Response of<i>scid</i>mice to establishment of<i>Leishmania major</i>infection

Guy, Rebecca A.; Belosevic, Miodrag

doi:10.1111/j.1365-2249.1995.tb03719.x

Cited by 18 publications

(9 citation statements)

References 28 publications

(15 reference statements)

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“…The L. major 5ASKH infection model was consistent with reports that lesion development by either L. major (MHOM/UZ/91/PM2) or L. amazonensis (MPRO/ BR/72/M1845) was similar or less in the presence of lymphocytes [7,8]. The L. major Friedlin infection model also explains the previous report that delayed or no lesion development in the absence of T/B lymphocytes by L. major (WHOM/IR/-/173) [9,10] or L. amazonensis (MHOM/BR/77/LTB0016) [12] infection. Thus, the impact of lymphocytes for pathogenesis can be determined by the genetic background of L. major.…”

Section: Discussionsupporting

confidence: 89%

“…The distinct impact of lymphocytes for the pathogenesis of CL was confirmed to be attributed to the genetic background of L. major. Our results clarified the contradictory findings of previous independent studies, in which lesion development by CL was either similar [7,8], delayed or less pronounced [9,10,12] in the absence of T/B lymphocyte-mediated immune responses compared to wild-type mice. The L. major 5ASKH infection model was consistent with reports that lesion development by either L. major (MHOM/UZ/91/PM2) or L. amazonensis (MPRO/ BR/72/M1845) was similar or less in the presence of lymphocytes [7,8].…”

Section: Discussionsupporting

confidence: 87%

“…Some studies showed that lesion development was independent of T/B cells in CL models using L. major [7] or Leishmania amazonensis [8]. Other studies showed that lesion development caused by L. major [9,10] or L. amazonensis [11] infection was delayed and less severe in the absence of T/B cells. Soong et al showed that CD4 + T lymphocytes are indispensable for pathogenesis during L. amazonensis infection [12].…”

Section: Introductionmentioning

confidence: 99%

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Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner

et al. 2019

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“…Dissemination is inhibited by the administration of recombinant IL-12 and resistant mouse strains restrict the spread of the parasites [30]. While several susceptible mouse strains have been reported to show some increase in dissemination [60]–[62], disseminated parasite loads in CD11c cre IL-4Rα -/lox mice were unusually dramatic, with relatively higher parasite burdens in the spleens and footpads compared to other susceptible strains. Unexpectedly, parasites were even identified within the brain of some of the CD11c cre IL-4Rα -/lox mice.…”

Section: Discussionmentioning

confidence: 99%

Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection

et al. 2013

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In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions.

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“…In the absence of CD4+ T cells (e.g., in severe combined immunodeficient [SCID] mice), L. major infections are uncontrolled and extensive disseminated disease results [6,7]. However, with intact adaptive immune systems, most mouse strains (e.g., C57Bl/6, CBA, C3H) develop lesions at the site of L.…”

Section: Introductionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Slows the Progression of Experimental Cutaneous Leishmaniasis in Susceptible BALB/c and SCID Mice

et al. 2013

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In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.

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Response ofscidmice to establishment ofLeishmania majorinfection

Cited by 18 publications

References 28 publications

Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner

Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner

Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection

2,3,7,8-Tetrachlorodibenzo-p-dioxin Slows the Progression of Experimental Cutaneous Leishmaniasis in Susceptible BALB/c and SCID Mice

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