RESUMO
Toxoplasmosis is caused by Toxoplasma gondii, an apicomplexan parasite that is able to infect any nucleated cell in any warm-blooded animal. Toxoplasma gondii infects around 2 billion people and, whilst only a small percentage of infected people will suffer serious disease, the prevalence of the parasite makes it one of the most damaging zoonotic diseases in the world. Toxoplasmosis is a disease with multiple manifestations: it can cause a fatal encephalitis in immunosuppressed people; if first contracted during pregnancy, it can cause miscarriage or congenital defects in the neonate; and it can cause serious ocular disease, even in immunocompetent people. The disease has a complex epidemiology, being transmitted by ingestion of oocysts that are shed in the faeces of definitive feline hosts and contaminate water, soil and crops, or by consumption of intracellular cysts in undercooked meat from intermediate hosts. In this review we examine current and future approaches to control toxoplasmosis, which encompass a variety of measures that target different components of the life cycle of T. gondii. These include: education programs about the parasite and avoidance of contact with infectious stages; biosecurity and sanitation to ensure food and water safety; chemo- and immunotherapeutics to control active infections and disease; prophylactic options to prevent acquisition of infection by livestock and cyst formation in meat; and vaccines to prevent shedding of oocysts by definitive feline hosts.
Assuntos
Toxoplasma , Toxoplasmose Animal , Toxoplasmose , Animais , Gatos , Feminino , Humanos , Oocistos , Gravidez , Prevalência , Toxoplasmose/prevenção & controle , Toxoplasmose Animal/prevenção & controle , ZoonosesRESUMO
Toxoplasmic encephalitis is an AIDS-defining condition. The decline of IFN-γ-producing CD4+ T cells in AIDS is a major contributing factor in reactivation of quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important to characterize CD4-independent mechanisms that constrain acute T. gondii infection. We investigated the in vivo regulation of IFN-γ production by CD8+ T cells, DN T cells and NK cells in response to acute T. gondii infection. Our data show that processing of IFN-γ by these non-CD4 cells is dependent on both IL-12 and IL-18 and the secretion of bioactive IL-18 in response to T. gondii requires the sensing of viable parasites by multiple redundant inflammasome sensors in multiple hematopoietic cell types. Importantly, our results show that expansion of CD8+ T cells, DN T cells and NK cell by S4B6 IL-2 complex pre-treatment increases survival rates of mice infected with T. gondii and this is dependent on IL-12, IL-18 and IFN-γ. Increased survival is accompanied by reduced pathology but is independent of expansion of TReg cells or parasite burden. This provides evidence for a protective role of IL2C-mediated expansion of non-CD4 cells and may represent a promising lead to adjunct therapy for acute toxoplasmosis.
Assuntos
Interferon gama/biossíntese , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Interleucina-2/farmacologia , Toxoplasmose/imunologia , Toxoplasmose/prevenção & controle , Animais , Encéfalo/parasitologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-2/química , Camundongos , Toxoplasma/efeitos dos fármacos , Toxoplasma/fisiologia , Toxoplasmose/metabolismoRESUMO
Apicomplexans are obligate intracellular parasites that scavenge essential nutrients from their hosts via transporter proteins on their plasma membrane. The identities of the transporters that mediate amino acid uptake into apicomplexans are unknown. Here we demonstrate that members of an apicomplexan-specific protein family-the Novel Putative Transporters (NPTs)-play key roles in the uptake of cationic amino acids. We show that an NPT from Toxoplasma gondii (TgNPT1) is a selective arginine transporter that is essential for parasite survival and virulence. We also demonstrate that a homologue of TgNPT1 from the malaria parasite Plasmodium berghei (PbNPT1), shown previously to be essential for the sexual gametocyte stage of the parasite, is a cationic amino acid transporter. This reveals a role for cationic amino acid scavenging in gametocyte biology. Our study demonstrates a critical role for amino acid transporters in the survival, virulence and life cycle progression of these parasites.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Apicomplexa/metabolismo , Parasitos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Animais , Apicomplexa/crescimento & desenvolvimento , Arginina/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Feminino , Gametogênese/fisiologia , Estágios do Ciclo de Vida/fisiologia , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oócitos/metabolismo , Parasitos/crescimento & desenvolvimento , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/metabolismo , Proteínas de Protozoários/metabolismo , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/metabolismoRESUMO
Prospective application of serum cytokines, lipopolysaccharide (LPS), and heat shock proteins (eHSPs) requires reliable measurement of these biomarkers that can signify exercise-induced heat stress in hot conditions. To accomplish this, both short-term (7 day) reliability (at rest, n = 12) and the acute responsiveness of each biomarker to exercise in the heat (pre and post 60-min cycling, 34.5°C and 70% RH, n = 20) were evaluated. Serum was analysed for the concentration of C-reactive protein (CRP), interleukin-6 (IL-6), heat shock protein 72 (eHSP72), immunoglobulin M (IgM) and LPS. Test-retest reliability was determined as the coefficient of variation (CV). Biomarkers with the least short-term within-participant variation were IL-6 (19%, ±20%; CV, ±95% confidence limits (CL)) and LPS (23%, ±13%). Greater variability was observed for IgM, eHSP72 and CRP (CV range 28-38%). IL-6 exhibited the largest increase in response to acute exercise (95%, ±11%, P = < 0.001) and although CRP had a modest CV (12%, ±7%), it increased substantially post-exercise (P = 0.02, ES; 0.78). In contrast, eHSP72 and LPS exhibited trivial changes post-exercise. It appears variation of common inflammatory markers after exercise in the heat is not always discernible from short-term (weekly) variation.
Assuntos
Exercício Físico/fisiologia , Transtornos de Estresse por Calor/diagnóstico , Temperatura Alta/efeitos adversos , Mediadores da Inflamação/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Proteínas de Choque Térmico HSP72/sangue , Transtornos de Estresse por Calor/sangue , Humanos , Umidade/efeitos adversos , Imunoglobulina M/sangue , Interleucina-6/sangue , Lipopolissacarídeos/sangue , Masculino , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis. PRINCIPAL FINDINGS: Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFκB activation in P2X7R-deficient mice. CONCLUSIONS: Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation.
Assuntos
Suscetibilidade a Doenças , Ileíte/genética , Ileíte/parasitologia , Receptores Purinérgicos P2X7/deficiência , Toxoplasma , Toxoplasmose Animal/genética , Toxoplasmose Animal/parasitologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ileíte/metabolismo , Ileíte/patologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Toxoplasmose Animal/metabolismoRESUMO
ATP is an extracellular signal for the immune system, particularly during an inflammatory response. It is sensed by the P2X7 receptor, the expression of which is upregulated by pro-inflammatory cytokines. Activation of the P2X7 receptor opens a cation-specific channel that alters the ionic environment of the cell, activating several pathways, including (i) the inflammasome, leading to production of IL-1ß and IL-18; (ii) the stress-activated protein kinase pathway, resulting in apoptosis; (iii) the mitogen-activated protein kinase pathway, leading to generation of reactive oxygen and nitrogen intermediates; and (iv) phospholipase D, stimulating phagosome-lysosome fusion. The P2X7 receptor can initiate host mechanisms to remove pathogens, most particularly those that parasitise macrophages. At the same time, the P2X7 receptor may be subverted by pathogens to modulate host responses. Moreover, recent genetic studies have demonstrated significant associations between susceptibility or resistance to parasites and bacteria, and loss-of-function or gain-of-function polymorphisms in the P2X7 receptor, underscoring its importance in infectious disease.
Assuntos
Infecções Bacterianas/metabolismo , Doenças Parasitárias/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Animais , Apoptose , Bactérias/imunologia , Infecções Bacterianas/imunologia , Suscetibilidade a Doenças , Humanos , Inflamassomos/metabolismo , Interleucina-18/biossíntese , Interleucina-1beta/biossíntese , Canais Iônicos/metabolismo , Macrófagos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Parasitos/imunologia , Doenças Parasitárias/imunologia , Fosfolipase D/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
The P2X7R is highly expressed on the macrophage cell surface, and activation of infected cells by extracellular ATP has been shown to kill intracellular bacteria and parasites. Furthermore, single nucleotide polymorphisms that decrease receptor function reduce the ability of human macrophages to kill Mycobacterium tuberculosis and are associated with extrapulmonary tuberculosis. In this study, we show that macrophages from people with the 1513C (rs3751143, NM_002562.4:c.1487A>C) loss-of-function P2X7R single nucleotide polymorphism are less effective in killing intracellular Toxoplasma gondii after exposure to ATP compared with macrophages from people with the 1513A wild-type allele. Supporting a P2X7R-specific effect on T. gondii, macrophages from P2X7R knockout mice (P2X7R-/-) are unable to kill T. gondii as effectively as macrophages from wild-type mice. We show that P2X7R-mediated T. gondii killing occurs in parallel with host cell apoptosis and is independent of NO production.
Assuntos
Macrófagos/imunologia , Receptores Purinérgicos P2/genética , Toxoplasmose/genética , Animais , Apoptose/imunologia , Separação Celular , Citometria de Fluxo , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico/biossíntese , Óxido Nítrico/imunologia , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2/imunologia , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Toxoplasma , Toxoplasmose/imunologia , Toxoplasmose/metabolismo , Toxoplasmose Animal/genética , Toxoplasmose Animal/metabolismoRESUMO
BACKGROUND: The nature of the immune response to infection is dependent on the type of infecting organism. Intracellular organisms such as Toxoplasma gondii stimulate a Th1-driven response associated with production of IL-12, IFN-gamma, nitric oxide and IgG2a antibodies and classical activation of macrophages. In contrast, extracellular helminths such as Fasciola hepatica induce Th2 responses characterised by the production of IL-4, IL-5, IL-10 and IgG1 antibodies and alternative activation of macrophages. As co-infections with these types of parasites commonly exist in the field it is relevant to examine how the various facets of the immune responses induced by each may influence or counter-regulate that of the other. PRINCIPAL FINDINGS: Regardless, of whether F. hepatica infection preceded or succeeded T. gondii infection, there was little impact on the production of the Th1 cytokines IL-12, IFN-gamma or on the development of classically-activated macrophages induced by T. gondii. By contrast, the production of helminth-specific Th2 cytokines, such as IL-4 and IL-5, was suppressed by infection with T. gondii. Additionally, the recruitment and alternative activation of macrophages by F. hepatica was blocked or reversed by subsequent infection with T. gondii. The clinical symptoms of toxoplasmosis and the survival rate of infected mice were not significantly altered by the helminth. CONCLUSIONS: Despite previous studies showing that F. hepatica suppressed the classical activation of macrophages and the Th1-driven responses of mice to bystander microbial infection, as well as reduced their ability to reject these, here we found that the potent immune responses to T. gondii were capable of suppressing the responses to helminth infection. Clearly, the outcome of particular infections in polyparasitoses depends on the means and potency by which each pathogen controls the immune response.
Assuntos
Fasciola hepatica/imunologia , Fasciolíase/imunologia , Células Th1/imunologia , Células Th2/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Doença Aguda , Animais , Anticorpos Anti-Helmínticos/imunologia , Anticorpos Antiprotozoários/imunologia , Citocinas/biossíntese , Fasciolíase/sangue , Fasciolíase/complicações , Imunoglobulina G/sangue , Ativação de Macrófagos/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/parasitologia , Camundongos , Baço/citologia , Baço/imunologia , Baço/parasitologia , Células Th1/parasitologia , Células Th2/parasitologia , Toxoplasmose Animal/sangue , Toxoplasmose Animal/complicaçõesRESUMO
Toxoplasma gondii is a unique intracellular parasite. It can infect a variety of cells in virtually all warm-blooded animals. It has a worldwide distribution and, overall, around one-third of people are seropositive for the parasite, with essentially the entire human population being at risk of infection. For most people, T. gondii causes asymptomatic infection but the parasite can cause serious disease in the immunocompromised and, if contracted for the first time during pregnancy, can cause spontaneous abortion or congenital defects, which have a substantial emotional, social and economic impact. Toxoplasma gondii provokes one of the most potent innate, pro-inflammatory responses of all infectious disease agents. It is also a supreme manipulator of the immune response so that innate immunity to T. gondii is a delicate balance between the parasite and its host involving a coordinated series of cellular interactions involving enterocytes, neutrophils, dendritic cells, macrophages and natural killer cells. Underpinning these interactions is the regulation of complex molecular reactions involving Toll-like receptors, activation of signalling pathways, cytokine production and activation of anti-microbial effector mechanisms including generation of reactive nitrogen and oxygen intermediates.