Repeated Exposure Induces Periportal Fibrosis in<i>Schistosoma mansoni-</i>Infected Baboons: Role of TGF-β and IL-4

Farah, Idle O.; Mola, Paul W.; Kariuki, Thomas; Nyindo, Mramba; Blanton, Ronald E.; King, Christopher L.

doi:10.4049/jimmunol.164.10.5337

Cited by 75 publications

(53 citation statements)

References 41 publications

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“…Symmers' fibrosis in the chimpanzee was morphologically indistinguishable from that in man but did not produce portal hypertension (Sadun et al 1970), probably because of the extensive portal-systemic collaterals formed. Njenga et al (1998) and Nyindo and Farah (1999) describe, but do not convincingly illustrate, Symmers'-like periportal fibrosis in S. mansoni-infected baboons and Farah et al (2000) relate portal fibrosis in baboons to reinfection and TGF-β and IL-4 production.…”

Section: Symmers' Clay Pipestem Fibrosismentioning

confidence: 92%

Experimental models of Schistosoma mansoni infection

Cheever

Lenzi²,

Lenzi³

et al. 2002

Mem. Inst. Oswaldo Cruz

123

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Section: Symmers' Clay Pipestem Fibrosismentioning

confidence: 92%

Experimental models of Schistosoma mansoni infection

Cheever

Lenzi²,

Lenzi³

et al. 2002

Mem. Inst. Oswaldo Cruz

123

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“…Cell cultures for determination of T cell reactivity and cytokine production were set up as previously described (37). Briefly, peripheral blood mononuclear cells (PBMCs) were separated from whole blood mixed in 1:2 part Alsever solution (2.05% dextrose, 0.8% trisodium citrate, 0.055% citric acid, and 0.42% sodium chloride) by centrifugation at 2,000 rpm and 24°C for 20 min with Ficoll Paque (Pharmacia Ciotech, St. Albans, United Kingdom), washed twice in phosphate-buffered saline (PBS; 1,500 rpm and 4°C for 10 min), and resuspended in 10 ml of complete medium (RPMI 1640; Sigma-Aldrich, St. Louis, MO) enriched with 10% heat-inactivated fetal bovine serum (Gibco, Canada), 2 mM L-glutamine (Fisher Biotech, Wembley, West Australia, Australia), 25 mM HEPES (Sigma-Aldrich, Dorset, United Kingdom), 80 g/ml gentamicin (Sigma-Aldrich, Dorset, United Kingdom), and 0.22% (vol/vol) sodium bicarbonate (Sigma-Aldrich, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…The protocols for measurement of cytokines in baboon cell cultures have previously been described (37). Briefly, cytokine cell culture supernatants were tested for the presence of IFN-␥, IL-6, IL-10, and TNF-␣ by sandwich enzyme-linked immunosorbent assay (ELISA).…”

Section: Methodsmentioning

confidence: 99%

Protective Effect of Chronic Schistosomiasis in Baboons Coinfected with Schistosoma mansoni and Plasmodium knowlesi

et al. 2016

Self Cite

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c Malaria and schistosomiasis coinfections are common, and chronic schistosomiasis has been implicated in affecting the severity of acute malaria. However, whether it enhances or attenuates malaria has been controversial due the lack of appropriately controlled human studies and relevant animal models. To examine this interaction, we conducted a randomized controlled study using the baboon (Papio anubis) to analyze the effect of chronic schistosomiasis on severe malaria. Two groups of baboons (n ‫؍‬ 8 each) and a schistosomiasis control group (n ‫؍‬ 3) were infected with 500 Schistosoma mansoni cercariae. At 14 and 15 weeks postinfection, one group was given praziquantel to treat schistosomiasis infection. Four weeks later, the two groups plus a new malaria control group (n ‫؍‬ 8) were intravenously inoculated with 10 5 Plasmodium knowlesi parasites and monitored daily for development of severe malaria. A total of 81% of baboons exposed to chronic S. mansoni infection with or without praziquantel treatment survived malaria, compared to only 25% of animals infected with P. knowlesi only (P ‫؍‬ 0.01). Schistosome-infected animals also had significantly lower parasite burdens (P ‫؍‬ 0.004) than the baboons in the P. knowlesi-only group and were protected from severe anemia. Coinfection was associated with increased spontaneous production of interleukin-6 (IL-6), suggesting an enhanced innate immune response, whereas animals infected with P. knowlesi alone failed to develop mitogen-driven tumor necrosis factor alpha and IL-10, indicating the inability to generate adequate protective and balancing immunoregulatory responses. These results indicate that chronic S. mansoni attenuates the severity of P. knowlesi coinfection in baboons by mechanisms that may enhance innate immunity to malaria. P olyparasitism is common in low-resource countries, especially in sub-Saharan Africa. Coinfections may alter disease outcomes and affect both drug and vaccine efficacies (1, 2). The majority of studies on coinfections have focused on interactions between malaria and chronic helminth infections. Interest in studying malaria and schistosomiasis, in particular, comes from the major overlap of the two diseases in areas where they are endemic and the fact that these infections account for a large proportion of global morbidity and mortality (3, 4). Because of the chronicity of schistosome infection, most studies have focused on its impact on susceptibility to clinical malaria.Studies on malaria and schistosomiasis coinfections in human and animal models have generated contradicting results. Although some animal studies have shown that chronic schistosomiasis protects against severe malaria (5), others have reported that a concurrent schistosome infection enhances the severity of malaria (6-10). Many factors may account for these differences, including mouse strain, duration and intensity of the helminth infection, Plasmodium strain or species, inoculum size, or route of malaria infection (skin or blood stage) (11). An important limitat...

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“…32,33 IL-4 expression is enhanced in the fibrotic liver of Schistosoma-infected baboons, and anti-IL-4 therapy markedly diminishes hepatic fibrosis in Schistosomainfected mice. 34,35 We have therefore hypothesized that IL-4 overexpression could contribute to the accelerated progression toward fibrosis that occurs during severe chronic recurrent hepatitis C after LT, by inducing intrahepatic fibroblast activation and collagen overproduction. During this study, we examined the profibrotic effects of IL-4 on human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms.…”

mentioning

confidence: 99%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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Interleukin-4 (IL-4) is overexpressed in liver grafts in a context of severe recurrent hepatitis C, during which the development of fibrosis is dramatically accelerated. In this study, we examined the effects of IL-4 on the activation and collagen production of cultured human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms. The myofibroblastic nature of cells was evaluated morphologically using activation markers (smooth muscle a-actin, vimentin and prolyl 4-hydroxylase). Quiescent hIHFs were obtained by cell incubation in serum-free medium or cell culture on Matrigel. We first analyzed IL-4 receptor expression, STAT-6 activation by IL-4, and STAT-6 inhibition by an anti-IL-4 antibody or by STAT-6 small-interfering RNA (siRNA) transfection. We then focused on collagen production, using quantitative real-time PCR to analyze the effect of IL-4 on the mRNA expression of collagens I, III and IV, and on collagen levels in supernatants of hIHFs, using the Sircol collagen assay. hIHFs cultured in plastic wells appeared to be morphologically activated. The expression of activation markers was reduced by serum deprivation or culture on Matrigel, and restored by IL-4 incubation. The IL-4 receptor was expressed by hIHFs, and STAT-6 was activated following incubation with IL-4. Both anti-IL-4 antibody and STAT-6 siRNA transfection inhibited this activation. The treatment of hIHFs with IL-4 increased the mRNA expression of collagens I, III and IV (Po0.05) and elevated collagen levels in supernatants (P ¼ 0.01 vs untreated cells). Therefore, IL-4 exerts profibrotic effects by activating hIHFs and inducing collagen production and secretion. This effect requires IL4-R binding and STAT-6 activation. IL-4 may thus be involved in accelerated course of fibrogenesis during recurrent hepatitis C.

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Repeated Exposure Induces Periportal Fibrosis inSchistosoma mansoni-Infected Baboons: Role of TGF-β and IL-4

Cited by 75 publications

References 41 publications

Experimental models of Schistosoma mansoni infection

Experimental models of Schistosoma mansoni infection

Protective Effect of Chronic Schistosomiasis in Baboons Coinfected with Schistosoma mansoni and Plasmodium knowlesi

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

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