Effects of cyclic AMP on in vivo cytotoxic T lymphocytes generation

Chronic schistosomiasis mansoni is associated with a modulation of schistosome egg-associated cell-mediated granuloma formation. In this study the injection of a cell-free sonicate from either spleen or thymus cells from chronic Schistosoma mansoni-infected mice (> 15 weeks) passively modulated granuloma size in acutely infected (6–8 weeks) syngeneic mice. Cell-free sonicates from age-matched uninfected mice did not suppress granuloma formation. The chronic extracts also suppressed the soluble schistosome egg antigenic preparation-elicited delayed skin test reactivity in 7–8 week infected animals, but failed to suppress the unrelated antigen-elicited reactivity to bovine serum albumin (BSA) of BSA-sensitized animals.     

Increased synovial fluid levels of interleukin-12, sCD25 and sTNF-RII/sTNF-RI ratio delineate a cytokine pattern characteristic of immune arthropathies

The assessment of cytokines and their soluble receptors in the synovial fluid (SF) of inflammatory arthropathies may be useful in studying pathogenetic and immunoregulatory mechanisms underlying different diseases. The aim of this work was to study the cytokine network occurring in inflammatory arthropathies and to identify a cytokine profile which is characteristic of an immune-mediated synovitis. Levels of IL-12, as well as IL-4, IL-8, IL-10, IFN-gamma, sCD25, TNF-alpha and its soluble receptors were measured in the SF of various arthropathies, i.e. non-inflammatory arthropathies: "control" meniscus pathology (n = 21), osteoarthritis (n = 22) and chronic crystal arthritis (n = 9); a non-immune inflammatory arthropathy: acute crystal arthritis (n = 11); 2 immune inflammatory arthropathies: reactive arthritis (ReA) (n = 23) and rheumatoid arthritis (RA) (n = 44). SF levels of IL-10, TNF-alpha and sTNF-RII were found to be increased in the three inflammatory arthropathies compared to the "control" meniscus group. Within the inflammatory group, acute crystal arthritis was characterized by a significantly higher sTNF-RI/TNF-alpha ratio and ReA by a significantly lower sTNF-RII/TNF-alpha ratio compared to the two other diseases. The two immune arthropathies, RA and ReA, were characterized by increased SF levels of IL-12, sCD25 and of the sTNF-RII/sTNF-RI ratio. ReA differed however from RA by showing lower IL-8 and IL-4 levels, higher IFN-gamma levels and a higher IL-12/IL-10 ratio, suggesting a more prevalent Th1 profile in ReA SF. Our data indicate that the measurement of SF cytokines and soluble receptors may discriminate between each inflammatory arthropathy and might be useful in clinical practice.     

sTNFR-II and sICAM-1 are associated with acute disease and hepatic inflammation in schistosomiasis japonica

Soluble intracellular adhesive molecule 1 (sICAM-1) and tumour necrosis factor receptors I (TNFR-1) and II (TNFR-II) have been shown to be associated with numerous liver disorders. Shedding of these membrane proteins can be triggered by the Th1 cytokines, TNF-alpha and IFN-gamma, which are associated with susceptibility or resistance to hepatic schistosomiasis, respectively. Further, TNF-alpha receptors and sICAM-1 have been implicated in periportal fibrosis in advanced human schistosomiasis mansoni and correlate with schistosome granuloma formation in the murine model. We measured serum levels of sICAM-1, TNFR-I and TNFR-II in Chinese patients with different clinically defined stages of schistosomiasis japonica and controls; these included 35 patients with acute schistosomiasis, 45 patients with chronic schistosome infections, 34 advanced patients with evidence of severe morbidity and 20 patients with no known history of exposure to infection. Markedly elevated levels of soluble TNFRs (sTNFRs) and sICAM-1 were observed in the acute and advanced patients compared with the chronic and control groups. Mean sTNFR-II levels were significantly higher in acute patients compared with advanced (P<0.00001) and chronic patients (P<0.00001) and showed the strongest association of the markers with acute disease (odds ratio (OR)=1.099). sTNFR-II and sICAM-1 levels both correlated with infection intensity and there were significant positive correlations observed between eosinophil count and infection intensity (P=0.0072) and sICAM-1 (P=0.0014). Although there were significantly higher levels of antigen-specific IgG4 and total IgG in infected individuals compared with controls, none correlated with infection intensity. Further, no differences in IgG4 and total IgG levels were observed between the acute and chronic groups. The results suggest sTNFRs and sICAM-1 are associated with liver inflammation and disease progression. Measurement of sTNFR-II and sICAM-1 levels in serum could serve as additional markers for the diagnosis of acute stage disease and the monitoring of hepatic inflammation in human schistosomiasis japonica.     

Involvement of extracellular matrix proteins in the course of experimental paracoccidioidomycosis

We aimed at determining involvement of extracellular matrix proteins (ECMp) and an ECM-binding adhesin (32-kDa protein) from Paracoccidioides brasiliensis, in the course of experimental paracoccidioidomycosis. BALB/c mice were infected with P. brasiliensis conidia previously incubated with soluble laminin, fibronectin and fibrinogen or a mAb against the fungal adhesin. Inflammatory response, chitin levels and cytokine production at different postinfection periods were determined. Chitin was significantly decreased in lungs of mice infected with ECMp-treated conidia when compared with controls at week 8, especially with laminin and fibrinogen. Contrariwise, when animals were infected with mAb-treated conidia no differences in chitin content were found. The observed inflammatory reaction in lungs was equivalent in all cases. IFN-gamma increased significantly in lungs from mice infected with soluble ECMp - (at day 4 and week 12) or mAb-treated conidia (at week 12) when compared with animals infected with untreated conidia. Significant increased levels of tumour necrosis factor-alpha were observed at 8 weeks in animals infected with ECMp-treated conidia while no differences were observed during the remaining periods. These findings point toward an inhibitory effect of ECMp on P. brasiliensis conidia infectivity and suggest that these proteins may interfere with conidia initial adhesion to host tissues probably modulating the immune response in paracoccidioidomycosis.     

Immunoregulation in experimental schistosomiasis: in vitro induction and assay of spleen cell suppressor activity

Spleen cells from normal CBA/J mice or mice infected with Schistosoma mansoni were exposed for 48 to 72 hr to either concanavalin A (Con A), soluble egg antigen (SEA), or soluble worm antigenic preparation (SWAP), treated with mitomycin C to prevent further DNA synthesis, and admixed with either normal or sensitized syngeneic spleen cells exposed to a concentration gradient of phytohemagglutinin (PHA) or SEA, respectively. Both nonspecific (by Con A) and "antigen-specific" (by SEA and SWAP in infected mice only) induction of suppression was observed when using PHA-induced blastogenesis as the final assay. The number of mice with inducible splenic suppressive activity and the degree of PHA suppression induced by exposure to SEA appeared to decline between 8 and 20 weeks of infection. In contrast, when the response of spleen cells from mice infected for 8 weeks to SEA served as the final assay, strong suppressive activity was induced from the spleen cells of all chronically infected mice (20 weeks of infection). This model permits parallel analysis of the induction of suppressor activity by nonspecific and schistosome antigen-specific signals during the course of this chronic, immunoregulated condition, schistosomiasis mansoni.     

新型染料木素磺酸酯的合成及对小鼠血吸虫病肝肉芽肿的影响

为寻找抗血吸虫病的新候选化合物,通过正交实验,高选择性、高产率地合成了染料木素的磺酸酯衍生物。结果表明:小鼠感染血吸虫病,经过衍生物治疗后,由血吸虫导致的肉芽肿面积有不同程度的降低,其中低剂量组降低到23.2%,与溶剂组比较,差异显著(P<0.05),优于原药的27.1%及阳性对照组秋水仙碱的27.0%。说明该化合物对血吸虫导致的肉芽肿有一定抑制作用,该化合物有进一步研究价值。     

Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection

The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host.     

A regulatory effect of the balance between TNF-alpha and IL-6 in the granulomatous and inflammatory response to Rhodococcus aurantiacus infection in mice

After i.v. inoculation with Rhodococcus aurantiacus, wild-type (WT) mice develop nonnecrotic, epithelioid granulomas. Because a high level of TNF-alpha is observed during the initial phase postinfection, we examined the extent to which TNF-alpha contributes to granulomatous inflammation using TNF-alpha gene-deficient (TNF-alpha(-/-)) mice. Despite a lack of R. aurantiacus proliferation, TNF-alpha(-/-) mice displayed high mortality rates within 5 days postinfection, as well as a high level of IL-6 in their spleens. Histological examination showed an absence of granuloma formation in TNF-alpha(-/-) mice. Pretreatment of TNF-alpha(-/-) mice with rTNF-alpha failed to restore this granuloma formation but accelerated bacterial removal and cellular recruitment. This rTNF-alpha administration also attenuated IL-6 production, resulting in increased survival rates of TNF-alpha(-/-) mice. Heat-killed R. aurantiacus induced in vitro enhanced mRNA expression and production of IL-6 in macrophages and DCs from TNF-alpha(-/-) mice when compared with WT controls, and treatment of TNF-alpha(-/-) mouse cells with rTNF-alpha decreased the IL-6 secretion. Moreover, anti-TNF-alpha or anti-IL-6 treatment increased IL-6 or TNF-alpha production by WT mouse cells, respectively. These data suggest that the production of TNF-alpha and IL-6 can be negatively regulated by each other. Administration of rIFN-gamma to TNF-alpha(-/-) mice caused immature granulomas in livers, and treatment with both rTNF-alpha and rIFN-gamma led to the formation of mature granulomas. Overall, TNF-alpha appears crucial for bacterial clearance, cellular recruitment, and granuloma formation. The balance between TNF-alpha and IL-6 during the early phase of infection controls the development of the inflammatory response to R. aurantiacus infection.     

Adoptive suppression of granuloma formation by T lymphocytes and by lymphoid cells sensitive to cyclophosphamide.

Egg-induced granulomas formed in mice with chronic Schistosoma mansoni infection are smaller than those which develop during early (8-week) infection. Adoptive transfer of spleen cells from chronically infected mice (15–25 week), which displayed modulated granulomas, to 6-week-infected recipients effectively suppressed active granuloma formation in the recipients by 8 weeks after infection. Pretreatment of these suppressive spleen cells with anti-Thy 1.2 serum and complement eliminated their suppressive capacity. Administration of cyclophosphamide (CY) (20 mg/kg, 3 times/week for 3 weeks) to 12- to 15-week-infected mice reversed modulation of granuloma formation resulting in larger granulomas at 15 weeks. This abrogation of suppression was reflected in the spleens of the CY-treated mice, as seen by the inability of their spleen cells to adoptively transfer suppression to 6-week-infected mice. This regimen of CY treatment did not significantly alter anti-schistosome egg antigen hemagglutinating antibody titers. It is reasoned that the modulation of granuloma formation observed during chronic schistosomiasis mansoni is in part dependent upon a T lymphocyte and a CY-sensitive spleen cell.     

Basophil depletion downregulates Schistosoma mansoni egg-induced granuloma formation

Granuloma formation around parasite eggs during schistosomal infection is considered to be controlled by Th2 cytokines. However, it is still controversial which cell populations are responsible for the host Th2 cytokine-dependent granuloma formation. Basophils have recently attracted attention because of their ability to produce large amounts of IL-4. Therefore, we investigated whether basophils play an essential role in the induction of granuloma formation induced by Schistosoma mansoni eggs. Together with our previous observation that basophil numbers increased markedly in the spleen at 7 weeks postinfection, immunohistochemical staining using anti-mMCP8 monoclonal antibody (mAb) showed basophil infiltration in the granulomatous lesions formed around parasite eggs. To examine the roles of basophils more directly, we treated mice with anti-CD200R3 mAb to deplete basophils. Depletion of basophils resulted in a reduction of basophil number with concomitant downregulation of egg granuloma formation at 7 weeks postinfection. Moreover, we observed a significant reduction in the size of egg granulomas formed in basophil-depleted mice in the pulmonary granuloma model. Taken together, these findings indicated that basophils are essential for S. mansoni egg-induced granuloma formation, and this may serve as a novel therapeutic target in ameliorating the pathology of schistosomiasis.     

日本血吸虫性病兔肝纤维化的酶组织化学研究

目的观察日本血吸虫感染家兔导致肝脏发生纤维化后的肝组织酶学改变.方法将23只成年健康大耳白兔分为正常对照组(N)8只,模型组(M)15只,M组采用腹贴法(日本血吸虫尾蚴180条/只,持续15min)感染血吸虫,六周后服用吡喹酮行杀虫治疗.于实验的第13周将全部动物麻醉后剖腹取肝组织.肝组织行HE染色和电镜观察;酶组织化学方法检测单胺氧化酶(MAO)、一氧化氮合酶(NOS)、琥珀酰脱氢酶(SDH)、乳酸脱氢酶(LDH)在器官的表达活性.结果在血吸虫感染家兔的第13周可观察到肝组织明显纤维化;模型组中MAO、NOS、LDH活性明显高于正常对照组,而SDH活性则明显降低.结论慢性血吸虫感染引起的肝纤维化导致肝细胞缺血缺氧,影响NOS、SDH、LDH活性,加重肝细胞损伤.     

Expression of defective virus and cytokine genes in murine AIDS.

A syndrome characterized by severe immunodeficiency and lymphoproliferation develops in susceptible strains of mice infected with a mixture of murine leukemia viruses (MuLVs) designated LP-BM5 MuLV. The etiologic agent in this mixture has been shown to be a replication-defective virus (BM5d) with a 4.8-kb genome that required replication-competent helper viruses, primarily ecotropic (BM5e), for cell-to-cell spread in the host. In the present study, we studied the expression of BM5d and BM5e in tissues of infected mice at various times after inoculation in relation to the expression of cytokine genes that may contribute to the pathogenesis of this disorder. Northern (RNA) analysis of total RNA showed that BM5d was expressed at significant levels in lymphoid tissues within 1 week of infection and that the levels of expression increased with time after inoculation. By 16 weeks postinfection, BM5d was expressed in all tissues examined. Expression of BM5e was relatively more restricted to lymphoid tissues and was detected at lower levels than expression of BM5d at early times after infection, but this virus was expressed in all tissues by 16 weeks. Infection with the virus mixture was associated with constitutive expression of tumor necrosis factor in all tissues examined and of interleukin-1 (IL-1) in lymphoid tissues within 1 week of infection, and at later times with widespread expression of these cytokines and gamma interferon. Also, the levels of interferon regulatory factor 1 mRNA were significantly increased in all infected tissues during the infection. In contrast, expression of IL-3, IL-4, IL-5, and IL-6 was not detectable by Northern analysis of the respective mRNAs in any infected tissue at early or late times postinfection.     

The substance P receptor is necessary for a normal granulomatous response in murine schistosomiasis mansoni

Immune cells within the granulomas of murine schistosomiasis mansoni make the neuropeptide substance P (SP) and express neurokine 1 receptor, which is the specific receptor for substance P (SPr). It was determined if mice with deletion of the SPr (SPr-/-) would develop a normal granulomatous response to schistosome ova during the course of natural infection. Mean liver granuloma size was smaller in SPr-/- mice compared with that of wild-type control animals. Although flow analysis revealed little difference in the cellular composition of the granulomas, both splenocytes and granuloma cells from SPr-/- mice produced much less IFN-gamma and IgG2a and less IgE. The expression of Th2 cytokines (IL-4/IL-5) and IgG1 was comparable to the wild-type control. The mouse with targeted disruption of its SPr had the nonmammalian gene encoding the enzyme beta-galactosidase inserted in exon 1 of the SPr gene. There was beta-galactosidase activity in many mononuclear cells scattered throughout the schistosome granulomas of SPr-/- mice. Also, a granuloma T cell line derived from this transgenic mouse produced beta-galactosidase. These results provide further evidence that in murine schistosomiasis SPr is displayed commonly on granuloma inflammatory cells and is important for granuloma development and expression of IFN-gamma circuitry in this natural infection.     

Molecular mechanisms for changes in hepatic protein synthesis induced by schistosomiasis infection in mice

Mice infected with Schistosoma mansoni and littermate controls were evaluated serially for 12 weeks. Infected mice gained weight at the same rate as controls, but starting with the sixth week their livers became enlarged with granulomas and fibrous tissue, and they developed hypoalbuminemia. To evaluate the regulation of the albumin and type I collagen gene expression, total RNA was isolated from infected and control mice and translated in an mRNA-dependent rabbit reticulocyte lysate system. Protein synthesis was decreased 1.5-3-fold with RNA from infected vs. control liver. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the cell-free products showed a reduction in albumin but an increase in type I procollagen synthesis in infected mice. Immunoprecipitation of the cell-free product confirmed that albumin synthesis was reduced in greater proportion than other liver proteins in schistosome-infected mice. Hybridization of RNA from infected liver with cloned mouse albumin cDNA (pmalb-2) demonstrated a reduction in albumin mRNA to 37% of control, while hybridization with a chick type I pro alpha 2 collagen cDNA probe (pCg-45) revealed increased procollagen mRNA in infected liver beginning at 6 weeks postinfection. These results suggest that in murine schistosomiasis a reduction in biologically active albumin mRNA results in decreased albumin synthesis and may be responsible in part for hypoalbuminemia. In addition, increased collagen mRNA is associated with increased collagen synthesis during hepatic fibrosis.     

Schistosoma mansoni: higher free proline levels in the livers of infected mice

The concentration of L-hydroxyproline in the liver of ICR female mice increased rapidly during the 8th to 11th weeks of Schistosoma mansoni infection. Free L-proline concentration began to increase about the 7th week and reached its maximum at the 8th to 9th weeks of the infection, when the granulomatous response to the schistosome eggs in the liver was most prominent, as indicated by the increase in liver wet weight and its deoxyribonucleic acid concentration. A significant increment in the total activity of ornithine-delta-transaminase (EC 2.6.1.13) and the decrease in the specific activity of proline oxidase (EC 1.4.3.2) became detectable in the liver homogenate of infected mice on the 8th week. However, changes in these enzymatic activities were not parallel to that of the hepatic free L-proline content. Intraperitoneal administration of S. mansoni egg granulomas or 15,000g x 30 min supernatant fluid of their extracts into uninfected, normal mice significantly increased the hepatic free L-proline content without any appreciable effect on the enzymatic activities of proline oxidase and ornithine-delta-transaminase. These findings suggest that S. mansoni egg granulomas contain a factor(s) which may be responsible for the elevation of free L-proline content in the fibrotic liver caused by experimental schistosomiasis mansoni.     

Repeated exposure induces periportal fibrosis in Schistosoma mansoni-infected baboons: role of TGF-beta and IL-4

Recently, we observed that repeated Schistosoma mansoni infection and treatment boost Th2-associated cytokines and TGF-beta production in baboons. Other studies have shown that some chronically infected baboons develop hepatic fibrosis. Because TGF-beta, IL-2, and IL-4 have been shown to participate in development of fibrosis in murine schistosomiasis, the present study examined whether repeated exposure stimulates hepatic fibrosis in olive baboons. To test this hypothesis, animals were exposed to similar numbers of S. mansoni cercariae given once or repeatedly. After 19 wk of infection, animals were cured with praziquantel and reinfected once or multiple times. Hepatic granulomatous inflammation and fibrosis were assessed from serial liver biopsies taken at weeks 6, 9, and 16 after reinfection and egg Ag (schistosome egg Ag)-specific cytokine production by PBMC were measured simultaneously. Periportal fibroblast infiltration and extracellular matrix deposition (fibrosis), angiogenesis, and biliary duct hyperplasia developed in some animals. The presence and amount of fibrosis directly correlated with the frequency of exposure. Fibrosis was not associated with adult worm or tissue egg burden. The amount of fibrosis correlated with increased schistosome egg Ag-driven TGF-beta at 6, 9, and 16 wk postinfection (rs = 0.9, 0.8, and 0.54, respectively, all p < 0.01) and IL-4 production (p = 0.02) at 16 wk postinfection and not IFN-gamma, IL-2, IL-5, or IL-10. These data suggest that repeated exposure is a risk factor for periportal fibrosis by a mechanism that primes lymphocytes to produce increased levels of profibrotic molecules that include TGF-beta and IL-4.     

Anti-idiotypic T lymphocyte responsiveness in murine Schistosomiasis mansoni

Pooled sera from CBA/J mice infected for greater than or equal to 16 weeks with the blood fluke Schistosoma mansoni were immunoaffinity purified using soluble schistosome egg antigens (SEA) coupled to Sepharose 4B. The bound and then eluted fraction was shown to contain only immunoglobulins and to have anti-SEA activity. These anti-SEA antibodies stimulated proliferation of lymph node cells from mice infected with S. mansoni for 8, 12, or greater than or equal to 16 weeks but not from uninfected mice. The cells stimulated by anti-SEA antibodies were nylon wool adherent, Thy-1.2+, L3T4+, Lyt-2-lymphocytes. Immunoglobulins without anti-SEA activity isolated from the sera of syngeneic uninfected mice were not stimulatory for cells from normal or infected animals. Thus the responding T cells appear to be stimulated by the idiotypes expressed on the syngenic anti-SEA antibodies. These data present evidence for anti-idiotypic cellular reactions in murine schistosomiasis that could play important immunoregulatory roles in this disease.     

Vasoactive intestinal peptide stimulates T lymphocytes to release IL-5 in murine schistosomiasis mansoni infection.

In murine schistosomiasis, granulomas form around ova deposited in the liver and intestines of infected mice. The granulomas have eosinophils that produce vasoactive intestinal peptide (VIP) and T cells that display VIP receptors. IL-5 is a lymphokine important for the development and maturation of eosinophils. It seemed plausible that VIP, released from eosinophils, may interact with lymphocyte VIP receptors and modulate IL-5 production as part of a feedback regulatory circuit. Thus, we determined whether granuloma T cells make IL-5 and whether VIP modulates IL-5 production. Isolated granuloma cells enriched for T lymphocytes spontaneously released IL-5. Culture of these cells in the presence of VIP increased IL-5 secretion. Spleen cells were also studied. Spleen cells from infected mice did not spontaneously release IL-5 or express IL-5 mRNA and VIP did not stimulate these resting spleen cells to produce this IL. However, these cells did express IL-5 mRNA and secreted IL-5 in response to Con A or soluble egg Ag. VIP could not appreciably modulate IL-5 release when cells were cultured with VIP and the Ag or mitogen. Spleen cells washed free of Con A ceased IL-5 secretion within 24 h. These preactivated splenic T cells resumed vigorous IL-5 secretion in response to either Con A or VIP. Yet only Con A prominently induced IL-5 mRNA expression. VIP was an effective stimulus at concentrations equal to or above the kDa of the VIP receptor on both splenic and granuloma T cells (10(-8) M). It is concluded that, in murine schistosomiasis, VIP invokes IL-5 release from activated T cells that are not undergoing immediate TCR stimulation.     

Circulating miRNAs: Potential Novel Biomarkers for Hepatopathology Progression and Diagnosis of Schistosomiasis Japonica in Two Murine Models

Background

Schistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models.

Methodology/Principal Findings

Two mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica.

Conclusions/Significance

We provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite-derived miRNAs.