Leishmanization: Use of an old method for evaluation of candidate vaccines against leishmaniasis

Khamesipour, Ali; Dowlati, Yahya; Asilian, Ali; Hashemi-Fesharki, R.; Javadi, Amir; Noazin, Sassan; Modabber, Farrokh

doi:10.1016/j.vaccine.2005.02.015

Cited by 182 publications

(136 citation statements)

References 24 publications

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“…We speculate that the well characterized down-regulation of the glucose transporter activity in Leishmania amastigotes (18) may facilitate the switch from glycolysis to gluconeogenesis in this stage. Our findings suggest that inhibitors of gluconeogenesis may be useful in preventing growth of intracellular Leishmania and that gluconeogenic mutants, such as ⌬fbp, that persist but are poorly proliferative in macrophages, constitute a useful platform for development of attenuated live vaccines (32)(33)(34).…”

Section: Discussionmentioning

confidence: 90%

Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase

Naderer

Ellis

Sernee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

117

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Leishmania are protozoan parasites that replicate within mature phagolysosomes of mammalian macrophages. To define the biochemical composition of the phagosome and carbon source requirements of intracellular stages of L. major, we investigated the role and requirement for the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP). L. major FBP was constitutively expressed in both extracellular and intracellular stages and was primarily targeted to glycosomes, modified peroxisomes that also contain glycolytic enzymes. A L. major FBP-null mutant was unable to grow in the absence of hexose, and suspension in glycerol-containing medium resulted in rapid depletion of internal carbohydrate reserves. L. major ⌬fbp promastigotes were internalized by macrophages and differentiated into amastigotes but were unable to replicate in the macrophage phagolysosome. Similarly, the mutant persisted in mice but failed to generate normal lesions. The data suggest that Leishmania amastigotes reside in a glucose-poor phagosome and depend heavily on nonglucose carbon sources. Feeding experiments with [ 13 C]fatty acids showed that fatty acids are poor gluconeogenic substrates, indicating that amino acids are the major carbon source in vivo. The need for amino acids may have forced Leishmania spp. to adapt to life in the mature phagolysosome.gluconeogenesis ͉ intracellular pathogens ͉ phagolysosome ͉ carbohydrate ͉ mannan L eishmania are parasitic protozoa that cause a spectrum of important diseases in Ͼ12 million people worldwide, ranging from self-healing cutaneous lesions to nonhealing mucocutaneous and visceral disease. There are no effective vaccines against leishmaniasis, and current drug treatments are characterized by low efficacy, high toxicity, and expense or, in the case of front-line antimonial drugs, widespread resistance (1). Infection of humans and other animal hosts is initiated by flagellated promastigotes that develop within the digestive tract of the sandfly vector and are injected into the skin during a sandfly blood meal. Promastigotes are internalized into mature phagolysosomes of a number of phagocytic host cells, including neutrophils, dendritic cells, and macrophages but proliferate only within the latter (2). The proliferative intracellular stages are aflagellate amastigotes that remain within the phagolysosome and perpetuate infection in the host through repeated cycles of macrophage infection.Very few other microbial pathogens are capable of proliferating within macrophage phagolysosomes (3), and little is known about the nutrient composition of this compartment or the metabolic responses of persistent Leishmania amastigote stages (4). Glucose uptake appears to be essential in promastigote infection of macrophages, because promastigotes of a Leishmania mexicana mutant lacking all glucose transporters are unable to infect macrophages (5). However, this mutant fails to differentiate into amastigotes in vitro (5), and the hexose requirements of this stage are largely unknown. Glucose and other hexoses are a pot...

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Section: Discussionmentioning

confidence: 90%

Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase

Naderer

Ellis

Sernee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

117

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“…These cutaneous lesions ulcerate, resolve, and ultimately stimulate powerful immunity against the disease. Robust induction of this immunity is the basis of leishmanization, an effective vaccination procedure in which the inoculation of live L. major has been used with great success (12); safety concerns, however, have led to the abandonment of such vaccination (17). In contrast to L. major, Leishmania donovani causes visceral leishmaniasis, a severe systemic illness that is often fatal if untreated.…”

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confidence: 99%

Leishmania majorInfection Activates NF-κB and Interferon Regulatory Factors 1 and 8 in Human Dendritic Cells

et al. 2008

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The salient feature of dendritic cells (DC) is the initiation of appropriate adaptive immune responses by discriminating between pathogens. Using a prototypic model of intracellular infection, we previously showed that Leishmania major parasites prime human DC for efficient interleukin-12 (IL-12) secretion. L. major infection is associated with self-limiting cutaneous disease and powerful immunity. In stark contrast, the causative agent of visceral leishmaniasis, Leishmania donovani, does not prime human DC for IL-12 production. Here, we report that DC priming by L. major infection results in the early activation of NF-B transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. The inhibition of NF-B activation by the pretreatment of DC with caffeic acid phenethyl ester blocks L. major-induced IRF-1 and IRF-8 activation and IL-12 expression. We further demonstrate that IRF-1 and IRF-8 obtained from L. major-infected human DC specifically bind to their consensus binding sites on the IL-12p35 promoter, indicating that L. major infection either directly stimulates a signaling cascade or induces an autocrine pathway that activates IRF-1 and IRF-8, ultimately resulting in IL-12 transcription.Leishmania major is the causative agent of cutaneous leishmaniasis, which is characterized by the development of lesions at sand fly bite sites. These cutaneous lesions ulcerate, resolve, and ultimately stimulate powerful immunity against the disease. Robust induction of this immunity is the basis of leishmanization, an effective vaccination procedure in which the inoculation of live L. major has been used with great success (12); safety concerns, however, have led to the abandonment of such vaccination (17). In contrast to L. major, Leishmania donovani causes visceral leishmaniasis, a severe systemic illness that is often fatal if untreated.Healing of cutaneous leishmaniasis has been attributed to the development of a strong Th1 immune response in the vertebrate host. Interleukin-12 (IL-12) is up-regulated in L. major-infected human dendritic cells (DC), whereas visceral leishmaniasis agents do not induce IL-12 production (28). Those previous studies revealed that L. donovani does not actively inhibit IL-12 production; rather, L. major primes human DC for IL-12 production. This strong induction of IL-12 by L. major-infected DC sets the stage for a strong and robust Th1 immune response that leads to lesion healing and immunity against the disease. Elucidation of the mechanisms that mediate the strong immunity elicited by L. major will undoubtedly have consequences for vaccine development against all Leishmania species as well as other infections, where strong cell-mediated immune responses are essential for resistance.IL-12 belongs to a family of cytokines including IL-23, IL-27, and ciliary neutrotrophic factor receptor (CNTFR). The bioactive form of this proinflammatory cytokine is a unique heterodimeric protein composed of p35 and p40 subunits that are encoded by...

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“…In leishmaniasis, recovery and protection against further infection are mainly dependent on induction of a Th1-type immune response (36), which justifies the search for an effective vaccine against leishmaniasis. Development of an effective anti-Leishmania vaccine is theoretically possible due to the fact that recovery from cutaneous leishmaniasis or leishmanization induces long-lasting protection against further infection, yet there is no vaccine available against any form of human leishmaniasis (18,25,29,45).…”

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confidence: 99%

Coencapsulation of CpG Oligodeoxynucleotides with RecombinantLeishmania majorStress-Inducible Protein 1 in Liposome Enhances Immune Response and Protection against Leishmaniasis in Immunized BALB/c Mice

Badiee

Jaafari

Samiei

et al. 2008

Clin Vaccine Immunol

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CpG oligodeoxynucleotides (CpG ODN) have been shown to have potent adjuvant activity for a wide range of antigens. The purpose of this study was to determine the potential benefit of using liposomes as a delivery vehicle to enhance the adjuvant activity of CpG ODN with Leishmania major stress-inducible protein 1 (LmSTI1) antigen in induction of the Th1 response in a murine model of leishmaniasis. BALB/c mice were immunized subcutaneously three times in 3-week intervals with liposomal recombinant LmSTI1 (Lip-rLmSTI1), rLmSTI1 coencapsulated with CpG ODN in a liposome (Lip-rLmSTI1-CpG ODN), rLmSTI1 plus CpG ODN in phosphate-buffered saline (PBS), rLmSTI1 plus non-CpG ODN in PBS, rLmSTI1 in PBS, empty liposome, or PBS. The intensity of infection induced by L. major promastigote challenge was measured by footpad swelling. A significant (P < 0.001) inhibition of infection in mice immunized with Lip-rLmSTI1-CpG ODN was shown compared to the other groups, and no parasite was detected in the spleens of this group 14 weeks after challenge. The highest immunoglobulin G2a (IgG2a) titer and the highest IgG2a/IgG1 ratio were also shown in the sera of mice immunized with Lip-rLmSTI1-CpG ODN before and 14 weeks after challenge. The results indicated the superiority of CpG ODN in its liposomal form over its soluble form to induce the Th1 response when used in association with rLmSTI1 antigen. It seems that using a liposome delivery system carrying CpG ODN as an adjuvant coencapsulated with Leishmania antigen plays an important role in vaccine development strategies against leishmaniasis.

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Leishmanization: Use of an old method for evaluation of candidate vaccines against leishmaniasis

Cited by 182 publications

References 24 publications

Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase

Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase

Leishmania majorInfection Activates NF-κB and Interferon Regulatory Factors 1 and 8 in Human Dendritic Cells

Coencapsulation of CpG Oligodeoxynucleotides with RecombinantLeishmania majorStress-Inducible Protein 1 in Liposome Enhances Immune Response and Protection against Leishmaniasis in Immunized BALB/c Mice

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