Differences in the onset of the inflammatory response to cutaneous leishmaniasis in resistant and susceptible mice (original) (raw)
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Eosinophils and mast cells in leishmaniasis
Immunologic Research, 2014
Leishmania spp. are parasitic protozoa endemic in tropical and subtropical regions and the causative agent of leishmaniasis, a collection of syndromes whose clinical manifestations vary according to host and pathogen factors. Leishmania spp. are inoculated into the mammalian host by the bite of an infected sand fly, whereupon they are taken up by phagocytosis, convert into the replicative amastigote stage within macrophages, reproduce, spread to new macrophages and cause disease manifestations. A curative response against leishmaniasis depends in the classical activation of macrophages and the IL-12-dependent onset of an adaptive type 1 response characterized by the production of IFN-γ. Emerging evidence suggests that neutrophils, dendritic cells and other immune cells can serve as either temporary or stable hosts for Leishmania spp. Furthermore, it is becoming apparent that the initial interactions of the parasite with resident or early recruited immune cells can shape both the macrophage response and the type of adaptive immune response being induced. In this review, we compile a growing number of studies demonstrating how the earliest interactions of Leishmania spp. with eosinophils and mast cells influence the macrophage response to infection and the development of the adaptive immune response, hence, determining the ultimate outcome of infection.
The Journal of Infectious Diseases, 2002
This study investigated whether Leishmania species, the etiologic agent of cutaneous (Leishmania major) and visceral (Leishmania donovani) leishmaniasis, could differentially elicit early inflammatory events in vivo correlating with the subsequent development of their reciprocal pathogenesis. By use of the murine air pouch system, injection of Leishmania led to a rapid and transient accumulation of a mixed population of leukocytes, and L. major recruited 31-fold more leukocytes than did controls, compared with 7-fold more leukocytes for L. donovani. L. major promastigotes were better than L. donovani promastigotes at inducing proinflammatory cytokine secretion and chemokine gene expression in pouch exudates. L. major infection elicited significantly increased chemokine receptor gene expression, compared with L. donovani infection. Collectively, the data reveal that L. major is a strong inducer of the early inflammatory response, compared with L. donovani, and suggest that such an immunologic event potentially could restrain this parasite to the inoculation site, favoring the development of local swelling and cutaneous lesions.
Acta Tropica, 1991
We used previously immunized (partially resistant) and naive (highly susceptible) BALB/c mice infected with Leishrnania amazonensis for evaluating the role of granulocytes in the course of murine leishmaniasis. The animals were examined at different times post-infection and granulocytes counted in lesion tissues examined ultra-structurally. Polymorphonuclear granulocytes predominated during the early phase of infection and their number decreased with progression of infection; their number was similar in both groups during the early and intermediate phases of infection, though slightly higher in immunized animals during the late phase. Eosinophils represented approximately 10% of cells in the inflammatory infiltrate, being higher during the intermediate phase, and not differing between the groups. Another approach was the evaluation of granulocyte migration to the peritoneal cavity of susceptible BALB/c mice or resistant C57BL/6 mice under several stimuli. There was no statistically significant difference between resistant and susceptible animals in any of the treatments. Despite the influx of granulocytes to the lesion and its possible role in the initial destruction of injected Leishmania, this aspect does not seem to have an important effect on the outcome of the leishmanial infection.
Alterations of the immune response associated with chronic experimental leishmaniasis
Infection and Immunity, 1979
BALB/c mice infected with Leishmania mexicana developed a chronic infection usually accompanied by the appearance of metastatic lesions. Throughout the 20 weeks of observation, infected mice ;howed an impairment in both in vivo delayed hypersensitivity response and in vitro lymphocyte reactivity to leishmanial antigen. Four to 8 weeks after inoculation infected mice displayed a transitory enhancement of spleen cell responses to phytohemagglutinin P, concanavalin A, and lipopolysaccharide. At the same time, immunization with sheep erythrocytes resulted in a greater number of immunoglobulin P, lipopolysaccharide, and sheep erythrocytes diminished progressively, whereas reactivity to concanavalin A was markedly augmented. When cocultivated with spleen cells from mice infected for 12 to 20 weeks, normal lymphocyte responses to phytohemagglutinin P, concanavalin A, and lipopolysaccharide were drastically reduced. These results suggest a role for suppressor cells in chronic experimental c...
Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene. Series A: Medical Microbiology, Infectious Diseases, Virology, Parasitology, 1987
A compari son has been made between the capacity of macrophages of BALBlc "nonhealer" mice and C57BU6 "healer" mice to deal in vitro with Leishmania tropica (L. tropica) par asites in order to obtain a more detailed picture of the inherent contribution of macrophages to the susceptibility of BALBlc mice to infection with L. tropica and the resulting fatal course of the disease. In comparison to macrophages of C57BU6 origin, BALBlc macroph ages showed a higher par asite uptake and a higher infection rate; they allowed a more rapid tran sformation of L. tropica proma stigotes into amastigotes and displayed less leishmanicidal activities. Lymphok ine-rich culture supernatants induced activation of macrophage s resulting in killing of L. tropica by macrophages of both , "nonhealer" and "healer" mice. These supernatants also induced expression of la-antigen s on infected "non-healer" and "healer" macropha ges. The results of this study clearly point to the critical role of macrophage functions to either support a systemic leishmaniasis or to alternatively mount a protective immune response leading to a self-healing course of the disease. Zusammenfassung In der vorliegenden vergleichenden Studie wurde die Rolle von Makrophagen bei der Infektion von BALBlc Mausen mit Leishmania tropica (L. tropica) und dem darau s resultierenden Iatalen Krankheitsverlauf untersucht. Dazu wurde die Interaktion von L. tropica mit Makrophagen von BALB/c "non-healer" Mausen und Makrophagen von C57BU6 "healer" Mausen verglichen. Es zeigte sich, daIS BALBlc Makrophagen eine hohere Infektionsrate aufwiesen und mehr Parasiten aufnahmen als C57BU6 Makrophagen. In BALBlc Makrophagen wurde zudem eine schnellere Umwandlung von promastigoten L. tropica in die amastigote Form sowie eine schlechtere Abtotung der Parasiten beobachtet. Durch Zellkulturiiber stande, die Lymphokine enthielten, konnten Makrophagen sowohl von C57BU6 als auch von BALBlc Mausen zu einer verstarkten Abtotung von intrazellularen Para siten akt i-1 Supported by the Deutsche Forschungsgemeinschaft Murine Cutaneous Leishmaniasis 595 viert werden. Die Uberstande induzierten auch die Expression von Ia-Antigenen auf infizierten Makrophagen von den beiden Mausestammen, Die Ergebnisse der Studie machen deutlich, daf Makrophagen eine entscheidende Rolle bei der Infektion von Mausen mit L. tropica zukommt, in dem sie den Krankheitsverlauf entweder ungiinstig beeinflussen oder aber zur Entwicklung einer schiitzenden Immunreaktion gegen die Parasiten beitragen.
Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner
PLOS Neglected Tropical Diseases, 2019
Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and is caused by several species of Leishmania parasite. Clinical presentation of CL varies from a self-healing infection to a chronic form of the disease determined by the virulence of infecting Leishmania species and host immune responses to the parasite. Mouse models of CL show contradictory roles of lymphocytes in pathogenesis, while acquired immune responses are responsible for host protection from diseases. To reconcile the inconclusive roles of acquired immune responses in pathogenesis, we infected mice from various genetic backgrounds with two pathogenic strains of Leishmania major, Friedlin or 5ASKH, and assessed the outcome of the infections. Our findings showed that the genetic backgrounds of L. major determine the impact of lymphocytes for pathogenesis. In the absence of lymphocytes, L. major Friedlin induced the lowest inflammatory reaction and pathology at the site of infection, while 5ASKH infection induced a strong inflammatory reaction and severe pathology. Lymphocytes ameliorated 5ASKH mediated pathology, while it exacerbated pathology during Friedlin infection. Excess inflammatory reactions, like the recruitment of macrophages, neutrophils, eosinophils and production of pro-inflammatory cytokines, together with uncontrolled parasite growth in the absence of lymphocytes during 5ASKH infection may induce severe pathology development. Taken together our study provides insight into the impact of differences in the genetic background of Leishmania on CL pathogenesis.
Immunological factors governing resistance and susceptibility of mice to Leishmania major infection
Revista latinoamericana de microbiología
Infection with Leishmania sp. is particularly suitable for the study of immunoregulatory mechanisms associated with host susceptibility or resistance. The clinical spectrum of this infection results from parasite virulence factors and host immune responses, some of which acting in a host protective manner while others exacerbate the disease. In the mouse model, factors governing resistance to Leishmania major infection mainly depends on the IFN-gamma activation of the leishmanicidal function of macrophages, and the Fas/ FasL-dependent T-cell cytotoxicity against infected macrophages. On the other hand, the immunological factors of susceptibility involve: I) the early upregulation of IL-4 production induced by the LACK antigen, II) the upregulation of IL-2 production, III) the high production of TGF-beta as macrophage deactivating factor, and IV) the production of IL-10 by the L. major infected macrophages, inhibited their microbicidal activity.
Infection and Immunity, 2001
Virulence variability was investigated by analyzing the experimental pathogenicity of 19 Leishmania major strains in susceptible BALB/c mice. Twelve strains were isolated from Tunisian patients with zoonotic cutaneous leishmaniasis; seven strains were isolated in Syria (n ؍ 1), Saudi Arabia (n ؍ 2), Jordan (n ؍ 2), or Israel (n ؍ 2). BALB/c mice were injected in the hind footpad with 2 ؋ 10 6 amastigotes of the various isolates, and lesion progression was recorded weekly for 9 weeks. Interleukin-4 (IL-4) and gamma interferon (IFN-␥) production of lymph node mononuclear cells activated in vitro with parasite antigens were evaluated 5 weeks after infection. We show that disease progression induced by different L. major isolates was largely heterogeneous although reproducible results were obtained when using the same isolate. Interestingly, isolates from the Middle East induced a more severe disease than did the majority of Tunisian isolates. Strains with the highest virulence tend to generate more IL-4 and less IFN-␥ in vitro at week 5 postinfection as well as higher levels of early IL-4 mRNA in the lymph node draining the inoculation site at 16 h postinfection. These results suggest that L. major isolates from the field may differ in virulence, which influences the course of the disease induced in mice and the type of immune response elicited by the infected host.
Microbes and Infection, 2000
Most experimental studies on leishmaniasis compare two different inbred strains of mice that are resistant or susceptible to one species of Leishmania. In the present study we characterized some cytokines and nitric oxide production as well as histological changes related to resistance and susceptibility in isogenic CBA mice infected with Leishmania major or Leishmania amazonensis. CBA mice are capable of controlling infection with L. major, but they succumb to infection with L. amazonensis. Cells from susceptible L. amazonensis-infected CBA mice produced interleukin (IL)-4 and IL-10 but no interferon (IFN)-γ. On the other hand, resistant L. major-infected CBA mice produced IFN-γ and IL-10, but IL-4 was detected only in the first week of infection. Histopathological studies showed patterns of tissue responses at the site of the infection and in the draining lymph nodes that correlated with resistance or susceptibility. Resistant mice showed a mixed inflammatory cell infiltration and granulomas in the lesions, whereas in susceptible mice only heavily parasitized macrophages were seen. Our results indicate an important role of the parasite species in determining the pattern of immune response. L. amazonensis induces a Th2-type immune response, whereas L. major induces a Th1-type response. These factors must be identified and taken into account in the strategies for the development of vaccines against leishmaniasis. The model presented here will be useful for the study of such factors.