title: Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis.
abstract: This study aimed to evaluate the immuno-prophylactic and -therapeutic effect of p110δ-specific pharmacological inhibitors (CAL-101 and IC87114), either alone or in combination with amphotericin B, against experimental cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL).
  
  
  
  Female BALB/c mice were infected intravenously with Leishmania donovani or subcutaneously with Leishmania major Prophylactic treatment was initiated 24 h prior to infection, whereas therapeutic treatments with or without amphotericin B were initiated either 1 week or 2 weeks post-infection. At different times post-infection, mice were sacrificed and parasite burden, regulatory T cell (Treg) numbers and cytokine production were assessed in the liver, spleen, draining lymph nodes and footpads. In addition, direct cytolytic effects of the inhibitors on parasite growth in axenic cultures and inside infected and uninfected macrophages were also assessed.
  
  
  
  Prophylactic and therapeutic administration of p110δ pharmacological inhibitors significantly reduced cutaneous lesion (in CL) and parasite burdens (in VL and CL) in the spleens, livers and footpads of infected mice. The reduction in parasite burden was associated with a concomitant reduction in Treg numbers and cytokine production by liver, spleen and lymph node cells. Combined low-dose CAL-101 and amphotericin B therapy caused complete clearance of parasites in mice infected with L. donovani CONCLUSIONS: Our studies clearly show a novel therapeutic option for leishmaniasis based on CAL-101 monotherapy or CAL-101 and amphotericin B combination therapy. These observations have important and direct implications for antimicrobial immunotherapy and drug/vaccine development against leishmaniasis.
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Forough
authors.initials: F
authors.lastname: Khadem
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Mou
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Aida
authors.initials: A
authors.lastname: Feiz Barazandeh
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Medical Microbiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Keynan
authors.affiliation: Department of Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada jude.uzonna@umanitoba.ca.|Department of Medical Microbiology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jude E
authors.initials: JE
authors.lastname: Uzonna
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D018791:CD4 Lymphocyte Count; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis; D004359:Drug Therapy, Combination; D005260:Female; D056747:Immunomodulation / Q000187:drug effects; D007893:Leishmania donovani / Q000187:drug effects* / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; C477872:IC 87114; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D011799:Quinazolines; D052999:Quinazolinones; D000666:Amphotericin B; D058534:Class I Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; D000225:Adenine; C552946:idelalisib