and activity of MKP-1 and MKP-3, which, in turn, reciprocally regulated CD40-induced p38 MAPK and ERK1/2 phosphorylation and effector functions in macrophages. Triptolide, an inhibitor of MKP-1 expression, and lentivirally expressed MKP-1 short hairpin RNA enhanced CD40-induced anti-leishmanial functions and significantly protected susceptible BALB/c mice from L. major infection. Similarly, lentivirally overexpressed MKP-3 significantly reduced disease progression and parasite burden in susceptible BALB/c mice. Thus, to our knowledge, our data show for the first time that CD40 reciprocally regulates MKP-1 and MKP-3 expression and activity while the MKPs contribute to the reciprocal CD40 signaling-regulated anti-leishmanial functions. The findings reveal a novel parasite-devised immune evasion strategy and an effective target to redirect CD40-regulated immune responses.

Topics: Animals; CD40 Antigens; Diterpenes; Dual Specificity Phosphatase 1; Dual Specificity Phosphatase 6; Epoxy Compounds; Immune Evasion; Interleukin-10; Interleukin-12; Leishmania major; Leishmaniasis, Cutaneous; Macrophages; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Phosphorylation; Polymerase Chain Reaction; RNA, Small Interfering

Over a 5 month period (October 1996 to February 1997), a rotating company of 146 servicemen belonging to the Navy Airborne 6th Regiment were assigned along the Maroni River in French Guyana. During this mission, the medical personnel treated 387 local residents. Etiologies comprised 51 malaria attacks including 46 involving Plasmodium falciparum and 4 rattlesnake envenomations. The most common cause of consultation by military personnel was mycotic and staphylococcal skin infections, but 5 cases involving poor acclimatization were treated during the hot and dry season. Seven malaria attacks involving Plasmodium falciparum including 2 that were severe occurred despite prophylaxis using chloroquine-proguanil. Treatment with halofantrine was successful in all but one case which required combined chemotherapy using quinine and doxycycline. Five cases of cutaneous leishmaniasis were observed in subjects involved in jungle training. No case of HIV infection was detected upon returning home since most personnel either followed the recommendation to abstain from sex (51 p. 100) or used a condom (90 p. 100 of personnel who had sexual relations). These data illustrate the health risks for mainland French nationals in the region of the Maroni River and underline the need for preventive measures and education.

Topics: Acclimatization; Animals; Anti-Bacterial Agents; Antimalarials; Chloroquine; Condoms; Crotalid Venoms; Crotalus; Dermatomycoses; Doxycycline; France; French Guiana; Health Education; HIV Infections; Humans; Leishmaniasis, Cutaneous; Malaria, Falciparum; Military Personnel; Phenanthrenes; Quinine; Risk Factors; Sexual Abstinence; Snake Bites; Staphylococcal Skin Infections; Tropical Medicine