Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Elso, CM; Kumar, Beena; Smyth, Gordon K.; Foote, Simon J.; Handman, Emanuela

doi:10.1038/sj.gene.6364056

Cited by 19 publications

(26 citation statements)

References 35 publications

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“…Mice congenic for all three resistant lmr alleles [strain C.B6-(lmr1, lmr2)] were generated on the susceptible Bc background and were shown to be more resistant to L. major and more able to heal noninfectious wounds than Bc mice, exhibiting a statistically significant tendency toward the phenotype of the donor strain B6. Furthermore, resistance to L. major was independent of T helper cell responses (12,13,30). The conclusions from these studies were that lmr1, -2, and -3 control the rate of wound healing and L. major host response independently of T helper cell responses and that a vigorous wound healing response was required for lesion resolution during L. major infection.…”

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confidence: 61%

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

et al. 2010

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Genetic linkage studies of the host response to Leishmania major, the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection, but to date, the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1, to both L. major resistance and enhanced wound healing. We have previously mapped the L. major response locus, lmr2, to proximal chromosome 9 in a genetic cross between the resistant C57BL/6 strain and the susceptible BALB/c strain. We now show that the presence of the resistant C57BL/6 lmr2 allele in susceptible BALB/c mice confers an enhanced L. major resistance and wound healing phenotype. Fine mapping of the lmr2 locus permitted the localization of the lmr2 quantitative trait locus to a 5-Mb interval comprising 21 genes, of which microarray analysis was able to identify differential expression in 1 geneFli1. Analysis of Fli1 expression in wounded and L. major-infected skin and naïve and infected lymph nodes validated the importance of Fli1 in lesion resolution and wound healing and identified 3 polymorphisms in the Fli1 promoter, among which a GA repeat element may be the important contributor.Cutaneous leishmaniasis (CL) caused by the intracellular protozoan Leishmania major is a parasitic disease transmitted by blood-sucking sandflies. Skin macrophages are infected, and a skin lesion or granuloma develops at the site of infection (31). The severity of human CL varies, with phenotypes ranging from self-healing lesions to persistent lesions lasting years and leading to systemic disease (1). The severity of disease depends on the host's ability to form protective granulomas; in their absence, the parasites spread, resulting in diffuse cutaneous leishmaniasis. Studies of CL in mice have been of immense interest because they allow extensive experimental manipulation and reproduce many of the features of the human disease. To identify factors that modulate lesion resolution in infected individuals, we conducted genetic studies on two inbred mouse strains, C57BL/6 (B6) and BALB/c (Bc), that differ in their susceptibility to L. major. Resistance to L. major, epitomized by B6 mice, is characterized by the rapid healing of skin lesions, while the susceptibility in Bc mice is characterized by lesion chronicity and progression and systemic spread of the parasites.We previously identified three loci (lmr1, lmr2, and lmr3) mediating lesion resolution during L. major infection (28, 29). Mice congenic for all three resistant lmr alleles [strain C.B6-(lmr1, lmr2)] were generated on the susceptible Bc background and were shown to be more resistant to L. major and more able to heal noninfectious wounds than Bc mice, exhibiting a statistically significant tendency toward the phenotype of the donor strain B6. Furthermore, resistance to L. major was independent of T helper cell responses (12,13,30). The conclusions from these stud...

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confidence: 61%

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

et al. 2010

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“…In a study investigating L. major infections in Balb/c mice, high levels of IL-4 in the draining lymph nodes correlated with the lesion size, thus indicating the disease severity. 10 Other authors have associated a TH2 response with high production of IL-4 to an enhanced susceptibility of some strains of mice to Leishmania amazonensis. 2 In contrast, Kropf et al have shown that IL-4-deficient BALB/c mice infected with L. major developed progressive lesions.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Leishmaniasis in Naturally Infected Dogs is Associated with a T Helper-2-biased Immune Response

et al. 2005

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Abstract. Skin lesions are a frequent manifestation of Leishmania infantum infections in Mediterranean countries. This study demonstrates by real-time reverse transcriptase-polymerase chain reaction the local cytokine response in skin biopsies from Leishmania-infected dogs (n ϭ 10). As controls, we investigated skin biopsies from healthy (n ϭ 10) and fleabite hypersensitive dogs (n ϭ 10). We established a quantitative PCR to determine the parasite burden in biopsies. The objective was to elucidate whether a correlation exists between parasite number, histologic response, and T helper-1 (TH1)/T helper-2 (TH2) cytokine expression in lesional skin of naturally infected dogs. In Leishmania-infected dogs, interleukin-4 (IL-4), tumor necrosis factor ␣ (TNF-␣) and interferon-␥ (IFN-␥) messenger RNA production was significantly higher than controls. Furthermore, dogs with a high Leishmania burden had a significantly higher IL-4 expression, whereas no difference was noted with regard to expression of other cytokines. By comparing the pattern of inflammation and cytokine expression, a clear trend became evident in that levels of IL-4, TNF-␣, and IFN-␥ were elevated in biopsies with a periadnexal nodular pattern and in biopsies where the severity of the periadnexal infiltrate was equal to the perivascular to interstitial infiltrate. Expression of IL-4, IL-13, and TNF-␣ was slightly increased in biopsies where plasma cells prevailed on lymphocytes, whereas expression of IFN-␥ was moderately higher when lymphocytes were predominating. In summary, the present study demonstrates that the local immune response in naturally occurring leishmaniasis includes TH1 as well as TH2 cytokine subsets. Furthermore, respective data suggest that increased expression of the TH2-type cytokine IL-4 is associated with both severe clinical signs and a high parasite burden in the skin lesions.

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“…The virulent cloned line V121, derived from the L. major isolate LRC-L137 (MHOM͞IL͞67͞ JerichoII), was used to infect bone marrow-derived macrophages at a ratio of five parasites per cell, as described (21). Mice were infected with L. major as described (19,20).…”

Section: Methodsmentioning

confidence: 99%

“…These mice differ in susceptibility from their parental lines, exhibiting a statistically significant tendency toward the phenotype of the donor, away from that of the recipient strain (19). Mice congenic for resistance loci lmr1-3 show no role for T cell modulation of the susceptibility phenotype (19,20), suggesting that T cell responses may act elsewhere in the process (9).…”

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confidence: 99%

The wound repair response controls outcome to cutaneous leishmaniasis

Sakthianandeswaren

Elso

Simpson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Chronic microbial infections are associated with fibrotic and inflammatory reactions known as granulomas showing similarities to wound-healing and tissue repair processes. We have previously mapped three leishmaniasis susceptibility loci, designated lmr1, -2, and -3, which exert their effect independently of T cell immune responses. Here, we show that the wound repair response is critically important for the rapid cure in murine cutaneous leishmaniasis caused by Leishmania major. Mice congenic for leishmaniasis resistance loci, which cured their lesions more rapidly than their susceptible parents, also expressed differentially genes involved in tissue repair, laid down more ordered collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast monolayers from these mice repaired in vitro wounds faster, and this process was accelerated by supernatants from infected macrophages. Because these effects are independent of T cell-mediated immunity, we conclude that the rate of wound healing is likely to be an important component of innate immunity involved in resistance to cutaneous leishmaniasis.fibroblasts ͉ leishmania ͉ macrophages ͉ resistance ͉ wound healing

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Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Cited by 19 publications

References 35 publications

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

Cutaneous Leishmaniasis in Naturally Infected Dogs is Associated with a T Helper-2-biased Immune Response

The wound repair response controls outcome to cutaneous leishmaniasis

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