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Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.
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Virus del Dengue/inmunología , Inmunidad/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo/inmunología , Línea Celular Tumoral , Chlorocebus aethiops , Reacciones Cruzadas/inmunología , Femenino , Humanos , Células K562 , Ratones , Embarazo , Células VeroRESUMEN
HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1ß) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1ß. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1ß in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.
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Infecciones por VIH/inmunología , VIH-1/patogenicidad , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Tonsila Palatina/citología , Antagonistas del Receptor Purinérgico P2X/farmacología , Bencenosulfonatos/farmacología , Regulación hacia Abajo , Regulación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/inmunología , Humanos , Modelos Biológicos , Tonsila Palatina/efectos de los fármacos , Tonsila Palatina/inmunología , Tonsila Palatina/virología , Piridinas/farmacología , Tetrazoles/farmacología , Técnicas de Cultivo de Tejidos , Virulencia/efectos de los fármacos , Zidovudina/farmacologíaRESUMEN
West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.
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Receptores CCR7/inmunología , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/patogenicidad , Animales , Encéfalo/virología , Linfocitos T CD8-positivos/patología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Células Dendríticas/patología , Interacciones Huésped-Patógeno , Leucocitosis/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR7/deficiencia , Carga Viral , Virus del Nilo Occidental/fisiologíaRESUMEN
West Nile virus (WNV) is a re-emerging pathogen and the leading cause of epidemic encephalitis in the United States. Inflammatory monocytes are a critical component of the cellular infiltrate found in the CNS during WNV encephalitis, although the molecular cues involved in their migration are not fully understood. In mice, we previously showed that WNV infection induces a CCR2-dependent monocytosis that precedes monocyte migration into the CNS. Currently, the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in directing monocyte mobilization and leukocyte migration into the CNS is unclear. In this study, we demonstrate that, although both CCL2 and CCL7 are required for efficient monocytosis and monocyte accumulation in the CNS, only CCL7 deficiency resulted in increased viral burden in the brain and enhanced mortality. The enhanced susceptibility in the absence of CCL7 was associated with the delayed migration of neutrophils and CD8(+) T cells into the CNS compared with WT or Ccl2(-/-) mice. To determine whether CCL7 reconstitution could therapeutically alter the survival outcome of WNV infection, we administered exogenous CCL7 i.v. to WNV-infected Ccl7(-/-) mice and observed a significant increase in monocytes and neutrophils, but not CD8(+) T cells, within the CNS, as well as an enhancement in survival compared with Ccl7(-/-) mice treated with a linear CCL7 control peptide. Our experiments suggest that CCL7 is an important protective signal involved in leukocyte trafficking during WNV infection, and it may have therapeutic potential for the treatment of acute viral infections of the CNS.
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Movimiento Celular , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Leucocitosis/metabolismo , Monocitos/metabolismo , Fiebre del Nilo Occidental/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/virología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL7/genética , Quimiocina CCL7/farmacología , Chlorocebus aethiops , Encefalitis Viral/genética , Encefalitis Viral/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Expresión Génica , Interacciones Huésped-Patógeno , Leucocitosis/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Vero , Fiebre del Nilo Occidental/genética , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/fisiologíaRESUMEN
BACKGROUND: West Nile virus (WNV) is an emerging cause of meningitis and encephalitis in the United States. Although severe neuroinvasive disease and death can occur in rare instances, the majority of infected individuals remain asymptomatic or present with a range of clinical manifestations associated with West Nile fever. METHODS: To better understand the interindividual variability associated with the majority of WNV infections, we evaluated the association of cytokine/chemokine production and outcome of infection among 115 WNV-positive US blood donors identified in 2008-2011. All subjects self-reported symptoms as having occurred during the 2 weeks following blood donation, using a standardized questionnaire. RESULTS: We discovered that, prior to seroconversion, an early potent, largely type I interferon-mediated response correlated with development of a greater number of symptoms in WNV-infected individuals. Interestingly, individuals who developed fewer symptoms had not only a more modest type I interferon response initially, but also a protracted cytokine response after seroconversion, marked by the production of monocyte and T-cell-associated chemokines. CONCLUSIONS: Collectively, our data suggest that, although an early type I interferon response appears to be crucial to control WNV infection, successful immunity may require a modest early response that is maintained during the course of infection.
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Citocinas/metabolismo , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/patología , Virus del Nilo Occidental/inmunología , Adulto , Anciano , Donantes de Sangre , Femenino , Estudios de Seguimiento , Humanos , Interferón Tipo I/metabolismo , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Symmetric and asymmetric crystal structures of the apo and transition state analogue forms, respectively, of the dimeric rabbit muscle creatine kinase have invoked an "induced fit" explanation for asymmetry between the two subunits and their active sites. However, previously reported thiol reactivity studies at the dual active-site cysteine 283 residues suggest a more latent asymmetry between the two subunits. The role of that highly conserved active-site cysteine has also not been clearly determined. In this work, the S-H vibrations of Cys283 were observed in the unmodified MM isoform enzyme via Raman scattering, and then one and both Cys283 residues in the same dimeric enzyme were modified to covalently attach a cyano group that reports on the active-site environment via its infrared CN stretching absorption band while maintaining the catalytic activity of the enzyme. Unmodified and Cys283-modified enzymes were investigated in the apo and transition state analogue forms of the enzyme. The narrow and invariant S-H vibrational bands report a homogeneous environment for the unmodified active-site cysteines, indicating that their thiols are hydrogen bonded to the same H-bond acceptor in the presence and absence of the substrate. The S-H peak persists at all physiologically relevant pH's, indicating that Cys283 is protonated at all pH's relevant to enzymatic activity. Molecular dynamics simulations identify the S-H hydrogen bond acceptor as a single, long-resident water molecule and suggest that the role of the conserved yet catalytically unnecessary thiol may be to dynamically rigidify that part of the active site through specific H-bonding to water. The asymmetric and broad CN stretching bands from the CN-modified Cys283 suggest an asymmetric structure in the apo form of the enzyme in which there is a dynamic exchange between spectral subpopulations associated with water-exposed and water-excluded probe environments. Molecular dynamics simulations indicate a homogeneous orientation of the SCN probe group in the active site and thus rule out a local conformational explanation at the residue level for the multipopulation CN stretching bands. The homogeneous simulated SCN orientation suggests strongly that a more global asymmetry between the two subunits is the cause of the CN probe's broad and asymmetric infrared line shape. Together, these spectral observations localized at the active-site cysteines indicate an intrinsic, dynamic asymmetry between the two subunits that exists already in the apo form of the dimeric creatine kinase enzyme, rather than being induced by the substrate. Biochemical and methodological consequences of these conclusions are considered.
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Forma MM de la Creatina-Quinasa/química , Forma MM de la Creatina-Quinasa/fisiología , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/fisiología , Animales , Dominio Catalítico/fisiología , Cristalografía por Rayos X/métodos , Estructura Secundaria de Proteína , Conejos , VibraciónRESUMEN
OBJECTIVE: Sexual minority (SM) youth experience a greater mental health burden compared with their heterosexual peers. This study aimed to characterize mental health disparities among SM compared with non-SM youth, test main and interactive associations of SM identity and stressors targeting SM youth at the individual level (interpersonal SM discrimination) and structural level (state-level structural SM stigma) with youth mental health, and explore the contribution of interpersonal SM discrimination to the mental health burden of SM youth. METHOD: Participants included 11,622 youth (ages 9-13; 47.6% assigned female at birth) from the Adolescent Brain Cognitive Development (ABCD) Study. Linear mixed-effects models tested main and interactive associations of SM identity, interpersonal SM discrimination, and structural SM stigma with mental health measures (self-reported overall psychopathology, suicidal ideation, and suicide attempts), adjusting for demographics and other interpersonal stressors not specific to SM (other discrimination types, peer victimization, and cyberbullying). Longitudinal mediation models tested whether interpersonal SM discrimination mediated the associations between SM identity and mental health measures. RESULTS: SM youth (n = 1,051) experienced more interpersonal SM discrimination and overall psychopathology compared with their non-SM peers (n = 10,571). Adjusting for demographics, there were significant associations (main effects) of interpersonal SM discrimination and structural SM stigma with overall psychopathology. When further adjusting for other non-SM-related stressors, the main effect of structural SM stigma was no longer significant. Interpersonal SM discrimination was also significantly associated with suicidal ideation and attempt, accounting for demographics, while structural SM stigma was not. Accounting for both demographics and other non-SM stressors, there was a significant interaction between SM identity and structural SM stigma in association with psychopathology (p = .02), such that, compared with their peers, SM youth showed a greater association between structural SM stigma and psychopathology. Longitudinal mediation revealed that interpersonal SM discrimination was a significant mediator explaining approximately 10% to 15% of the variance of the pathways between SM identity and all mental health outcomes. CONCLUSION: Results delineate contributions of interpersonal discrimination and structural stigma targeting SM youth to their heightened mental health burden in early adolescence. These findings underscore the need to address microlevel and macrolevel SM discrimination and structural stigma when caring for this population. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.
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Salud Mental , Minorías Sexuales y de Género , Masculino , Recién Nacido , Humanos , Femenino , Adolescente , Intento de Suicidio , Ideación Suicida , Grupos MinoritariosRESUMEN
The amino acid histidine (His) has a number of unique roles that can dictate function in proteins, and these roles are typically conferred through noncovalent interactions that depend on the protonation state of His's 4-substituted imidazole ring. His's protonation state can vary near physiological pH, and a probe of His's variable protonation state and its resulting noncovalent interactions that has both high time resolution and no sample limitations could find wide use in determining the role of particular His residues in proteins. Here we use a classic deuterium exchange reaction to replace the C2-H hydrogen atom of the His imidazole ring with deuterium, leading to a unique aromatic C2-D stretching vibration whose frequency is sensitive to environmental changes across the entire imidazole ring. Using nonresonant Raman spectroscopy, we demonstrate using model compounds that the frequency of this C2-D vibration shifts by 35 cm(-1) upon changes in the His protonation state. The C2-D band is a very weak infrared absorber, so this vibration is not expected to be useful in infrared transmission experiments for proteins. Solvent-dependent Raman experiments indicate that the C2-D band of the neutral imidazole ring is sensitive to H-bonding interaction with donors and acceptors of varying strengths, suggesting that the C2-D frequency can be used to identify H-bonding partners of specific His residues. Raman spectra at varying concentrations of Cu(2+) also show the C2-D band's sensitivity to metal coordination, with differences due to changes in the coordination environment. The strong Raman signal of this band and the sampling flexibility of Raman spectroscopy suggest that this vibration could be very useful in documenting the local role of His residues in many His-containing proteins and protein assemblies.
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Histidina/química , Protones , Espectrometría Raman , Enlace de Hidrógeno , Proteínas/química , Proteínas/metabolismo , Espectrofotometría Infrarroja , VibraciónRESUMEN
Background: Allostatic load is the cumulative "wear and tear" on the body due to chronic adversity. We aimed to test poly-environmental (exposomic) and polygenic contributions to allostatic load and their combined contribution to early adolescent mental health. Methods: We analyzed data on N = 5,035 diverse youth (mean age 12) from the Adolescent Brain Cognitive Development Study (ABCD). Using dimensionality reduction method, we calculated and overall allostatic load score (AL) using body mass index [BMI], waist circumference, blood pressure, blood glycemia, blood cholesterol, and salivary DHEA. Childhood exposomic risk was quantified using multi-level environmental exposures before age 11. Genetic risk was quantified using polygenic risk scores (PRS) for metabolic system susceptibility (type 2 diabetes [T2D]) and stress-related psychiatric disease (major depressive disorder [MDD]). We used linear mixed effects models to test main, additive, and interactive effects of exposomic and polygenic risk (independent variables) on AL (dependent variable). Mediation models tested the mediating role of AL on the pathway from exposomic and polygenic risk to youth mental health. Models adjusted for demographics and genetic principal components. Results: We observed disparities in AL with non-Hispanic White youth having significantly lower AL compared to Hispanic and Non-Hispanic Black youth. In the diverse sample, childhood exposomic burden was associated with AL in adolescence (beta=0.25, 95%CI 0.22-0.29, P<.001). In European ancestry participants (n=2,928), polygenic risk of both T2D and depression was associated with AL (T2D-PRS beta=0.11, 95%CI 0.07-0.14, P<.001; MDD-PRS beta=0.05, 95%CI 0.02-0.09, P=.003). Both polygenic scores showed significant interaction with exposomic risk such that, with greater polygenic risk, the association between exposome and AL was stronger. AL partly mediated the pathway to youth mental health from exposomic risk and from MDD-PRS, and fully mediated the pathway from T2D-PRS. Conclusions: AL can be quantified in youth using anthropometric and biological measures and is mapped to exposomic and polygenic risk. Main and interactive environmental and genetic effects support a diathesis-stress model. Findings suggest that both environmental and genetic risk be considered when modeling stress-related health conditions.
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Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.
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Microbioma Gastrointestinal , Microbiota , Esquizofrenia , Humanos , Esquizofrenia/microbiología , Proyectos Piloto , Biomarcadores , CitocinasRESUMEN
Recent findings show that the perinatal maternal and infant microbiomes have profound potential to impact long term health outcomes. Of particular interest are the ways in which the microbiome influences the developing brain during one of its most critical windows. Schizophrenia and psychosis risk are strongly connected to disruptions in perinatal neurodevelopment. In this review we present an overview of critical aspects in development of both the microbiome and brain, discuss their overlap, and consider what role the microbiome plays in schizophrenia risk during the perinatal window. Considering this, we discuss ways in which expecting and new mothers may reduce offspring schizophrenia risk.
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Microbiota , Trastornos Psicóticos , Esquizofrenia , Encéfalo , Femenino , Humanos , Lactante , Madres , EmbarazoRESUMEN
PURPOSE: Suicidal ideation and attempts in youth are a growing health concern, and more data are needed regarding their biological underpinnings. Asthma is a common chronic inflammatory disorder in youth and has been associated with suicidal ideation and attempts in adolescent and adult populations, but data in younger children and early adolescents are lacking. We wished to study associations of asthma with childhood suicidality considering asthma's potential as a clinically relevant model for childhood chronic immune dysregulation. METHODS: Using data from the Adolescent Brain Cognitive Development (ABCD) Study (n = 11,876, 47.8% female, mean age 9.9 years at baseline assessment and 12.0 years at two-year follow-up), we assessed associations between asthma and suicidal ideation and attempts through baseline to two-year follow-up. RESULTS: Asthma history as defined by parent report (n = 2282, 19.2% of study population) was associated with suicide attempts (SA) (odds ratio (OR) = 1.44, p = 0.01), and this association remained significant even when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.46, p = 0.028). History of asthma attacks was associated with both suicidal ideation (SI) and SA when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.27, p = 0.042; OR = 1.83, p = 0.004, respectively). The association of asthma attack with SA remained significant when controlling for self-reported psychopathology (OR = 1.92, p = 0.004). The total number of asthma attacks was associated with both SI and SA (OR = 1.03, p = 0.043; OR = 1.06, p = 0.05, respectively). CONCLUSIONS: Findings suggest an association between asthma and suicidality in early adolescence. Further research is needed to investigate mechanisms underlying this relationship.
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Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathycandidiasisectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.
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Inmunidad Mucosa , Micosis , Humanos , Membrana Mucosa , Animales , RatonesRESUMEN
Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
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Candida albicans/inmunología , Candidiasis Mucocutánea Crónica/genética , Candidiasis Mucocutánea Crónica/inmunología , Inmunidad Mucosa/inmunología , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/inmunología , Adolescente , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Mucosa/genética , Vigilancia Inmunológica/genética , Vigilancia Inmunológica/inmunología , Interferón gamma/genética , Interleucinas/genética , Quinasas Janus/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Mucosa Bucal/inmunología , Mucosa Bucal/patología , Receptores de Interleucina-17/genética , Factor de Transcripción STAT1/genética , Linfocitos T/inmunología , Adulto Joven , Interleucina-22RESUMEN
Early life adversity and prenatal stress are consistently associated with an increased risk for schizophrenia, although the exact pathogenic mechanisms linking the exposures with the disease remain elusive. Our previous view of the HPA stress axis as an elegant but simple negative feedback loop, orchestrating adaptation to stressors among the hypothalamus, pituitary, and adrenal glands, needs to be updated. Research in the last two decades shows that important bidirectional signaling between the HPA axis and intestinal mucosa modulates brain function and neurochemistry, including effects on glucocorticoid hormones and brain-derived neurotrophic factor (BDNF). The intestinal microbiome in earliest life, which is seeded by the vaginal microbiome during delivery, programs the development of the HPA axis in a critical developmental window, determining stress sensitivity and HPA function as well as immune system development. The crosstalk between the HPA and the Microbiome Gut Brain Axis (MGBA) is particularly high in the hippocampus, the most consistently disrupted neural region in persons with schizophrenia. Animal models suggest that the MGBA remains influential on behavior and physiology across developmental stages, including the perinatal window, early childhood, adolescence, and young adulthood. Understanding the role of the microbiome on critical risk related stressors may enhance or transform of understanding of the origins of schizophrenia and offer new approaches to increase resilience against stress effects for preventing and treating schizophrenia.
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West Nile virus (WNV) infection outcomes vary among individuals, with most infections resulting in asymptomatic or mild flu-like symptoms. We previously reported an association between early cytokine production and symptom outcome following WNV infection in US blood donors. In this meta-analysis, we found that WNV-infected females reported more symptoms than WNV-infected males, despite similar initial viremia and type I interferon responses. As the infection progressed, males exhibited a protracted cytokine response-marked by sustained CCL2 (MCP-1), CCL11 (eotaxin-1), CXCL10 (IP-10) and IL-15-that was absent in females. Our results suggest that sex differences may be a factor in sustaining WNV immunity.
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Citocinas/biosíntesis , Fiebre del Nilo Occidental/metabolismo , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/fisiología , Biomarcadores , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Índice de Severidad de la Enfermedad , Factores Sexuales , Evaluación de Síntomas , Carga Viral , Fiebre del Nilo Occidental/diagnósticoRESUMEN
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.
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Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Autoinmunidad/fisiología , Linfocitos/inmunología , Neumonía/inmunología , Neumonía/patología , Adolescente , Adulto , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Neumonía/metabolismo , Estudios Prospectivos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto JovenRESUMEN
Several reports have demonstrated that mouse Cx3cr1 signaling promotes monocyte/macrophage survival. In agreement, we previously found that, in a mouse model of systemic candidiasis, genetic deficiency of Cx3cr1 resulted in increased mortality and impaired tissue fungal clearance associated with decreased macrophage survival. We translated this finding by showing that the dysfunctional CX3CR1 variant CX3CR1-M280 was associated with increased risk and worse outcome of human systemic candidiasis. However, the impact of this mutation on human monocyte/macrophage survival is poorly understood. Herein, we hypothesized that CX3CR1-M280 impairs human monocyte survival. We identified WT (CX3CR1-WT/WT), CX3CR1-WT/M280 heterozygous, and CX3CR1-M280/M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation-induced cell death in CX3CR1-WT/WT and CX3CR1-WT/M280 but not in CX3CR1-M280/M280 monocytes. CX3CL1-induced survival of CX3CR1-WT/WT monocytes is mediated via AKT and ERK activation, which are both impaired in CX3CR1-M280/M280 monocytes, associated with decreased blood monocyte counts in CX3CR1-M280/M280 donors at steady state. Instead, CX3CR1-M280/M280 does not affect monocyte CX3CR1 surface expression or innate immune effector functions. Together, we show that homozygocity of the M280 polymorphism in CX3CR1 is a potentially novel population-based genetic factor that influences human monocyte signaling.
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Receptor 1 de Quimiocinas CX3C/genética , Supervivencia Celular/genética , Monocitos/fisiología , Apoptosis/inmunología , Receptor 1 de Quimiocinas CX3C/metabolismo , Técnicas de Cultivo de Célula , Supervivencia Celular/inmunología , Células Cultivadas , Quimiocina CX3CL1/inmunología , Quimiocina CX3CL1/metabolismo , Medio de Cultivo Libre de Suero , Voluntarios Sanos , Homocigoto , Humanos , MutaciónRESUMEN
The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc-Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.