Sandfly Maxadilan Exacerbates Infection with <i>Leishmania major</i> and Vaccinating Against It Protects Against <i>L. major</i> Infection

Morris, Robin V.; Shoemaker, Charles B.; David, John R.; Lanzaro, Gregory C.; Titus, Richard G.

doi:10.4049/jimmunol.167.9.5226

Cited by 203 publications

(208 citation statements)

References 35 publications

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“…Maxadilan is a component of the salivary glands of Lutzomyia longipalpis that exacerbates L. major infection to a degree comparable to that observed with whole saliva [49]. Thus, we also investigated the effect of synthetic Maxadilan (SMAX) on the OVA-induced neutrophil migration in immunized animals.…”

Section: Effect Of Maxadilan On Ova-induced Neutrophil Migration In Imentioning

confidence: 99%

Effect of salivary gland extract ofLeishmania vector,Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis

Monteiro¹,

Nogueira²,

Souza³

et al. 2005

Eur. J. Immunol.

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Salivary gland extracts (SGE) from Lutzomyia longipalpis potentate L. major infection by inducing a Th2 immune response. However, the effect of SGE on the effector phase of immune response is not known. Herein, we demonstrate that SGE inhibited neutrophil migration in ovalbumin (OVA)-induced peritonitis in immunized mice. SGE pretreatment of mice inhibited OVA-induced CD4 + and CD8 + T lymphocyte migration. The OVA-induced production of TNF-a, IL-1b and leukotriene B4 (LTB 4 ), neutrophil chemotactic mediators in this model, were inhibited by SGE. On the other hand, SGE enhanced production of IL-10 and IL-4. In naive mice, SGE also blocked LTB 4 -induced neutrophil migration, but not that induced fMLP. Moreover, co-incubation of LTB 4 (but not fMLP, TNF-a and MIP-1a) with SGE inhibited the ability of LTB 4 to induce neutrophil migration in vivo and in vitro. Altogether, the results suggest that SGE has anti-inflammatory properties that are associated with inhibition of TNF-a and LTB 4 production and/or with the neutrophil chemotactic activity of LTB 4 . The effectiveness of SGE in inhibiting neutrophil migration and inflammatory mediators release in a Th1 immune inflammatory response model reinforces the need for isolation of the compounds responsible for these activities, which could be used as prototypes for the development new anti-inflammatory drugs. IntroductionParticipation of vector saliva in disease transmission has long been recognized. Saliva inoculated during blood feeding modulates the immune response allowing the infection to become established [1][2][3]. On the other hand, anti-vector saliva immunity may protect the host against some vector-borne diseases [4][5][6][7]. In leishmaniasis, there is evidence that the saliva of the vectors Lutzomyia and Phlebotomus contains substances with immunosuppressor, vasodilatator, anti-platelet and anticlotting activities [8][9][10][11][12][13]. In addition to increasing the hemorrhagic pool where sand flies feed [8,14], salivary components also induce host immunosuppression, which is fundamental for the establishment of Leishmania infection [10,[15][16][17][18][19] production and antigen presentation by infected macrophages [20][21][22]. Furthermore, they inhibit Th1 induction, enhancing the Th2-type response with an increase of IL-4 and IL-10 in the infection [23][24][25]. A predominance of the Th1 response has been reported in several inflammatory diseases, including rheumatoid arthritis, Crohn's disease, glomerulonephritis, and immune vasculitis [26][27][28][29]. The participation of neutrophils in the pathogenesis of tissue lesions in these diseases has long been recognized [30][31][32][33]. These cells are important sources of substances that promote tissue damage, such as reactive oxygen and nitrogen species, lysosomal enzymes and metalloproteases [34,35]. Indeed, the efficacy of the so-called disease modifying anti-inflammatory drugs in several inflammatory diseases, such as rheumatoid arthritis is usually associated with their ability to decrease neutro...

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Section: Effect Of Maxadilan On Ova-induced Neutrophil Migration In Imentioning

confidence: 99%

Effect of salivary gland extract ofLeishmania vector,Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis

Monteiro¹,

Nogueira²,

Souza³

et al. 2005

Eur. J. Immunol.

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“…Maxadilan is thus an immunomodulatory component of the sand fly saliva. Maxadilan has been shown to facilitate the transmission and establishment of leishmaniasis [8] although it is not clear if maxadilan is the only active component of sand fly saliva that exacerbates the infection. When vaccinated against maxadilan, mice are protected against infection with Leishmania major [8].…”

Section: Maxadilan and Leishmaniasismentioning

confidence: 99%

“…Maxadilan has been shown to facilitate the transmission and establishment of leishmaniasis [8] although it is not clear if maxadilan is the only active component of sand fly saliva that exacerbates the infection. When vaccinated against maxadilan, mice are protected against infection with Leishmania major [8]. This fascinating observation leads to the question of whether vaccines that protect against parasites could be directed at components of the parasite vector rather than, or addition to, the parasite.…”

Section: Maxadilan and Leishmaniasismentioning

confidence: 99%

Maxadilan, a PAC1 receptor agonist from sand flies

2007

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In 1991, a potent 61 amino acid vasodilator peptide, named maxadilan, was isolated from the salivary glands of the sand fly. Subsequently, it was shown that this peptide specifically and potently activated the mammalian PAC1 receptor, one of the three receptors for PACAP. These studies and the link between maxadilan and leishmaniasis are discussed. Keywordsmaxadilan; PAC1; receptor; PACAP; leishmaniasis Identification of maxadilan and its mammalian receptor.Blood-feeding or hematophagous insects express vasoactive compounds in their salivary glands. These compounds serve to counteract the hemostatic processes of the host when the insect obtains a blood meal. The bite of the New World sand fly Lutzomyia longipalpis, a vector of the protozoan disease leishmaniasis, results in the rapid development of a small area of long-lasting redness or erythema at the site (Fig. 1). Erythema is typically associated with vasodilatation. Lerner et al. [4] isolated the vasoactive principle responsible for this effect. Reversed-phase HPLC was used to fractionate sand fly salivary gland extracts. The fractions were injected into the skin of rabbits and activity was determined by the presence or absence of erythema. The erythema-inducing fraction was shown to contain a vasodilatory peptide, named, because of its high potency, maxadilan.The sand fly gene encoding maxadilan was cloned and sequenced a year later [5]. Maxadilan is a vasodilator 500 times more potent than calcitonin gene-related peptide (CGRP) [4], the most potent peptide described at that time. Furthermore, the erythema induced by picogram quantities of maxadilan injected into human skin persists for approximately 48 hours. The vasodilatory properties of maxadilan were subsequently shown to be endothelium-independent and to be, at least in part, mediated by alterations in the levels of intracellular cAMP in smooth muscle cells. In addition to its action on cutaneous vessels, maxadilan also had vasodilatory activity on rabbit aorta and mesenteric artery [2].Maxadilan was demonstrated to bind to brain extracts from various species including human and mouse [9]. It also bound to neural crest-derived cell lines including the rat pheochromocytoma line PC12, and the human neuroblastoma line NBfl [10]. These results suggested that maxadilan could activate one of the receptors for vasoactive neuropeptides. The CGRP receptors were the initial candidates, because CGRP appeared to induce a similar clinical Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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“…A number of reports using animal models have shown that mice pre-exposed to phlebotomine saliva, or some of its components, are protected against Leishmania infection in vivo [8,[11][12][13][14][15], thus suggesting that salivary proteins could be used as targets for vaccination against leishmaniasis [16,17]. However, the anti-saliva IR as well as its possible implications on Leishmania infection following exposure to sand flies in humans have not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Human anti‐saliva immune response following experimental exposure to the visceral leishmaniasis vector, Lutzomyia longipalpis

et al. 2007

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Experiments in animals verified that phlebotomine saliva enhances Leishmania infection, and vaccination with saliva prevents disease. We have shown that individuals from an endemic area of visceral leishmaniasis displayed robust antibody responses to saliva from the vector Lutzomyia longipalpis, which correlated with anti-parasite cellmediated immunity. Here, we explored human anti-saliva responses following exposure to sand flies, using an in vivo bite model in which normal volunteers were exposed four times to 30 laboratory-reared Lu. longipalpis. Following the third exposure, normal volunteers developed diverse dermatological reactions at the site of insect bite. Serum from normal volunteers displayed high levels of anti-salivary gland sonicate IgG1, IgG4 and IgE as well as several salivary gland proteins. Furthermore, following in vitro stimulation with salivary gland sonicate, there was an increased frequency of CD4 + CD25 + and CD8 + CD25 + T cells as well as IFN-c and IL-10 synthesis. Strikingly, 1 year after the first exposure, PBMC from the volunteers displayed recall IFN-c responses that correlated with a significant reduction in infection rates using a macrophage-lymphocyte autologous culture. Together, these data suggest that human immunization against sand fly saliva is feasible and recall responses are obtained even 1 year after exposure, opening perspectives for vaccination in man.

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Sandfly Maxadilan Exacerbates Infection with Leishmania major and Vaccinating Against It Protects Against L. major Infection

Cited by 203 publications

References 35 publications

Effect of salivary gland extract ofLeishmania vector,Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis

Effect of salivary gland extract ofLeishmania vector,Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis

Maxadilan, a PAC1 receptor agonist from sand flies

Human anti‐saliva immune response following experimental exposure to the visceral leishmaniasis vector, Lutzomyia longipalpis

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