Genetics of Host Response to Leishmania tropica in Mice – Different Control of Skin Pathology, Chemokine Reaction, and Invasion into Spleen and Liver

Kobets, Tatyana; Havelková, Helena; Grekov, Igor; Volkova, Valeriya; Vojtíšková, Jarmila; Slapničková, Martina; Kurey, Iryna; Sohrabi, Yahya; Svobodová, Milena; Démant, Peter; Lipoldová, Marie

doi:10.1371/journal.pntd.0001667

Cited by 27 publications

(44 citation statements)

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“…These experiments revealed that manifestations of the disease after infection with L. tropica are strongly influenced by genotype of the host. We have found that females of the RC strain CcS-16 that contains 12.5% genes of the resistant donor strain STS and 87.5% genes of the susceptible strain BALB/c [43], [47] developed the largest skin lesions and exhibited a unique systemic chemokine reaction, characterized by additional transient early peaks of CCL3 and CCL5, which were present neither in CcS-16 males nor in any other tested RC strain [46]. In order to establish the genetic basis of these differences, we prepared F 2 hybrids between BALB/c and CcS-16, infected them with L. tropica and measured their skin lesions, splenomegaly, hepatomegaly, parasite numbers in spleen, liver and inguinal lymph nodes, and serum level of CCL3, CCL5 and CCL7 during the transient early peak.…”

Section: Introductionmentioning

confidence: 80%

“…Multiple functions are also exerted by Ltr3 on chromosome 3, which controls splenomegaly (in interaction with Ltr2 ), parasite numbers in spleen, and levels of CCL3 and CCL5 in serum. We have analyzed genetic control of early levels of chemokines, as there is a unique early peak in the CcS-16 females [46]. However, comparison of genetic control of CCL3 and CCL5 levels with genetic control of development of skin lesions indicates that there is no simple correlation between the chemokines levels and manifestations of disease.…”

Section: Discussionmentioning

confidence: 99%

“…Parental strains BALB/c, STS and RC strains CcS-3, CcS-5, CcS-11, CcS-12, CcS-16, CcS-18, and CcS-20 were infected with L. tropica and skin lesions, cytokine and chemokine levels in serum, splenomegaly, hepatomegaly, and parasite numbers in organs were measured [46]. These experiments revealed that manifestations of the disease after infection with L. tropica are strongly influenced by genotype of the host.…”

Section: Introductionmentioning

confidence: 99%

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Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse

et al. 2013

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Background L. tropica can cause both cutaneous and visceral leishmaniasis in humans. Although the L. tropica-induced cutaneous disease has been long known, its potential to visceralize in humans was recognized only recently. As nothing is known about the genetics of host responses to this infection and their clinical impact, we developed an informative animal model. We described previously that the recombinant congenic strain CcS-16 carrying 12.5% genes from the resistant parental strain STS/A and 87.5% genes from the susceptible strain BALB/c is more susceptible to L. tropica than BALB/c. We used these strains to map and functionally characterize the gene-loci regulating the immune responses and pathology.MethodsWe analyzed genetics of response to L. tropica in infected F2 hybrids between BALB/c×CcS-16. CcS-16 strain carries STS-derived segments on nine chromosomes. We genotyped these segments in the F2 hybrid mice and tested their linkage with pathological changes and systemic immune responses.Principal FindingsWe mapped 8 Ltr (Leishmania tropica response) loci. Four loci (Ltr2, Ltr3, Ltr6 and Ltr8) exhibit independent responses to L. tropica, while Ltr1, Ltr4, Ltr5 and Ltr7 were detected only in gene-gene interactions with other Ltr loci. Ltr3 exhibits the recently discovered phenomenon of transgenerational parental effect on parasite numbers in spleen. The most precise mapping (4.07 Mb) was achieved for Ltr1 (chr.2), which controls parasite numbers in lymph nodes. Five Ltr loci co-localize with loci controlling susceptibility to L. major, three are likely L. tropica specific. Individual Ltr loci affect different subsets of responses, exhibit organ specific effects and a separate control of parasite load and organ pathology.ConclusionWe present the first identification of genetic loci controlling susceptibility to L. tropica. The different combinations of alleles controlling various symptoms of the disease likely co-determine different manifestations of disease induced by the same pathogen in individual mice.

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Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse

et al. 2013

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“…The observations of progeny having a phenotype, which is beyond the range of the phenotype of its parents, are not rare in traits controlled by multiple genes. It was detected in different tests of immune responses of RC strains in vitro [51–56] and in vivo [21, 57–60], and in analysis of expression quantitative trait loci (QTLs) from the livers of chromosome substitution strains [61]. These observations are due to multiple gene-gene interactions of QTLs, which in new combinations of these genes in RC or chromosomal substitution strains can lead to the appearance of new phenotypes that exceed their range in parental strains.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental data have shown different sex influence on susceptibility to relatively closely related pathogen species [20, 21], different sex biases in susceptibility to the same Leishmania species in different host genotypes [21, 22], and different sex and genetic influence on organ-specific pathology [21, 23, 24]. For example, high resistance to skin lesions induced by L. mexicana was observed in females but not in males of DBA/2 mice, but the sex effect was opposite in L. major infection [20].…”

Section: Introductionmentioning

confidence: 99%

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

et al. 2016

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BackgroundSex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis. The disease is caused by parasites that enter to the skin and can spread to the lymph nodes, spleen, liver, bone marrow, and sometimes lungs. Parasites induce host defenses including cell infiltration, leading to protective or ineffective inflammation. These responses are often influenced by host genotype and sex. We analyzed the role of sex in the impact of specific gene loci on eosinophil infiltration and its functional relevance.MethodsWe studied the genetic control of infiltration of eosinophils into the inguinal lymph nodes after 8 weeks of Leishmania major infection using mouse strains BALB/c, STS, and recombinant congenic strains CcS-1,-3,-4,-5,-7,-9,-11,-12,-15,-16,-18, and -20, each of which contains a different random set of 12.5% genes from the parental “donor” strain STS and 87.5% genes from the “background” strain BALB/c. Numbers of eosinophils were counted in hematoxylin-eosin-stained sections of the inguinal lymph nodes under a light microscope. Parasite load was determined using PCR-ELISA.ResultsThe lymph nodes of resistant STS and susceptible BALB/c mice contained very low and intermediate numbers of eosinophils, respectively. Unexpectedly, eosinophil infiltration in strain CcS-9 exceeded that in BALB/c and STS and was higher in males than in females. We searched for genes controlling high eosinophil infiltration in CcS-9 mice by linkage analysis in F2 hybrids between BALB/c and CcS-9 and detected four loci controlling eosinophil numbers. Lmr14 (chromosome 2) and Lmr25 (chromosome 5) operate independently from other genes (main effects). Lmr14 functions only in males, the effect of Lmr25 is sex independent. Lmr15 (chromosome 11) and Lmr26 (chromosome 9) operate in cooperation (non-additive interaction) with each other. This interaction was significant in males only, but sex-marker interaction was not significant. Eosinophil infiltration was positively correlated with parasite load in lymph nodes of F2 hybrids in males, but not in females.ConclusionsWe demonstrated a strong influence of sex on numbers of eosinophils in the lymph nodes after L. major infection and present the first identification of sex-dependent autosomal loci controlling eosinophilic infiltration. The positive correlation between eosinophil infiltration and parasite load in males suggests that this sex-dependent eosinophilic infiltration reflects ineffective inflammation.

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Heterogeneity of humoral immune response to Leishmania tropica in an experimental model

2019

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Genetics of Host Response to Leishmania tropica in Mice – Different Control of Skin Pathology, Chemokine Reaction, and Invasion into Spleen and Liver

Cited by 27 publications

References 55 publications

Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse

Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

Heterogeneity of humoral immune response to Leishmania tropica in an experimental model

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