المؤلفون: Daria L. Ivanova, Ryan Krempels, Stephen L. Denton, Kevin D. Fettel, Giandor M. Saltz, David Rach, Rida Fatima, Tiffany Mundhenke, Joshua Materi, Ildiko R. Dunay, Jason P. Gigley

المصدر: Frontiers in Cellular and Infection Microbiology, Vol 10 (2020)

مصطلحات موضوعية: 0301 basic medicine, Microbiology (medical), LAG3, T cell, 030106 microbiology, Immunology, lcsh:QR1-502, Toxoplasma gondii, NK cells, Microbiology, lcsh:Microbiology, 03 medical and health sciences, Immune system, medicine, Cytotoxic T cell, biology, chronic infection, Acquired immune system, biology.organism_classification, Chronic infection, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, ILC, CD8 T cell exhaustion, CD8

الوصف: NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination, and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and alters cyst burdens in brain. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis in spleen. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell characteristics. NK cells are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. These NK cells are found in both spleen and brain. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced on CD8+ T cells. Blockade of NKp46 rescued the chronically infected mice from death and reduced the number of NKG2A+ cells. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8402cbe6d11ad00c00b439e90761767b
https://doi.org/10.3389/fcimb.2020.00313

المؤلفون: Rainer H. Müller, Hartmut Stocker, Markus M. Heimesaat, Faris Nadiem Bushrab, Ildiko R. Dunay, Klaus Borner, Oliver Liesenfeld, Michael Kurowski, Rudolf Fitzner, Keikawus Arastéh

مصطلحات موضوعية: Antiprotozoal Agents, Sulfadiazine, Pharmacology, Mass Spectrometry, Mice, Meninges, Maintenance therapy, medicine, Animals, Pharmacology (medical), Experimental Therapeutics, Lung, Atovaquone, Chromatography, High Pressure Liquid, Brain Chemistry, business.industry, Therapeutic effect, Clindamycin, Brain, medicine.disease, Survival Analysis, Toxoplasmosis, Mice, Inbred C57BL, Infectious Diseases, Pyrimethamine, Liver, Toxoplasmosis, Cerebral, Immunology, Injections, Intravenous, Female, business, Encephalitis, medicine.drug, Naphthoquinones

الوصف: Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for “acute” intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral “maintenance” therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii , developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d22ede4c83674b48449f8d485893dfe
https://europepmc.org/articles/PMC529229/

المؤلفون: Ildiko R. Dunay, Klaus J. Erb, Oliver Liesenfeld

المصدر: Infection and immunity. 72(7)

مصطلحات موضوعية: Immunology, Down-Regulation, Spleen, Microbiology, Mice, Th2 Cells, Immunity, Immunopathology, parasitic diseases, medicine, Animals, Nippostrongylus, Nippostrongylus brasiliensis, Antigens, Strongylida Infections, biology, Toxoplasma gondii, Th1 Cells, medicine.disease, biology.organism_classification, Toxoplasmosis, Infectious Diseases, medicine.anatomical_structure, Coinfection, Parasitology, Female, Fungal and Parasitic Infections, Toxoplasma

الوصف: Oral infection of C57BL/6 mice with 100 cysts of the protozoan parasite Toxoplasma gondii results in the development of small intestinal Th1-type immunopathology. In contrast, infection with intestinal helminths results in the development of protective Th2-type responses. We investigated whether infection with the helminth Nippostrongylus brasiliensis influences the development of T. gondii -induced Th1 responses and immunopathology in C57BL/6 mice infected with T. gondii . Prior as well as simultaneous infection of mice with N. brasiliensis did not alter the course of infection with 100 cysts of T. gondii . Coinfected mice produced high levels of interleukin-12 (IL-12) and gamma interferon (IFN-γ), developed small intestinal immunopathology, and died at the same time as mice infected with T. gondii . Interestingly, local and systemic N. brasiliensis -induced Th2 responses, including IL-4 and IL-5 production by mesenteric lymph node and spleen cells and numbers of intestinal goblet cells and blood eosinophils, were markedly lower in coinfected than in N. brasiliensis -infected mice. Similar effects were seen when infection with 10 T. gondii cysts was administered following infection with N. brasiliensis . Infection of C57BL/6 mice with 10 T. gondii cysts prior to coinfection with N. brasiliensis inhibited the development of helminth-induced Th2 responses and was associated with higher and prolonged N. brasiliensis egg production. In contrast, oral administration of Toxoplasma lysate prior to N. brasiliensis infection had only a minor and short-lived effect on Th2 responses. Thus, N. brasiliensis -induced Th2 responses fail to alter T. gondii -induced Th1 responses and immunopathology, most likely because Th1 responses develop unchanged in C57BL/6 mice with a prior or simultaneous infection with N. brasiliensis . Our findings contribute to the understanding of immune regulation in coinfected animals and may assist in the design of immunotherapies for human Th1 and Th2 disorders.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9260fa7a68cf473e8fa6a5d093b4d491
https://pubmed.ncbi.nlm.nih.gov/15213122