Development of a safe live Leishmania vaccine line by gene replacement.

Titus, Richard G.; Gueiros‐Filho, Frederico J.; Freitas, Luiz Antônio Rodrigues de; Beverley, Stephen M.

doi:10.1073/pnas.92.22.10267

Cited by 204 publications

(169 citation statements)

References 37 publications

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“…long-term protection, the idea of using live-attenuated organisms as a vaccine against leishmaniasis has been pursued by several laboratories, but has been hampered by limited efficacy (11,22,23). We report here that lpg2 Ϫ parasites, which persist without causing overt cutaneous lesions (17), induce protection against virulent challenge in an experimental model, indicating that these parasites might be used as an attenuated vaccine for leishmaniasis.…”

Section: Discussionmentioning

confidence: 83%

“…These organisms have not gained acceptance as potential vaccine candidates because attenuated organisms may revert to virulence, and targeted deletion of essential or virulence genes results in either complete parasite destruction (11) or in mutants that induce only a delay in lesion development (10,12). For example, a conditional auxotroph produced by targeted deletion of an essential metabolic gene, dihydrofolate reductase thymidylate synthase (DHFR-TS) (13,14), induces only limited protection against virulent challenge, possibly due to their rapid elimination (11). Similarly, BALB/c mice infected with a Leishmania mexicana mutant lacking cysteine proteinases exhibited only a delay in lesion development when the animals were challenged with virulent parasites (12).…”

Section: Vaccination With Phosphoglycan-deficient Leishmania Majormentioning

confidence: 99%

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Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

118

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Long-term immunity to Leishmania may require the continued presence of parasites, but previous attempts to create attenuated parasites that persist without causing disease have had limited success. Since Leishmania major mutants that lack lipophosphoglycan and other secreted phosphoglycans, termed lpg2−, persist indefinitely in infected mice without inducing any disease, we tested their ability to provide protection to virulent L. major challenge. In response to leishmanial Ag stimulation, cells from lpg2−-infected mice produced minimal levels of IL-4 and IL-10, as well as very low levels of IFN-γ. Nevertheless, when BALB/c mice infected with lpg2− parasites were challenged with virulent L. major they were protected from disease. Thus, these findings report on attenuated parasites that may be used to induce long-term protection against leishmaniasis and indicate that the immunity induced can be maintained in the absence of a strong Th1 response.

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Section: Discussionmentioning

confidence: 83%

Section: Vaccination With Phosphoglycan-deficient Leishmania Majormentioning

confidence: 99%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

118

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“…Since purified proteins or protein fragments alone are poor immunogens (Titus et al 1995), they require the addition of an adjuvant or antigen-carrier system to be effective. The adjuvant should be selected according to the antigens to be used, animals to be vaccinated, route of administration, and side effects (Nagill and Kaur 2010).…”

Section: New Perspectives For Applications Of Proteoliposomesmentioning

confidence: 99%

Proteoliposomes in nanobiotechnology

et al. 2012

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Proteoliposomes are systems that mimic lipid membranes (liposomes) to which a protein has been incorporated or inserted. During the last decade, these systems have gained prominence as tools for biophysical studies on lipid-protein interactions as well as for their biotechnological applications. Proteoliposomes have a major advantage when compared with natural membrane systems, since they can be obtained with a smaller number of lipidic (and protein) components, facilitating the design and interpretation of certain experiments. However, they have the disadvantage of requiring methodological standardization for incorporation of each specific protein, and the need to verify that the reconstitution procedure has yielded the correct orientation of the protein in the proteoliposome system with recovery of its functional activity. In this review, we chose two proteins under study in our laboratory to exemplify the steps necessary for the standardization of the reconstitution of membrane proteins in liposome systems: (1) alkaline phosphatase, a protein with a glycosylphosphatidylinositol anchor, and (2) Na,K-ATPase, an integral membrane protein. In these examples, we focus on the production of the specific proteoliposomes, as well as on their biochemical and biophysical characterization, with emphasis on studies of lipid-protein interactions. We conclude the chapter by highlighting current prospects of this technology for biotechnological applications, including the construction of nanosensors and of a multiprotein nanovesicular biomimetic to study the processes of initiation of skeletal mineralization.

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“…Gene essentiality is also thought to be an important criteria for identification of therapeutic drug targets (Agüero et al, 2008). But there is a limitation to this approach as it fails to identify some targets such as hypoxanthine phosphoribosyl transferase as essential in Plasmodium falciparum (false negative) (Winzeler et al, 1999), while sometimes it yields false positives as in the case of dihydrofolate reductase in Leishmania major (Titus et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Novel Drug Targets for Food-Borne PathogenCampylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study

Mehla

Ramana

2015

OMICS: A Journal of Integrative Biology

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Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non-redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non-homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets. We conclude by underscoring that screening against these proteins with inhibitors may aid in future discovery of novel therapeutics against campylobacteriosis in ways that will be pathogen specific, and thus have minimal toxic effect on host. Omics-guided drug discovery and bioinformatics analyses offer the broad potential for veritable advances in global health relevant novel therapeutics.

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Development of a safe live Leishmania vaccine line by gene replacement.

Cited by 204 publications

References 37 publications

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Proteoliposomes in nanobiotechnology

Novel Drug Targets for Food-Borne PathogenCampylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study

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