Leishmania are obligate intracellular parasites that cause a wide range of diseases such as cutaneous, mucocutaneous and visceral leishmaniasis. Over 12 million people currently suffer from these diseases and approximately 2 million are infected annually. Cutaneous leishmaniasis (CL) manifests as localized skin lesions which may heal or lead to significant tissue destruction and disfigurement. There is a clear need for a topical treatment against CL because current therapy involves daily injections of antimonials (GlucantimeTM or PentostamTM) for prolonged periods, which are toxic and have poor patient compliance. In the Yucatan Peninsula, Mayan traditional healers use Pentalinon andrieuxii root for topical treatment of CL, which suggests that P. andrieuxii has a potential for use as a topical agent for the treatment of leishmaniasis. We have found that Pentalinon andrieuxii root hexane extract (PARHE) exhibits potent antileishmanial activity. Our published data indicate that PARHE kills Leishmania in vitro as efficiently as GlucantimeTM. In addition, our new preliminary data suggest that PARHE is effective in restricting parasite growth in the infected skin during L. mexicana infection. PARHE also increases leishmanicidal activity in macrophages and is not toxic to mammalian cells. This project will seek to evaluate the efficacy of PARHE as a topical agent to treat CL using mouse models (Aim 1) and to determine the chemical composition of PARHE for the future development of quality control procedures for the bioactive compound(s) (Aim 2). We hypothesize that PARHE will be an effective topical agent in the treatment of both Old world and New world cutaneous leishmaniasis. Our team is uniquely poised to perform these studies due to the complementary expertise in leishmaniasis (Satoskar), and phytochemistry and natural products development (Kinghorn). The data generated from this project will lay the foundations for a later R01 application focused on a more comprehensive study of PARHE and its active components in local or systemic treatment of the different forms of leishmaniasis, and for determining mechanisms of action of the antileishmanial molecules isolated from PARHE. Our studies are important because they will determine if a local application of PARHE prevents lesion development and/or promotes the cure of CL as well as identify bioactive molecules in PARHE which are important for future clinical applications.
The overall goal of this project is to develop a natural product as a potential topical agent to treat cutaneous leishmaniasis.
|Oghumu, Steve; Terrazas, Cesar A; Varikuti, Sanjay et al. (2015) CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15. FASEB J 29:1019-28|
|Oghumu, Steve; Stock, James C; Varikuti, Sanjay et al. (2015) Transgenic expression of CXCR3 on T cells enhances susceptibility to cutaneous Leishmania major infection by inhibiting monocyte maturation and promoting a Th2 response. Infect Immun 83:67-76|
|Tuladhar, Rashmi; Oghumu, Steve; Dong, Ran et al. (2015) Ox40L-Ox40 pathway plays distinct roles in regulating Th2 responses but does not determine outcome of cutaneous leishmaniasis caused by Leishmania mexicana and Leishmania major. Exp Parasitol 148:49-55|
|Oghumu, Steve; Gupta, Gaurav; Snider, Heidi M et al. (2014) STAT4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis. Eur J Immunol 44:450-9|
|Lezama-Davila, Claudio M; Pan, Li; Isaac-Marquez, Angelica P et al. (2014) Pentalinon andrieuxii root extract is effective in the topical treatment of cutaneous leishmaniasis caused by Leishmania mexicana. Phytother Res 28:909-16|
|Walker, Dawn M; Oghumu, Steve; Gupta, Gaurav et al. (2014) Mechanisms of cellular invasion by intracellular parasites. Cell Mol Life Sci 71:1245-63|
|Gupta, Gaurav; Oghumu, Steve; Satoskar, Abhay R (2013) Mechanisms of immune evasion in leishmaniasis. Adv Appl Microbiol 82:155-84|
|Lafuse, William P; Story, Ryan; Mahylis, Jocelyn et al. (2013) Leishmania donovani infection induces anemia in hamsters by differentially altering erythropoiesis in bone marrow and spleen. PLoS One 8:e59509|
|Pan, Li; Terrazas, Cesar; Lezama-Davila, Claudio M et al. (2012) Cordifolide A, a sulfur-containing clerodane diterpene glycoside from Tinospora cordifolia. Org Lett 14:2118-21|
|Cummings, Hannah E; Barbi, Joseph; Reville, Patrick et al. (2012) Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis. Proc Natl Acad Sci U S A 109:1251-6|
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