Identifying phenotypes involved in susceptibility to Schistosoma mansoni infection in F1B6CBA mice

Villar, Luis; Vicente, Belén; Blanco-Gómez, Adrián; Castellanos, Andrés; Pérez-Losada, Jesús; Muro, Antonio

doi:10.2478/s11686-014-0277-4

Cited by 4 publications

(10 citation statements)

References 43 publications

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“…mansoni -infected mice, treated with EDLF or PZQ+EDLF, further supporting an anti-inflammatory effect of EDLF-containing therapies, and thus ameliorating hepatic granulomatous inflammation and liver damage. However, no significant changes were detected in the total number of blood lymphocytes and monocytes following pretreatment with PZQ, EDLF or PZQ+EDLF when compared to infected untreated mice, showing figures similar to those previously reported [ 91 ]. On these grounds, our data indicate that the inclusion of EDLF in the prophylactic regimen leads to a dramatic change in the immune response elicited following S .…”

Section: Discussionsupporting

confidence: 89%

Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

et al. 2015

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BackgroundSchistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis.Methodology/Principal FindingsUsing in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.Conclusions/SignificanceTaken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

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Section: Discussionsupporting

confidence: 89%

Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

et al. 2015

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“…The data obtained in F1BX mice showed worms recoveries like resistant parental strains. Also, eggs in tissues and liver damage were intermediate to the parental strains obtained in previous works in our research group [24]. When we compared F1BX mice phenotypic variable with F1B6CBA we observe a lower number of worms, both males and females, and a lower number of eggs per gram of liver [15].…”

Section: Discussionsupporting

confidence: 53%

“…There was a different susceptibility to schistosomiasis in mice related to the genetic background but not to mouse sex We had previously studied the susceptibility/resistance to Schistosoma mansoni infection in C57BL/6J, CBA/2 mouse strains and the F1B6CBA [15]. Now we generated a backcross (F1BX) cohort of 105 mice to identify associated chromosomal regions with S. mansoni infection.…”

Section: Resultsmentioning

confidence: 99%

“…The susceptibility to infection in the F1B6CBA hybrid mice was between these two parental strains yielding intermediate susceptibility [15]. The strain differences in the response to S. mansoni also offer the chance to study the genetic factors influencing whether an animal can develop intense or mild worm recovery or lesions to this infection.…”

Section: Introductionmentioning

confidence: 99%

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Identification of genomic regions implicated in susceptibility toSchistosoma mansoniinfection in a murine genetic model (backcross)

Hernández-Goenaga

López‐Abán

Blanco-Gómez

et al. 2022

Preprint

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High levels of infection and severe liver fibrosis in schistosomiasis appear only in a few cases of infected people with high susceptibility. Tissue damage is caused by the inflammatory response to eggs trapped in the liver. The genetic background influences susceptibility to schistosome infection. To assess the genetic basis of susceptibility to schistosomiasis and identify the chromosomic regions involved, we used a backcross strategy to generate a mouse cohort with high variation in schistosomiasis susceptibility. Thus, we crossed the resistant C57BL/6 mouse strain with the susceptible CBA one; and later; the F1 females (C57 x CBA) were backcrossed with CBA males generating the F1BX cohort. The spectrum of phenotypes in the F1BX mice showed gradation from mild to severe disease, lacking a fully resistant group. We differentiated four levels of infection intensity using cluster and principal component analyses and K-means based on parasitological, pathological and immunological trait measurements. Mice were massively genotyped with 961 informative SNPs. We identify 19 new quantitative trait loci (QTL) associated with phenotype indicators of parasite burden, liver lesion, white blood cell populations, and antibody responses evaluated in the backcross cohort. Two QTLs on chromosomes 15 and 18 were simultaneously linked to the number of granulomas, grade of liver lesion and IgM levels. The human syntenic regions are located in chromosomes 8 and 18. None of the significant QTL identified coincided with previously reported mice association or were syntenic with human chromosomes.Author summaryHigh number of cases of infection and high levels of infection and liver fibrosis in schistosomiasis appear only in a few cases of people with high susceptibility, because the genetic background influences this susceptibility. To assess this, we used a backcross strategy crossing a resistant strain of mouse C57BL/6 with another susceptible CBA, and later F1 females were backcrossed with males susceptible, generating the F1BX cohort, which showed gradation from mild to severe disease. We differentiated four levels of infection according to cluster, principal component analysis and K-means, and based on parasitological, pathological and immunological measurements. Mice were massively genotyped and 19 quantitative trait loci (QTL) were identified, associated with phenotype indicators evaluated in backcross cohort. Two QTLs on chromosomes 15 and 18 were simultaneously linked to the number of granulomas, grade of liver lesion and IgM levels. None of the significant QTL identified coincided with previously reported mice association or were syntenic with human chromosomes.

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“…Susceptibility to schistosomiasis has been associated with genetic components, apart from socio-economic, environmental and ecological factors. 22 Thus, certain genotypes are thought to be more prone to schistosomiasis than others. The genes TNF-α and IL-10 have attracted considerable attention as possible contributors to susceptibility or resistance to infectious, non-communicable, immune-mediated and autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 and tumour necrosis factor alpha promoter region polymorphisms and susceptibility to urogenital schistosomiasis in young Zimbabwean children living in Schistosoma haematobium endemic regions

Marume

Vengesai

Mann

et al. 2020

Southern African Journal of Infectious Diseases

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Background: Host genetic factors can influence susceptibility, morbidity and mortality from schistosomiasis. The study explored the association between single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10) and tumour necrosis factor alpha (TNF-α) promoter regions and susceptibility to Schistosoma haematobium infection.Methods: Urine specimens were collected from 361 primary school children aged 5–15 years from schistosomiasis endemic areas of Manicaland and Mashonaland central provinces. Schistosoma haematobium was diagnosed using the urine filtration method. Only 272 participants provided adequate blood for genotyping. Genotyping was performed using the amplification refractory mutation system-polymerase chain reaction. The association between IL-10 and TNF-α SNPs and S. haematobium infection was analysed using the chi-square test.Results: Schistosoma haematobium infection was confirmed in 26.8% of the participants. No significant difference in S. haematobium prevalence between men (51.6% of those infected) and women (48.4%) (χ2 = 0.008, df = 1, p = 0.928) was observed. The total IL-10 -1082 G, IL-10 -819 C and TNF-α -308G allele distribution between S. haematobium infected and uninfected participants was 50.7% and 51.5% (χ2 = 0.025, df = 1, p = 0.87), 54.3% and 60.6% (χ2 = 1.187, df = 1, p = 0.187) and 82.1% and 80.9% (χ2 = 0.099, df = 1, p = 0.753), respectively, and the differences were not significant.Conclusion: Interleukin-10 -1082 G/A, IL-10 -819 C/T and TNF-α -308 G/A SNPs were not significantly associated with susceptibility to S. haematobium infection. The prevalence of schistosomiasis is still in the moderate range and is similar in boys and girls.

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Identifying phenotypes involved in susceptibility to Schistosoma mansoni infection in F1B6CBA mice

Cited by 4 publications

References 43 publications

Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel

Identification of genomic regions implicated in susceptibility toSchistosoma mansoniinfection in a murine genetic model (backcross)

Interleukin-10 and tumour necrosis factor alpha promoter region polymorphisms and susceptibility to urogenital schistosomiasis in young Zimbabwean children living in Schistosoma haematobium endemic regions

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