Pathogenicity and protective immunogenicity of cysteine proteinase-deficient mutants of Leishmania mexicana in non-murine models

Saravia, Nancy Gore; Escorcia, Blanca; Osorio, Yaneth; Valderrama, Liliana; Brooks, Darren R.; Arteaga, Lourdes; Coombs, Graham H.; Mottram, Jeremy C.; Travi, Bruno L.

doi:10.1016/j.vaccine.2005.05.045

Cited by 55 publications

(28 citation statements)

References 35 publications

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“…Second, Leishmania parasites are known to contain a vast repertoire of proteolytic enzymes encoding at least 154 peptidases (aspartic, cysteine, metallo, serine, and threonine peptidases) (53), and amastigotes of L. amazonensis and L. mexicana are notorious for their high cysteine protease/oligopeptidase B activities in specialized structures called megasomes (54,55). The cathepsin B-like cysteine proteinase is central to the parasites' ability to modulate NF-B signaling and to consequently inhibit IL-12 production by murine M⌽s (56), and targeted depletion of its encoding gene greatly reduces parasite virulence (57). At present, it is unclear how parasite components travel through the parasitophorous vacuole membrane to interfere with host signaling pathways and whether such down-modulation is specific to activation-related pathways.…”

Section: Down-modulation Of DC Functions By Leishmania Amastigotesmentioning

confidence: 99%

Modulation of Dendritic Cell Function by Leishmania Parasites

Soong

2008

The Journal of Immunology

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The interactions between Leishmania parasites and dendritic cells (DCs) are complex and involve paradoxical functions that can stimulate or halt T cell responses, leading to the control of infection or progression of disease. The magnitude and profile of DC activation vary greatly, depending upon the Leishmania species/strains, developmental stages, DC subsets, serum opsonization, and exogenous DC stimuli involved in the study. In general, the uptake of Leishmania parasites alone can trigger relatively weak and transient DC activation; however, the intracellular parasites (amastigotes) are capable of down-modulating LPS/IFN-γ-stimulated DC activation via multiple mechanisms. This review will highlight current data regarding the initial interaction of DC subsets with invading parasites, the alterations of DC signaling pathways and function by amastigotes, and the impact of DC functions on protective immunity and disease pathogenesis. Available information provides insight into the mechanisms by which DCs discriminate between the types of pathogens and regulate appropriate immune responses.

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Section: Down-modulation Of DC Functions By Leishmania Amastigotesmentioning

confidence: 99%

Modulation of Dendritic Cell Function by Leishmania Parasites

Soong

2008

The Journal of Immunology

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“…Similarly, a Th2-inducing activity of the cysteine protease antigen of Leishmania mexicana has been proposed to deviate immunity away from a protective Th1 response [3]. Several plausible mechanisms for adjuvant activity have been proposed based on their enzymatic activity on a number of immunological receptors and the potentiation of epithelial permeability [4].…”

Section: Introductionmentioning

confidence: 99%

Sensitizing and Th2 Adjuvant Activity of Cysteine Protease Allergens

Cunningham

Elliot

Lenzo

et al. 2012

Int Arch Allergy Immunol

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Background: Innate properties that enhance immune responses might increase the propensity of certain allergens to induce allergic sensitization. Either a direct adjuvant effect or the increased immune response to the allergen could then increase allergic responses to bystander antigens. Here, we report on a model that does not use Th2-skewing adjuvants and yet achieves sensitization solely via the nasal mucosa. Methods: Animals were sensitized with either enzymatically active, inactive or non-activated cysteine proteases via the nasal mucosa. Following two sensitization phases, mice were challenged with a higher dose of allergen. For bystander sensitization, mice received recombinant Der p 2 at sensitization in conjunction with the cysteine protease and were challenged with rDer p 2 alone. Sensitization was determined by measuring allergen-specific antibody responses and cytokine and cellular infiltrates into the lungs following challenge. Results: Sensitization for Th2-type lung hypersensitivity for both the cysteine protease and bystander antigens was readily achieved and both were dependent on the proteolytic activity of the allergen. Bystander adjuvant activity was demonstrated for mice that were low IgE responders to the cysteine protease, showing a response independent from the immune response to the enhancing cysteine protease. Airway hyperreactivity was induced in the susceptible NOD strain of mouse, and mice subjected to prolonged administration of papain maintained the ability to produce lung hypersensitivity and Th2-type responses. Conclusions: These experiments demonstrate that cysteine protease activity at low doses can be an adjuvant for respiratory Th2 responses for themselves and bystander antigens in the absence of another adjuvant.

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“…L. major deleted for phosphomannomutase-protected mice, despite no increase in either effector or memory response (9). In contrast, L. mexicana that also causes CL, deficient in cysteine proteinase genes (⌬cpa and ⌬cpb), conferred protection in mice and hamsters against homologous challenge (10,11). Among the vaccination studies in VL, mice immunized with a L. donovani strain deleted for biopterin transporter (BT1) were similarly protected (12).…”

mentioning

confidence: 99%

Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis

Selvapandiyan

Dey

Nylén

et al. 2009

The Journal of Immunology

155

217

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No vaccine is currently available for visceral leishmaniasis (VL) caused by Leishmania donovani. This study addresses whether a live attenuated centrin gene-deleted L. donovani (LdCen1−/−) parasite can persist and be both safe and protective in animals. LdCen1−/− has a defect in amastigote replication both in vitro and ex vivo in human macrophages. Safety was shown by the lack of parasites in spleen and liver in susceptible BALB/c mice, immune compromised SCID mice, and human VL model hamsters 10 wk after infection. Mice immunized with LdCen1−/− showed early clearance of virulent parasite challenge not seen in mice immunized with heat killed parasites. Upon virulent challenge, the immunized mice displayed in the CD4+ T cell population a significant increase of single and multiple cytokine (IFN-γ, IL-2, and TNF) producing cells and IFN-γ/IL10 ratio. Immunized mice also showed increased IgG2a immunoglobulins and NO production in macrophages. These features indicated a protective Th1-type immune response. The Th1 response correlated with a significantly reduced parasite burden in the spleen and no parasites in the liver compared with naive mice 10 wk post challenge. Protection was observed, when challenged even after 16 wk post immunization, signifying a sustained immunity. Protection by immunization with attenuated parasites was also seen in hamsters. Immunization with LdCen1−/− also cross-protected mice against infection with L. braziliensis that causes mucocutaneous leishmaniasis. Results indicate that LdCen1−/− can be a safe and effective vaccine candidate against VL as well as mucocutaneous leishmaniasis causing parasites.

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Pathogenicity and protective immunogenicity of cysteine proteinase-deficient mutants of Leishmania mexicana in non-murine models

Cited by 55 publications

References 35 publications

Modulation of Dendritic Cell Function by Leishmania Parasites

Modulation of Dendritic Cell Function by Leishmania Parasites

Sensitizing and Th2 Adjuvant Activity of Cysteine Protease Allergens

Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis

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