Critical role of TLR2 in triggering protective immunity with cyclophilin entrapped in oligomannose-coated liposomes against Neospora caninum infection in mice

AbstractGMMA are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes. We applied the GMMA technology for the development of an O-Antigen (OAg) based vaccine against Shigella sonnei, the most epidemiologically relevant cause of shigellosis. S. sonnei OAg has been identified as a key antigen for protective immunity, and GMMA are able to induce anti-OAg-specific IgG response in animal models and healthy adults. The contribution of protein-specific antibodies induced upon vaccination with GMMA has never been fully elucidated. Anti-protein antibodies are induced in mice upon immunization with either OAg-negative and OAg-positive GMMA. Here we demonstrated that OAg chains shield the bacteria from anti-protein antibody binding and therefore anti-OAg antibodies were the main drivers of bactericidal activity against OAg-positive bacteria. Interestingly, antibodies that are not targeting the OAg are functional against OAg-negative bacteria. The immunodominant protein antigens were identified by proteomic analysis. Our study confirms a critical role of the OAg on the immune response induced by S. sonnei GMMA. However, little is known about OAg length and density regulation during infection and, therefore, protein exposure. Hence, the presence of protein antigens on S. sonnei GMMA represents an added value for GMMA vaccines compared to other OAg-based formulations.

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A role for balance of interferon-gamma and interleukin-4 production in protective immunity against Neospora caninum infection

Veterinary Parasitology ◽

10.1016/s0304-4017(03)00286-3 ◽

2003 ◽

Author(s):

Y Nishikawa

Keyword(s):

Interferon Gamma ◽

Protective Immunity ◽

Neospora Caninum ◽

Interleukin 4 ◽

Caninum Infection

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Detection of Neospora caninum Infection in Aborted Equine Fetuses in Israel

Pathogens ◽

10.3390/pathogens9110962 ◽

2020 ◽

Vol 9 (11) ◽

pp. 962

Author(s):

Monica Leszkowicz Mazuz ◽

Lea Mimoun ◽

Gili Schvartz ◽

Sharon Tirosh-Levy ◽

Igor Savitzki ◽

...

Keyword(s):

Neospora Caninum ◽

Fluorescent Antibody ◽

Fetal Loss ◽

Antibody Test ◽

Transplacental Transmission ◽

Caninum Infection ◽

Parasite Detection ◽

Polymerase Chain ◽

Equine Abortion

In horses, Neospora caninum and Neospora hughesi have been associated with fetal loss, and neurological disease, respectively. This study investigated the role of Neospora spp. infection in equine abortion in Israel. The presence of anti-Neospora spp. antibodies was evaluated in 31 aborting mares by indirect fluorescent antibody test (IFAT) and the presence of parasite DNA in their aborted fetuses was evaluated by polymerase chain reaction (PCR), using two target loci (ITS1 and Nc5). The seroprevalence found in aborting mares was 70.9% and the prevalence by DNA detection in the aborted fetuses was 41.9%. Transplacental transmission from positive mares to their fetuses was 45.4% (10/22), while 33.3% (3/9) of fetuses of seronegative mares also tested positive for Neospora. The use of two PCR targets improved the sensitivity of parasite detection, and positive samples were identified by sequence analyses as N. caninum. These finding suggest that N. caninum could be a significant cause of abortion in horses, and that transplacental transmission in horses is an important way of transmission of N.caninum. The results presented here demonstrated the necessity to use several tests concurrently, including serological and molecular assays in order to confirm the involvement of Neospora in mare abortions.

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Effector CD8+ T Lymphocytes against Liver Stages of Plasmodium yoelii Do Not Require Gamma Interferon for Antiparasite Activity

Infection and Immunity ◽

10.1128/iai.00471-08 ◽

2008 ◽

Vol 76 (8) ◽

pp. 3628-3631 ◽

Cited By ~ 41

Author(s):

Sumana Chakravarty ◽

G. Christian Baldeviano ◽

Michael G. Overstreet ◽

Fidel Zavala

Keyword(s):

T Cells ◽

T Cell ◽

Protective Immunity ◽

Critical Role ◽

Plasmodium Yoelii ◽

Gamma Interferon ◽

Parasite Development ◽

Wild Type ◽

Ifn Γ

ABSTRACT The protective immune response against liver stages of the malaria parasite critically requires CD8+ T cells. Although the nature of the effector mechanism utilized by these cells to repress parasite development remains unclear, a critical role for gamma interferon (IFN-γ) has been widely assumed based on circumstantial evidence. However, the requirement for CD8+ T-cell-mediated IFN-γ production in protective immunity to this pathogen has not been directly tested. In this report, we use an adoptive transfer strategy with circumsporozoite (CS) protein-specific transgenic T cells to examine the role of CD8+ T-cell-derived IFN-γ production in Plasmodium yoelii-infected mice. We show that despite a marginal reduction in the expansion of naive IFN-γ-deficient CS-specific transgenic T cells, their antiparasite activity remains intact. Further, adoptively transferred IFN-γ-deficient CD8+ T cells were as efficient as their wild-type counterparts in limiting parasite growth in naive mice. Taken together, these studies demonstrate that IFN-γ secretion by CS-specific CD8+ T cells is not essential to protect mice against live sporozoite challenge.

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Macrophage Depletion Prior to Neospora caninum Infection Results in Severe Neosporosis in Mice

Clinical and Vaccine Immunology ◽

10.1128/cvi.00082-14 ◽

2014 ◽

Vol 21 (8) ◽

pp. 1185-1188 ◽

Cited By ~ 17

Author(s):

Chisa Abe ◽

Sachi Tanaka ◽

Fumiaki Ihara ◽

Yoshifumi Nishikawa

Keyword(s):

Interferon Gamma ◽

Interleukin 6 ◽

Protective Immunity ◽

Neospora Caninum ◽

Caninum Infection ◽

Content Type ◽

Murine Macrophages ◽

Macrophage Depletion ◽

Increased Sensitivity ◽

Ifn Γ

ABSTRACTWe observed that murine macrophages showed greater activation and increased interleukin 6 (IL-6), IL-12p40, and interferon gamma (IFN-γ) production duringNeospora caninuminfection. Many macrophages migrated to the site of infection. Furthermore, macrophage-depleted mice exhibited increased sensitivity toN. caninuminfection. This study indicates that macrophages are required for achieving protective immunity againstN. caninum.

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Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths

Mucosal Immunology ◽

10.1038/mi.2014.101 ◽

2014 ◽

Vol 8 (3) ◽

pp. 672-682 ◽

Cited By ~ 46

Author(s):

K Oeser ◽

C Schwartz ◽

D Voehringer

Keyword(s):

Immune Cells ◽

Protective Immunity ◽

Critical Role ◽

Innate Immune ◽

Innate Immune Cells ◽

Gastrointestinal Helminths ◽

Deficient Mice

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Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development of Pulmonary Tuberculosis

Pulmonary Medicine ◽

10.1155/2012/745483 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 96

Author(s):

Yone Vila Nova Cavalcanti ◽

Maria Carolina Accioly Brelaz ◽

Juliana Kelle de Andrade Lemoine Neves ◽

José Candido Ferraz ◽

Valéria Rêgo Alves Pereira

Keyword(s):

Immune Response ◽

Protective Immunity ◽

Critical Role ◽

Tnf Alpha ◽

Infection Site ◽

Ifn Gamma ◽

Major Function ◽

Reactive Nitrogen Intermediates ◽

Th1 And Th2 Responses

Host immune response againstMycobacterium tuberculosisis mediated by cellular immunity, in which cytokines and Th1 cells play a critical role. In the process of control of the infection by mycobacteria, TNF-alpha seems to have a primordial function. This cytokine acts in synergy with IFN-gamma, stimulating the production of reactive nitrogen intermediates (RNIs), thus mediating the tuberculostatic function of macrophages, and also stimulating the migration of immune cells to the infection site, contributing to granuloma formation, which controls the disease progression. IFN-gamma is the main cytokine involved in the immune response against mycobacteria, and its major function is the activation of macrophages, allowing them to exert its microbicidal role functions. Different from TNF-alpha and IFN-gamma, IL-10 is considered primarily an inhibitory cytokine, important to an adequate balance between inflammatory and immunopathologic responses. The increase in IL-10 levels seems to support the survival of mycobacteria in the host. Although there is not yet conclusive studies concerning a clear dichotomy between Th1 and Th2 responses, involving protective immunity and susceptibility to the disease, respectively, we can suggest that the knowledge about this responses based on the prevailing cytokine profile can help to elucidate the immune response related to the protection againstM. tuberculosis.

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Predominant role of interferon-γ in the host protective effect of CD8+ T cells against Neospora caninum infection

Scientific Reports ◽

10.1038/srep14913 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 10

Author(s):

Alexandra Correia ◽

Pedro Ferreirinha ◽

Sofia Botelho ◽

Ana Belinha ◽

Catarina Leitão ◽

...

Keyword(s):

T Cells ◽

Protective Effect ◽

Cd8 T Cells ◽

Neospora Caninum ◽

Interferon Γ ◽

Predominant Role ◽

Caninum Infection

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Pathological and immunological findings in placentas from pregnant BALB/c mice infected with Neospora caninum at early and late stages of gestation

Acta Parasitologica ◽

10.2478/s11686-011-0052-8 ◽

2011 ◽

Vol 56 (3) ◽

Cited By ~ 1

Author(s):

Inmaculada López-Pérez ◽

Esther Collantes-Fernández ◽

Silvia Rojo-Montejo ◽

Vanesa Navarro-Lozano ◽

Verónica Risco-Castillo ◽

...

Keyword(s):

Neospora Caninum ◽

Placental Tissue ◽

Parasite Load ◽

Late Gestation ◽

Histopathological Analysis ◽

Caninum Infection ◽

Tnf Α ◽

Ifn Γ ◽

Late Stages

AbstractNeospora caninum is transmitted from a cow to its foetus by vertical transmission and the timing of infection in gestation is an important factor in determining the disease outcome. Few studies have explored the role of the placenta in the outcome of N. caninum infection during pregnancy. Here, we described the N. caninum presence, parasite load, local immune response, and histopathological lesions at the materno-foetal interface after infection of BALB/c mice at early and late stages of gestation. In mice infected at early gestation, N. caninum DNA was detected in foetoplacentary units 7 days post-infection (PI) and in the placenta, but not in viable foetuses on day 14 PI, indicating that the parasite was multiplying primarily in the placental tissues without reaching the foetus. Moreover, parasite DNA was detected in resorptions, suggesting that foetal death could be a consequence of infection. An increase in IFN-γ, TNF-α and IL-10 expression was observed in N. caninum PCR-positive placentas, which could favour N. caninum foetal transmission and be harmful to both the placenta and the foetus. Histopathological analysis revealed necrosis affecting both the maternal and foetal sides of the placenta. At late gestation, transmission occurred rapidly following infection (day 3 PI), but parasite were rarely found. In addition, an increase in cytokine expression was observed in spleen and placental tissues from infected animals, while a downregulation in IL-4 expression was only observed in the spleen. Finally, necrosis in the placenta was limited to the maternal side, suggesting that the parasite is mainly multiplying in the placental tissue at this stage. Thus, the results of the present study indicate that the placenta may be actively involved in N. caninum pathogenesis.

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The Protective Role of TLR2 Mediates Impaired Autophagic Flux by Activating the mTOR Pathway During Neospora caninum Infection in Mice

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.788340 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jielin Wang ◽

Xiaocen Wang ◽

Pengtao Gong ◽

Fu Ren ◽

Xin Li ◽

...

Keyword(s):

Kinase Inhibitor ◽

Neospora Caninum ◽

Early Stage ◽

Infection Process ◽

Autophagic Flux ◽

Caninum Infection ◽

Early Stages

Autophagy has been shown to play an essential role in defending against intracellular bacteria, viruses, and parasites. Mounting evidence suggests that autophagy plays different roles in the infection process of different pathogens. Until now, there has been no conclusive evidence regarding whether host autophagy is involved in Neospora caninum infection. In the current study, we first monitored the activation of autophagy by N. caninum, which occurred mainly in the early stages of infection, and examined the role of host autophagy in N. caninum infection. Here, we presented evidence that N. caninum induced an increase in autophagic vesicles with double-membrane structures in macrophages at the early stage of infection. LC3-II expression peaked and decreased as infection continued. However, the expression of P62/SQSTM1 showed significant accumulation within 12 h of infection, indicating that autophagic flux was blocked. A tandem fluorescence protein mCherry-GFP-LC3 construct was used to corroborate the impaired autophagic flux. Subsequently, we found that N. caninum infection induced the activation of the TLR2–AKT–mTOR pathways. Further investigation revealed that TLR2–mTOR, accompanied by the blockade of autophagic flux, was responsible for impaired autophagy but was not associated with AKT. In vitro and in vivo, N. caninum replication was strongly blocked by the kinase inhibitor 3-methyladenine (3-MA, autophagy inhibitor). In contrast, rapamycin (Rapa, an autophagy inducer) was able to promote intracellular proliferation and reduce the survival rate of N. caninum-infected mice. On the other hand, the accumulation of autophagosomes facilitated the proliferation of N. caninum. Collectively, our findings suggest that activation of host autophagy facilitates N. caninum replication and may counteract the innate immune response of the host. In short, inhibition of the early stages of autophagy could potentially be a strategy for neosporosis control.

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