Impact of Schistosoma japonicum Infection on Collagen-Induced Arthritis in DBA/1 Mice: A Murine Model of Human Rheumatoid Arthritis

BACKGROUND: The hygiene hypothesis suggests that helminth infections prevent a range of autoimmune diseases. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the effects of S. japonicum infection on collagen-induced arthritis (CIA), male DBA/1 mice were challenged with unisexual or bisexual S. japonicum cercariae two weeks prior to bovine type II collagen (CII) immunization or at the onset of CIA. S. japonicum infection prior to CII immunization significantly reduced the severity of CIA. ELISA (enzyme linked immunosorbent assay) showed that the levels of anti-CII IgG and IgG2a were reduced in prior schistosome-infected mice, while anti-CII IgG1 was elevated. Splenocyte proliferation against both polyclonal and antigen-specific stimuli was reduced by prior schistosome infection as measured by tritiated thymidine incorporation ((3)H-TdR). Cytokine profiles and CD4(+) T cells subpopulation analysis by ELISA and flow cytometry (FCM) demonstrated that prior schistosome infection resulted in a significant down-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β and IL-6) and Th1 cells, together with up-regulation of the anti-inflammatory cytokine IL-10 and Th2 cells. Interestingly, the expansion of Treg cells and the reduction of Th17 cells were only observed in bisexually infected mice. In addition, prior schistosome infection notably reduced the expression of pro-inflammatory cytokines and receptor activator of NF-κB ligand (RANKL) in the inflamed joint. However, the disease was exacerbated at one week after infection when established CIA mice were challenged with bisexual cercariae. CONCLUSION/SIGNIFICANCE: Our data provide direct evidence that the Th2 response evoked by prior S. japonicum infection can suppress the Th1 response and pro-inflammatory mediator and that bisexual infection with egg-laying up-regulates the Treg response and down-regulates the Th17 response, resulting in an amelioration of autoimmune arthritis. The beneficial effects might depend on the establishment of a Th2-dominant response rather than the presence of the eggs. Our results suggest that anti-inflammatory molecules from the parasite could treat autoimmune diseases

Mast Cells Modulate Acute Toxoplasmosis in Murine Models

The role of mast cells (MCs) in Toxoplasma gondii infection is poorly known. Kunming outbred mice were infected intraperitoneally with RH strain T. gondii, either treated with compound 48/80 (C48/80, MC activator) or disodium cromoglycate (DSCG, MC inhibitor). Compared with infected controls, infected mice treated with C48/80 exhibited significantly increased inflammation in the liver (P \u3c 0.01), spleen (P \u3c 0.05), and mesentery (P \u3c 0.05) tissues, higher parasite burden in the peritoneal lavage fluids (P \u3c 0.01), and increased levels of mRNA transcripts of T. gondii tachyzoite surface antigen 1 (SAG1) gene in the spleen and liver tissues (P \u3c 0.01), accompanied with significantly increased Th1 cytokine (IFN-γ, IL-12p40, and TNF-α) (P \u3c 0.01) and decreased IL-10 (P \u3c 0.01) mRNA expressions in the liver, and increased IFN-γ (P \u3c 0.01) and IL-12p40 (P \u3c 0.01) but decreased TNF-α (P \u3c 0.01) and IL-4 (P \u3c 0.01) in the spleens of infected mice treated with C48/80 at day 9-10 p.i. Whereas mice treated with DSCG had significantly decreased tissue lesions (P \u3c 0.01), lower parasite burden in the peritoneal lavage fluids (P \u3c 0.01) and decreased SAG1 expressions in the spleen and liver tissues (P \u3c 0.01), accompanied with significantly increased IFN-γ (P \u3c 0.01) and IL-12p40 (P \u3c 0.05) in the liver, and decreased IFN-γ (P \u3c 0.05) and TNF-α (P \u3c 0.01) in the spleens; IL-4 and IL-10 expressions in both the spleen and liver were significantly increased (P \u3c 0.01) in the infected mice treated with DSCG. These findings suggest that mediators associated with the MC activation may play an important role in modulating acute inflammatory pathogenesis and parasite clearance during T. gondii infection in this strain of mice. Thus, MC activation/inhibition mechanisms are potential novel targets for the prevention and control of T. gondii infection

Variation detection based on next-generation sequencing of type Chinese 1 strains of Toxoplasma gondii with different virulence from China

A: Summary of annotation for SNPs; B: Summary of annotation for indels; C: Summary of annotation for SVs; D: Summary of annotation for CNVs. (DOCX 18 kb

Strategies Developed by Toxoplasma gondii to Survive in the Host

One of the most successful intracellular parasites, Toxoplasma gondii has developed several strategies to avoid destruction by the host. These include approaches such as rapid and efficient cell invasion to avoid phagocytic engulfment, negative regulation of the canonical CD40-CD40L-mediated autophagy pathway, impairment of the noncanonical IFN-γ-dependent autophagy pathway, and modulation of host cell survival and death to obtain lifelong parasite survival. Different virulent strains have even evolved different ways to cope with and evade destruction by the host. This review aims to illustrate every aspect of the game between the host and Toxoplasma during the process of infection. A better understanding of all aspects of the battle between Toxoplasma and its hosts will be useful for the development of better strategies and drugs to control the parasite

Effective Amelioration of Liver Fibrosis Through Lentiviral Vector Carrying Toxoplasma gondii gra15II in Murine Model

Our previous investigations indicated that in vitro polarization of mouse macrophages by Toxoplasma gondii type II strain dense granule protein 15 (GRA15II), one of the genotype-associated effectors of T. gondii, induced the phenotypes of classically activated macrophage (M1). Transfusion of the cells to mice may effectively alleviated hepatic fibrosis caused by schistosomiasis. The purpose of the study was to identify whether liver macrophages can be in vivo driven to M1 macrophages by lentiviral vector (LV) carrying GRA15II gene (LV-gra15II) and to explore the potential mechanism by which the LV-gra15II-activated liver macrophage (LV-gra15II-M) ameliorates the hepatic fibrosis in schistosomiasis. The mice were treated with LV-gra15II by hydrodynamic injection via the tail vein followed by challenge of Schistosoma japonicum (S. japonicum). Our experiments showed that LV-gra15II was successfully delivered to liver macrophages and GRA15II was persistently expressed in the macrophages of mice for at least 2 months. Furthermore, the LV-gra15II infected macrophages were polarized to M1 macrophages in vivo. Consequently, mice with schistosomiasis receiving LV-gra15II injection displayed a remarkable amelioration of liver granuloma formation and collagen deposition in association with downregulated expression of transforming growth factor-beta1, arginase 1 (Arg-1), α-smooth muscle actin, and an increased expression of matrix metalloproteinase 13 (MMP13). Simultaneously, no negative effects of liver function and vitality of mice were noted. The in vitro experiments indicated that the C-C motif chemokine ligand 2 and nitric oxide level were elevated in LV-gra15II-M cultural supernatants; hepatocyte growth factor expression was enhanced in LV-gra15II-M. In addition, LV-gra15II-M not only secreted MMP13, which greatly degraded type I collagen, but also induced murine hepatic stellate cell (HSC) line (JS1) apoptosis in the co-culture system. Taken together, we identified for the first time that LV-gra15II may in vivo drive liver macrophages to M1 macrophage phenotypes, which helps for alteration of the liver fibrotic microenvironment with collagen dissolution, HSC deactivation, apoptosis and hepatocyte protection. Our study gives an insight into the use of gene delivery with parasite-derived immunomodulatory factor as a potential immune cell activating agent to re-equilibrate the other pathogen-induced immune response in some chronic diseases

Protective Effect Against Toxoplasmosis in BALB/c Mice Vaccinated With Toxoplasma gondii Macrophage Migration Inhibitory Factor

Toxoplasma gondii is an obligate intracellular parasite responsible for toxoplasmosis, which can cause severe disease in the fetus and immunocompromised individuals. Developing an effective vaccine is crucial to control this disease. Macrophage migration inhibitory factor (MIF) has gained substantial attention as a pivotal upstream cytokine to mediate innate and adaptive immune responses. Homologs of MIF have been discovered in many parasitic species, and one homolog of MIF has been isolated from the parasite Toxoplasma gondii. In this study, the recombinant Toxoplasma gondii MIF (rTgMIF) as a protein vaccine was expressed and evaluated by intramuscular injection in BALB/c mice. We divided the mice into different dose groups of vaccines, and all immunizations with purified rTgMIF protein were performed at 0, 2, and 4 weeks. The protective efficacy of vaccination was analyzed by antibody assays, cytokine measurements and lymphoproliferative assays, respectively. The results obtained indicated that the rTgMIF vaccine elicited strong humoral and cellular immune responses with high levels of IgG antibody and IFN-γ production compared to those of the controls, in addition to slight higher levels of IL-4 production. After vaccination, a stronger lymphoproliferative response was also noted. Additionally, the survival time of mice immunized with rTgMIF was longer than that of the mice in control groups after challenge infection with virulent T. gondii RH tachyzoites. Moreover, the number of brain tissue cysts in vaccinated mice was reduced by 62.26% compared with the control group. These findings demonstrated that recombinant TgMIF protein is a potential candidate for vaccine development against toxoplasmosis

Observation of TeV gamma rays from the Cygnus region with the ARGO-YBJ experiment

We report the observation of TeV gamma-rays from the Cygnus region using the ARGO-YBJ data collected from 2007 November to 2011 August. Several TeV sources are located in this region including the two bright extended MGRO J2019+37 and MGRO J2031+41. According to the Milagro data set, at 20 TeV MGRO J2019+37 is the most significant source apart from the Crab Nebula. No signal from MGRO J2019+37 is detected by the ARGO-YBJ experiment, and the derived flux upper limits at 90% confidence level for all the events above 600 GeV with medium energy of 3 TeV are lower than the Milagro flux, implying that the source might be variable and hard to be identified as a pulsar wind nebula. The only statistically significant (6.4 standard deviations) gamma-ray signal is found from MGRO J2031+41, with a flux consistent with the measurement by Milagro.Comment: 14 pages, 4 figure

Observation of TeV gamma-rays from the unidentified source HESS J1841-055 with the ARGO-YBJ experiment

We report the observation of a very high energy \gamma-ray source, whose position is coincident with HESS J1841-055. This source has been observed for 4.5 years by the ARGO-YBJ experiment from November 2007 to July 2012. Its emission is detected with a statistical significance of 5.3 standard deviations. Parameterizing the source shape with a two-dimensional Gaussian function we estimate an extension \sigma=(0.40(+0.32,-0.22}) degree, consistent with the HESS measurement. The observed energy spectrum is dN/dE =(9.0-+1.6) x 10^{-13}(E/5 TeV)^{-2.32-+0.23} photons cm^{-2} s^{-1} TeV^{-1}, in the energy range 0.9-50 TeV. The integral \gamma-ray flux above 1 TeV is 1.3-+0.4 Crab units, which is 3.2-+1.0 times the flux derived by HESS. The differences in the flux determination between HESS and ARGO-YBJ, and possible counterparts at other wavelengths are discussed.Comment: 17 pages, 4 figures, have been accepted for publication in Ap

Long-term monitoring of the TeV emission from Mrk 421 with the ARGO-YBJ experiment

ARGO-YBJ is an air shower detector array with a fully covered layer of resistive plate chambers. It is operated with a high duty cycle and a large field of view. It continuously monitors the northern sky at energies above 0.3 TeV. In this paper, we report a long-term monitoring of Mrk 421 over the period from 2007 November to 2010 February. This source was observed by the satellite-borne experiments Rossi X-ray Timing Explorer and Swift in the X-ray band. Mrk 421 was especially active in the first half of 2008. Many flares are observed in both X-ray and gamma-ray bands simultaneously. The gamma-ray flux observed by ARGO-YBJ has a clear correlation with the X-ray flux. No lag between the X-ray and gamma-ray photons longer than 1 day is found. The evolution of the spectral energy distribution is investigated by measuring spectral indices at four different flux levels. Hardening of the spectra is observed in both X-ray and gamma-ray bands. The gamma-ray flux increases quadratically with the simultaneously measured X-ray flux. All these observational results strongly favor the synchrotron self-Compton process as the underlying radiative mechanism.Comment: 30 pages, 8 figure