RESUMEN
In this paper, we present a mathematical model of the immune response to parasites. The model is a type of predator-prey system in which the parasite serves as the prey and the immune response as the predator. The model idealizes the entire immune response as a single entity although it is comprised of several aspects. Parasite density is captured using logistic growth while the immune response is modeled as a combination of two components, activation by parasite density and an autocatalytic reinforcement process. Analysis of the equilibria of the model demonstrate bifurcations between parasites and immune response arising from the autocatalytic response component. The analysis also points to the steady states associated with disease resolution or persistence in leishmaniasis. Numerical predictions of the model when applied to different cases of Leishmania mexicana are in very close agreement with experimental observations.
Asunto(s)
Leishmania mexicana , Leishmaniasis , Humanos , Sistema InmunológicoRESUMEN
Chronic cutaneous disease of mice caused by the protozoan parasite Leishmania mexicana requires interleukin-10 (IL-10) and FcγRIII (an activating IgG receptor). Macrophages readily secrete IL-10 in response to IgG-coated amastigotes, making macrophages a prime candidate as the critical source of IL-10. However, indirect evidence suggested that macrophage IL-10 is not essential for chronic disease. I now show directly that mice lacking IL-10 from macrophages and granulocytes still have chronic disease, like wild-type C57BL/6 mice. However, T cell-derived IL-10 is required for chronic disease. CD4-cre IL-10flox/flox mice lack IL-10 from T cells (both CD4+ and CD8+) and heal their L. mexicana lesions, with parasite control. I had previously shown that depletion of CD25+ T cells had no effect on chronic disease, and thus, T cells other than CD25+ regulatory T (Treg) cells should be the important source of IL-10. Given that conventional T cells do not express FcγRs, there is likely to be an indirect pathway by which FcγRIII on some other cell engaged by IgG1-amastigote immune complexes induces IL-10 from T cells. Further work is needed to delineate these pathways.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-10/genética , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Animales , Anticuerpos Antiprotozoarios/inmunología , Femenino , Granulocitos/inmunología , Inmunoglobulina G/inmunología , Leishmania mexicana/patogenicidad , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de IgG/inmunologíaRESUMEN
STUDY OBJECTIVES: Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats. DESIGN: Animal study. SETTING: Academic Medical Center. PARTICIPANTS: OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats. INTERVENTIONS: TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain). MEASUREMENTS AND RESULTS: MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats. CONCLUSIONS: Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.
Asunto(s)
Tejido Adiposo/fisiopatología , Adiposidad , Obesidad/complicaciones , Obesidad/fisiopatología , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/fisiopatología , Lengua/fisiopatología , Animales , Estudios de Casos y Controles , Lípidos/análisis , Masculino , Músculo Masetero/anatomía & histología , Músculo Masetero/fisiología , Ratas , Ratas Zucker , Sistema Respiratorio/fisiopatología , Delgadez , Lengua/anatomía & histología , Lengua/química , Agua/análisisRESUMEN
Infection with the intracellular protozoan parasite Leishmania mexicana causes chronic disease in C57BL/6 mice, in which cutaneous lesions persist for many months with high parasite burdens (10(7)-10(8) parasites). This chronic disease process requires host IL-10 and FcγRIII. When Leishmania amastigotes are released from cells, surface-bound IgG can induce IL-10 and suppress IL-12 production from macrophages. These changes decrease IFN-γ from T cells and nitric oxide production in infected cells, which are both required for Leishmania control. However, antibodies targets and the kinetics of antibody production are unknown. Several groups have been unsuccessful in identifying amastigote surface proteins that bind IgG. We now show that glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by mouse IgG1 by 6 weeks of infection, with a rapid increase between 12 and 16 weeks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcγRIII-deficient mice. A single prominent spot on TLC is recognized by IgG, and the glycolipid is a glycosyl phosphatidylinositol containing a branched mannose structure. We show that the lipid structure of the GIPL (the sn-2 fatty acid) is required for antibody recognition. This GIPL is abundant in L. mexicana amastigotes, rare in stationary-phase promastigotes, and absent in L. major, consistent with a role for antibodies to GIPLs in chronic disease. A mouse monoclonal anti-GIPL IgG recognizes GIPLs on the parasite surface, and induces IL-10 from macrophages. The current work also extends this mouse analysis to humans, finding that L. mexicana-infected humans with localized and diffuse cutaneous leishmaniasis have antibodies that recognize GIPLs, can bind to the surface of amastigotes, and can induce IL-10 from human monocytes. Further characterization of the target glycolipids will have important implications for drug and vaccine development and will elucidate the poorly understood role of glycolipids in the immunology of infections.
Asunto(s)
Anticuerpos Antiprotozoarios/inmunología , Glicosilfosfatidilinositoles/inmunología , Inmunoglobulina G/inmunología , Interleucina-10/metabolismo , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Monocitos/parasitologíaRESUMEN
Murine norovirus (MNV) is a newly discovered and extremely prevalent pathogen of laboratory mouse colonies. MNV causes severe disease in some immunocompromised mouse strains and can cause persistent infections even in immunocompetent mice. Despite the fact that immunocompetent mice are generally asymptomatic, the possibility that MNV infection might alter immune responses makes its eradication a potentially useful goal for many facilities. Initial attempts by others to use a strategy of testing and culling were unsuccessful, whereas complete depopulation and facility decontamination was successful. However, these measures may be impractical, and finding less drastic approaches seemed prudent. Based on a report that cross-fostering of pups from MNV-positive mothers to MNV-negative ones could be successful in experimental MNV infection, we undertook a comprehensive fostering program using Swiss Webster mothers, careful sanitary measures, and fecal PCR testing to eradicate the virus from a mouse colony recently infected with MNV. We successfully decontaminated 17 of 18 (94%) litters and managed to prevent spread when a new MNV-infected mouse strain entered quarantine at our facility. These results suggest that cross-fostering, when performed in a setting of excellent sanitary procedures, may be practical for the large number of mouse facilities in which MNV is endemic.
Asunto(s)
Crianza de Animales Domésticos/métodos , Animales de Laboratorio/virología , Infecciones por Caliciviridae/veterinaria , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Norovirus , Enfermedades de los Roedores/prevención & control , Enfermedades de los Roedores/transmisión , Animales , Infecciones por Caliciviridae/prevención & control , Infecciones por Caliciviridae/transmisión , Vivienda para Animales , Ratones , Enfermedades de los Roedores/virología , Vigilancia de Guardia/veterinariaRESUMEN
Veterans with a history of mental health and substance abuse diagnoses, residing in assisted living facilities, are more likely to have an undiagnosed HIV infection related to high-risk behaviors. We determined (a) the cross-sectional prevalence of HIV infection among 65 veterans of unknown HIV serostatus with mental health diagnoses who resided in 11 community-assisted living facilities, and (b) whether patients who had not consented to standard physician-initiated blood testing in the previous 5 years would consent to rapid oral fluid HIV testing by nurses familiar to the subjects. We found an HIV prevalence of 3.1% in the subjects who agreed to be tested (n = 64, 98%). High test acceptance, especially in a group with little HIV screening experience, and the identified high prevalence of disease, suggest that this diagnostic method is effective. Patients' familiarity with the nurses who conducted the testing most likely supported the success of the procedure.
Asunto(s)
Serodiagnóstico del SIDA/métodos , Instituciones de Vida Asistida , Infecciones por VIH/complicaciones , Trastornos Mentales/complicaciones , Saliva/virología , Veteranos , Infecciones por VIH/epidemiología , Humanos , Prevalencia , Estados Unidos/epidemiologíaRESUMEN
There are >2 million new cases of leishmaniasis annually, and no effective vaccine has been developed to prevent infection. In murine infection, Leishmania mexicana, which lives intracellularly in host macrophages, has developed pathways to hijack host IgG to induce a suppressive IL-10 response through FcγRs, the cell-surface receptors for IgG. To guide vaccine development away from detrimental Ab responses, which can accompany attempts to induce cell-mediated immunity, it is crucial to know which isotypes of IgG are pathogenic in this infection. We found that IgG1 and IgG2a/c induce IL-10 from macrophages in vitro equally well but through different FcγR subtypes: IgG1 through FcγRIII and IgG2a/c through FcγRI primarily, but also through FcγRIII. In sharp contrast, mice lacking IgG1 develop earlier and stronger IgG2a/c, IgG3, and IgM responses to L. mexicana infection and yet are more resistant to the infection. Thus, IgG1, but not IgG2a/c or IgG3, is pathogenic in vivo, in agreement with prior studies indicating that FcγRIII is required for chronic disease. This calls into question the assumption that macrophages, which should secrete IL-10 in response to IgG1 and IgG2a/c immune complexes, are the most important source of IL-10 generated by IgG-FcγR engagement in L. mexicana infection. Further investigations are required to better determine the cell type responsible for this immunosuppressive FcγRIII-induced IL-10 pathway and whether IgG2a/c is protective.
Asunto(s)
Anticuerpos Antiprotozoarios/efectos adversos , Inmunoglobulina G/efectos adversos , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Animales , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/fisiología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/parasitología , Células de la Médula Ósea/patología , Células Cultivadas , Enfermedad Crónica , Femenino , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/sangre , Inmunoglobulina G/fisiología , Inmunoglobulina M/efectos adversos , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/sangre , Inmunofenotipificación , Leishmaniasis Cutánea/patología , Macrófagos/inmunología , Macrófagos/parasitología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones TransgénicosRESUMEN
The intracellular protozoan parasite Leishmania causes leishmaniasis, which is the second biggest killer worldwide among parasitic diseases, after malaria. As drug therapy for leishmaniasis is toxic and resistance is growing, a vaccine is an important weapon against this disease. Unfortunately, no effective vaccine exists for any human parasitic infection. Worse yet, nearly all effective vaccines whose mechanisms are known work through the induction of protective antibodies. Leishmania mexicana causes primarily chronic cutaneous disease. Not only are antibodies not effective at killing Leishmania, as it hides inside the parasitophorous vacuole of the host cell, but new research indicates that IgG antibodies may be crucial in suppressing the host immune response by generating an immunosuppressive interleukin-10 response. IL-10 is able to decrease the needed Th1-generated IFN-gamma and downregulates production of nitric oxide, a required effector mechanism of parasite killing. We have been studying the pathways that the host uses to partially control L. mexicana infection, which include STAT4, IFN-gamma, and inducible nitric oxide synthase, but found that the IL-12 pathway is suppressed by IL-10. We are now studying the mechanisms by which IgG, bound to parasites, can induce IL-10 through FcgammaR ligation and how this suppresses a healing immune response. We are examining which IgG isotypes bind to which FcgammaRs and whether macrophages are the necessary source of IL-10 for chronic disease. Elucidation of these mechanisms may help us to design vaccines that will not induce antibody-mediated immunosuppressive IL-10 responses.
Asunto(s)
Inmunoglobulina G/inmunología , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Receptores de IgG/inmunología , Animales , Humanos , Interleucina-10/inmunología , Leishmaniasis Cutánea/parasitología , Macrófagos/inmunología , Transducción de Señal/inmunología , Células TH1/inmunologíaRESUMEN
FcRgamma and interleukin-10 (IL-10) are both required for chronic disease in C57BL/6 mice with Leishmania mexicana parasite infection. FcRgamma is a component of several different FcRs and may be a component of some T-cell receptors. The initial antibody response to L. mexicana is an immunoglobulin G1 (IgG1) response, and IgG1 preferentially binds to FcgammaRIII in other systems. To begin to dissect the mechanisms by which FcgammaRs contribute to chronic disease, we infected FcgammaRIII knockout (KO) mice with L. mexicana. We show that FcgammaRIII KO mice are resistant to L. mexicana infection, resolving lesions in association with a stronger gamma interferon response, similar to IL-10 KO mice, with parasite control by 12 weeks. We found that the Leishmania-specific IgG response is unaltered in FcgammaRIII KO mice compared with that in wild-type controls. The frequencies of IL-10 production from lymph node CD25(+) CD4(+) T cells are the same in KO and wild-type mice, and depletion of CD25(+) cells did not alter the course of infection, implying that T(reg) cells may not be the mechanism for susceptibility to L. mexicana infection, unlike for L. major infection. However, IL-10 mRNA was greatly diminished in the lesions of FcgammaRIII KO mice compared to that of B6 controls. Furthermore, macrophages from FcgammaRIII KO and FcRgamma KO mice have the same profound defect in IL-10 production induced by IgG-opsonized amastigotes. We also found IL-10-dependent (major) and -independent (minor) inhibition of IL-12 mediated by FcgammaRIII, as well as parasite-mediated inhibition of IL-12 and induction of IL-10, independent of FcgammaR. Our data demonstrate a specific role for FcgammaRIII in suppressing protective immunity in L. mexicana infection, likely through macrophage IL-10 production in the lesion.
Asunto(s)
Inmunoglobulina G/inmunología , Interleucina-10/metabolismo , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Receptores de IgG/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Femenino , Regulación de la Expresión Génica , Interferón gamma/inmunología , Interleucina-10/deficiencia , Interleucina-10/genética , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgG/deficiencia , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Infection of C57BL/6 (B6) mice with Leishmania mexicana is associated with a minimal immune response and chronic disease. Here we show that B6 interleukin 10-/- (IL-10-/-) mice resolve their lesions and exhibit increased gamma interferon (IFN-gamma), nitric oxide production, and delayed-type hypersensitivity. This enhanced resistance was dependent upon IL-12p40, since treatment of L. mexicana-infected IL-10-/- mice with anti-IL-12p40 monoclonal antibody abrogated healing. Antibody-opsonized L. mexicana induced IL-10 production by B6 macrophages in vitro, implicating antibody binding to Fc receptors as a mechanism involved in IL-10 production in this infection. Furthermore, B6 FcRgamma-/- mice resolve L. mexicana lesions, and lymph node cells from these mice produced less IL-10 and more IFN-gamma than cells from infected wild-type mice. These data demonstrate that removal of IL-10 or FcgammaR leads to resolution of L. mexicana disease and support a model in which ligation of FcgammaR by L. mexicana-bound immunoglobulin G promotes IL-10 production, leading to chronic disease.
Asunto(s)
Interleucina-10/fisiología , Leishmania mexicana , Leishmaniasis Cutánea/inmunología , Receptores de IgG/fisiología , Animales , Enfermedad Crónica , Inmunoglobulina G/fisiología , Interleucina-12/fisiología , Subunidad p40 de la Interleucina-12 , Ratones , Óxido Nítrico/biosíntesis , Subunidades de Proteína/fisiologíaRESUMEN
C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Deltacpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Deltacpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Deltacpb-infected IL-12p40(-/-) and STAT4(-/-) mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-gamma response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.
Asunto(s)
Catepsina B/fisiología , Regulación hacia Abajo/inmunología , Leishmania mexicana/enzimología , Leishmania mexicana/inmunología , Leishmaniasis Cutánea/inmunología , Células TH1/inmunología , Células TH1/parasitología , Animales , Catepsina B/deficiencia , Catepsina B/genética , Catepsina B/inmunología , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Regulación hacia Abajo/genética , Regulación Enzimológica de la Expresión Génica/inmunología , Inmunidad Innata , Interferón gamma/antagonistas & inhibidores , Interferón gamma/biosíntesis , Interleucina-12/deficiencia , Interleucina-12/genética , Interleucina-12/fisiología , Subunidad p40 de la Interleucina-12 , Leishmania mexicana/genética , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/prevención & control , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidades de Proteína/deficiencia , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Vacunas Antiprotozoos/administración & dosificación , Vacunas Antiprotozoos/genética , Vacunas Antiprotozoos/inmunología , Factor de Transcripción STAT4 , Transducción de Señal/genética , Transducción de Señal/inmunología , Células TH1/metabolismo , Transactivadores/deficiencia , Transactivadores/genética , Transactivadores/fisiologíaRESUMEN
Leishmania mexicana, a New World protozoan parasite, induces small, chronic, but non-progressive lesions in C57BL/6 (B6) mice. In this study we investigated the role of IL-12, and subsequent Th1 factors, in controlling cutaneous L. mexicana infection. IL-12 treatment failed to promote disease resolution, suggesting that the inability of mice to heal is not related to a deficiency of endogenous IL-12 production. Surprisingly, L. mexicana-induced cutaneous lesions in wild-type and IL-12p40-deficient mice were indistinguishable, with similar parasite burdens, immune responses, and lesion histopathology. In contrast, iNOS, IFN-gamma, and STAT4-deficient mice developed progressive disease and uncontrolled parasite growth. These results differ dramatically from L. major infection, in which IL-12p40-deficient mice are highly susceptible, with very rapid lesion growth, very large parasite burdens, and the development of a strong Th2 response. These data uncover the existence of an alternate IFN-gamma and iNOS pathway for control of Leishmania lesions, which is IL-12 independent, but which unexpectedly requires STAT4.