Coarse particulate matter (PM10) induce an inflammatory response through the NLRP3 activation.

INTRODUCTION: PM exposure can induce inflammatory and oxidative responses; however, differences in these adverse effects have been reported depending on the chemical composition and size. Moreover, inflammatory mechanisms such as NLRP3 activation by PM10 have yet to be explored. OBJECTIVE: To assess the impact of PM10 on cell cytotoxicity and the inflammatory response through in vitro and in vivo models. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) from healthy donors were exposed to PM10. Cytotoxicity was determined using the LDH assay; the expression of inflammasome components and the production of pro-inflammatory cytokines were quantified through qPCR and ELISA, respectively; and the formation of ASC complexes was examined using confocal microscopy. For in vivo analysis, male C57BL6 mice were intranasally challenged with PM10 and bronchoalveolar lavage fluid was collected to determine cell counts and quantification of pro-inflammatory cytokines by ELISA. RNA was extracted from lung tissue, and the gene expression of inflammatory mediators was quantified. RESULTS: PM10 exposure induced significant cytotoxicity at concentrations over 100 µg/mL. Moreover, PM10 enhances the gene expression and release of pro-inflammatory cytokines in PBMCs, particularly IL-1ß; and induces the formation of ASC complexes in a dose-dependent manner. In vivo, PM10 exposure led to cell recruitment to the lungs, which was characterized by a significant increase in polymorphonuclear cells compared to control animals. Furthermore, PM10 induces the expression of several inflammatory response-related genes, such as NLRP3, IL-1ß and IL-18, within lung tissue. CONCLUSION: Briefly, PM10 exposure reduced the viability of primary cells and triggered an inflammatory response, involving NLRP3 inflammasome activation and the subsequent production of IL-1ß. Moreover, PM10 induces the recruitment of cells to the lung and the expression of multiple cytokines; this phenomenon could contribute to epithelial damage and, thus to the development and exacerbation of respiratory diseases such as viral infections.

Particulate matter impairs immune system function by up-regulating inflammatory pathways and decreasing pathogen response gene expression.

Airborne particulate matter produced by industrial sources and automobiles has been linked to increased susceptibility to infectious diseases and it is known to be recognized by cells of the immune system. The molecular mechanisms and changes in gene expression profiles induced in immune cells by PM have not been fully mapped out or systematically integrated. Here, we use RNA-seq to analyze mRNA profiles of human peripheral blood mononuclear cells after exposure to coarse particulate matter (PM10). Our analyses showed that PM10 was able to reprogram the expression of 1,196 genes in immune cells, including activation of a proinflammatory state with an increase in cytokines and chemokines. Activation of the IL-36 signaling pathway and upregulation of chemokines involved in neutrophil and monocyte recruitment suggest mechanisms for inflammation upon PM exposure, while NK cell-recruiting chemokines are repressed. PM exposure also increases transcription factors associated with inflammatory pathways (e.g., JUN, RELB, NFKB2, etc.) and reduces expression of RNases and pathogen response genes CAMP, DEFAs, AZU1, APOBEC3A and LYZ. Our analysis across gene regulatory and signaling pathways suggests that PM plays a role in the dysregulation of immune cell functions, relevant for antiviral responses and general host defense against pathogens.

PM10 promotes an inflammatory cytokine response that may impact SARS-CoV-2 replication in vitro.

Introduction: In the last decades, a decrease in air quality has been observed, mainly associated with anthropogenic activities. Air pollutants, including particulate matter (PM), have been associated with adverse effects on human health, such as exacerbation of respiratory diseases and infections. High levels of PM in the air have recently been associated with increased morbidity and mortality of COVID-19 in some regions of the world. Objective: To evaluate the effect of coarse particulate matter (PM10) on the inflammatory response and viral replication triggered by SARS-CoV-2 using in vitro models. Methods: Peripheral blood mononuclear cells (PBMC) from healthy donors were treated with PM10 and subsequently exposed to SARS-CoV-2 (D614G strain, MOI 0.1). The production of pro-inflammatory cytokines and antiviral factors was quantified by qPCR and ELISA. In addition, using the A549 cell line, previously exposed to PM, the viral replication was evaluated by qPCR and plaque assay. Results: SARS-CoV-2 stimulation increased the production of pro-inflammatory cytokines in PBMC, such as IL-1ß, IL-6 and IL-8, but not antiviral factors. Likewise, PM10 induced significant production of IL-6 in PBMCs stimulated with SARS-CoV-2 and decreased the expression of OAS and PKR. Additionally, PM10 induces the release of IL-1ß in PBMC exposed to SARS-CoV-2 as well as in a co-culture of epithelial cells and PBMCs. Finally, increased viral replication of SARS-CoV-2 was shown in response to PM10. Conclusion: Exposure to coarse particulate matter increases the production of pro-inflammatory cytokines, such as IL-1ß and IL-6, and may alter the expression of antiviral factors, which are relevant for the immune response to SARS-CoV-2. These results suggest that pre-exposure to air particulate matter could have a modest role in the higher production of cytokines and viral replication during COVID-19, which eventually could contribute to severe clinical outcomes.

Expression of the inflammasome components and its relationship with cardiovascular risk markers in people living with HIV-1 / Expresión de los componentes del inflamasoma y su relación con los marcadores de riesgo cardiovascular en personas con infección por HIV-1

Introduction: HIV-1 infection induces a chronic inflammatory state in which inflammasomes participate. The increase in inflammatory parameters is higher in individuals with active viral replication (progressors) than in those with viral control (HIV-1 controllers). This process triggers metabolic alterations related to changes in the lipid profile, which could increase the risk of cardiovascular events, even in patients with antiretroviral therapy. Objective: To establish whether there was a correlation between the expression of inflammasome components and cardiovascular risk markers in HIV-1 controllers and progressors with or without antiretroviral therapy. Materials and methods: We studied 13 HIV-1 controllers and 40 progressors (19 without antiretroviral therapy and 31 with therapy) and evaluated in them classic markers of cardiovascular risk. Using RT-PCR we quantified the expression of inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18, and caspase-1), TLR2, TLR4, TGF-ß, and IL-10. Results: Progressors with antiretroviral therapy had an increased expression of TLR2, TLR4, and IL-18 compared to HIV-1 controllers. They also showed high levels of triglycerides and VLDL, which positively correlated with the expression of the inflammasome components NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1. Conclusion: Progressors receiving antiretroviral therapy exhibited an increased expression of the inflammasome components, which correlated with the levels of triglycerides and VLDL. This supports the role of inflammation in cardiovascular risk during HIV-1 infection.

Introducción. La infección por el HIV-1 induce un estado de inflamación crónico en el que participan los inflamasomas. El incremento de los parámetros inflamatorios es mayor en individuos con replicación viral activa que en aquellos con control de la replicación viral. Este proceso desencadena alteraciones metabólicas relacionadas con cambios en el perfil lipídico, lo cual podría incrementar el riesgo de eventos cardiovasculares, incluso en pacientes con terapia antirretroviral. Objetivo. Establecer si existe correlación entre la expresión de los componentes de los inflamasomas y los marcadores de riesgo cardiovascular en individuos con control de la replicación viral y en aquellos con replicación viral activa con terapia antirretroviral o sin ella. Materiales y métodos. Se estudiaron 13 individuos con control de la replicación viral y 40 con replicación viral activa (19 sin terapia antirretroviral y 31 con terapia). Se evaluaron los marcadores clásicos de riesgo cardiovascular y se cuantificó mediante RT-PCR la expresión de los componentes de los inflamasomas (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18 y caspasa-1), TLR2, TLR4, TGF-ß e IL-10. Resultados. Se observó que los pacientes con replicación viral activa y con terapia antirretroviral presentaron un incremento en la expresión de TLR2, TLR4 e IL-18, comparados con los controladores del HIV-1. Además, mostraron grandes valores de triglicéridos y lipoproteína de muy baja densidad (Very Low Density Lipopretein, VLDL), lo que se correlaciona positivamente con la expresión de los componentes de los inflamasomas NLRP1, NLRP3, NLRC4, AIM2, ASC y caspasa-1. Conclusión. El aumento en la expresión de los componentes de los inflamasomas en los individuos con replicación viral activa y con terapia antirretroviral se correlacionó con las concentraciones de triglicéridos y VLDL, lo que sugiere el papel de la activación inmunitaria y la terapia antirretroviral en el riesgo cardiovascular.

Expresión de los componentes del inflamasoma y su relación con los marcadores de riesgo cardiovascular en personas con infección por HIV-1 / Expression of the inflammasome components and its relationship with cardiovascular risk markers in people living with HIV-1

Introducción. La infección por el HIV-1 induce un estado de inflamación crónico en el que participan los inflamasomas. El incremento de los parámetros inflamatorios es mayor en individuos con replicación viral activa que en aquellos con control de la replicación viral. Este proceso desencadena alteraciones metabólicas relacionadas con cambios en el perfil lipídico, lo cual podría incrementar el riesgo de eventos cardiovasculares, incluso en pacientes con terapia antirretroviral. Objetivo. Establecer si existe correlación entre la expresión de los componentes de los inflamasomas y los marcadores de riesgo cardiovascular en individuos con control de la replicación viral y en aquellos con replicación viral activa con terapia antirretroviral o sin ella. Materiales y métodos. Se estudiaron 13 individuos con control de la replicación viral y 40 con replicación viral activa (19 sin terapia antirretroviral y 31 con terapia). Se evaluaron los marcadores clásicos de riesgo cardiovascular y se cuantificó mediante RT-PCR la expresión de los componentes de los inflamasomas (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18 y caspasa-1), TLR2, TLR4, TGF-ß e IL-10. Resultados. Se observó que los pacientes con replicación viral activa y con terapia antirretroviral presentaron un incremento en la expresión de TLR2, TLR4 e IL-18, comparados con los controladores del HIV-1. Además, mostraron grandes valores de triglicéridos y lipoproteína de muy baja densidad (Very Low Density Lipopretein, VLDL), lo que se correlaciona positivamente con la expresión de los componentes de los inflamasomas NLRP1, NLRP3, NLRC4, AIM2, ASC y caspasa-1. Conclusión. El aumento en la expresión de los componentes de los inflamasomas en los individuos con replicación viral activa y con terapia antirretroviral se correlacionó con las concentraciones de triglicéridos y VLDL, lo que sugiere el papel de la activación inmunitaria y la terapia antirretroviral en el riesgo cardiovascular.

Introduction: HIV-1 infection induces a chronic inflammatory state in which inflammasomes participate. The increase in inflammatory parameters is higher in individuals with active viral replication (progressors) than in those with viral control (HIV-1 controllers). This process triggers metabolic alterations related to changes in the lipid profile, which could increase the risk of cardiovascular events, even in patients with antiretroviral therapy. Objective: To establish whether there was a correlation between the expression of inflammasome components and cardiovascular risk markers in HIV-1 controllers and progressors with or without antiretroviral therapy. Materials and methods: We studied 13 HIV-1 controllers and 40 progressors (19 without antiretroviral therapy and 31 with therapy) and evaluated in them classic markers of cardiovascular risk. Using RT-PCR we quantified the expression of inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, IL-1ß, IL-18, and caspase-1), TLR2, TLR4, TGF-ß, and IL-10. Results: Progressors with antiretroviral therapy had an increased expression of TLR2, TLR4, and IL-18 compared to HIV-1 controllers. They also showed high levels of triglycerides and VLDL, which positively correlated with the expression of the inflammasome components NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1. Conclusion: Progressors receiving antiretroviral therapy exhibited an increased expression of the inflammasome components, which correlated with the levels of triglycerides and VLDL. This supports the role of inflammation in cardiovascular risk during HIV-1 infection.

Viral respiratory infections and air pollutants.

Air pollution is a public health issue of global importance and a risk factor for developing cardiorespiratory diseases. These contaminants induce reactive oxygen species (ROS) and increased pro-inflammatory cytokines such as IL-1ß, IL-6, and IL-8, triggering the inflammatory response that alters cell and tissue homeostasis and facilitates the development of diseases. The effects of air pollutants such as ozone, particulate matter (PM10, PM2.5, and PM0.1), and indoor air pollutants on respiratory health have been widely reported. For instance, epidemiological and experimental studies have shown associations between hospital admissions for individual diseases and increased air pollutant levels. This review describes the association and relationships between exposure to air pollutants and respiratory viral infections, especially those caused by the respiratory syncytial virus and influenza virus. The evidence suggests that exposure to air contaminants induces inflammatory states, modulates the immune system, and increases molecules' expression that favors respiratory viruses' pathogenesis and affects the respiratory system. However, the mechanisms underlying these interactions have not yet been fully elucidated, so it is necessary to develop new studies to obtain information that will allow health and policy decisions to be made for the adequate control of respiratory infections, especially in the most vulnerable population, during periods of maximum air pollution.

Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms.

Due to the scarcity of therapeutic approaches for COVID-19, we investigated the antiviral and anti-inflammatory properties of curcumin against SARS-CoV-2 using in vitro models. The cytotoxicity of curcumin was evaluated using MTT assay in Vero E6 cells. The antiviral activity of this compound against SARS-CoV-2 was evaluated using four treatment strategies (i. pre-post infection treatment, ii. co-treatment, iii. pre-infection, and iv. post-infection). The D614G strain and Delta variant of SARS-CoV-2 were used, and the viral titer was quantified by plaque assay. The anti-inflammatory effect was evaluated in peripheral blood mononuclear cells (PBMCs) using qPCR and ELISA. By pre-post infection treatment, Curcumin (10 µg/mL) exhibited antiviral effect of 99% and 99.8% against DG614 strain and Delta variant, respectively. Curcumin also inhibited D614G strain by pre-infection and post-infection treatment. In addition, curcumin showed a virucidal effect against D614G strain and Delta variant. Finally, the pro-inflammatory cytokines (IL-1ß, IL-6, and IL-8) released by PBMCs triggered by SARS-CoV-2 were decreased after treatment with curcumin. Our results suggest that curcumin affects the SARS-CoV-2 replicative cycle and exhibits virucidal effect with a variant/strain independent antiviral effect and immune-modulatory properties. This is the first study that showed a combined (antiviral/anti-inflammatory) effect of curcumin during SARS-CoV-2 infection. However, additional studies are required to define its use as a treatment for the COVID-19.

Immune characterization of a Colombian family cluster with SARS-CoV-2 infection. / Caracterización inmunológica de un grupo familiar colombiano con infección por SARS-CoV-2

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.

Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.

Immune characterization of a Colombian family cluster with SARS-CoV-2 infection / Caracterización inmunológica de un grupo familiar colombiano con infección por SARS-CoV-2

Abstract | Introduction: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARS- CoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. Objective: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. Materials and methods: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. Results: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. Conclusion: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.

Resumen | Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56 bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.

Alteración en la expresión de proteínas transportadoras de colesterol y moléculas inmunomoduladoras en pacientes con VIH-1 / Altered expression of cholesterol transport proteins and immunomodulators molecules in HIV-1 infected patients

Debido a que la terapia antirretroviral no logra controlar la activación inmune asociada a la infección por VIH-1, el estudio de moléculas inmunomoduladoras puede proporcionar alternativas para su control. En este sentido, el propósito de este estudio fue evaluar la expresión transcripcional de moléculas asociadas con el metabolismo del colesterol-HDL (C-HDL) y con la respuesta inflamatoria mediada por el inflamasoma NLRP3 en pacientes infectados con VIH-1. En este estudio transversal, se incluyeron 23 pacientes VIH-1 sin tratamiento antirretroviral, con diferentes estadios de progresión, 7 de los cuales son controladores (Carga viral <2000 copias/mL) y 16 progresores (Carga viral >2000 copias/mL), además de 7 controles sanos. En células mononucleares de sangre periférica, se cuantificaron los niveles de la expresión transcripcional de ABCA-1, ABCA-3, Caspasa-5 y TXNIP mediante RT-PCR. Se evaluó la asociación de estos parámetros con variables demográficas y de laboratorio, y se encontró que los individuos VIH-1 progresores mostraron niveles significativamente menores de TXNIP y ABCA-3, sugiriendo que durante la infección por VIH-1 se produce una alteración en la expresión de estas moléculas. Dada la complejidad de las interacciones inmuno-metabólicas durante la infección por VIH-1, se necesitan estudios adicionales para establecer los mecanismos precisos involucrados en estas alteraciones

Because antiretroviral therapy fails to control the immune activation that occurs during HIV-1 infection, the study of immunomodulatory molecules may provide alternative strategies for their control. In this sense, the aim of the research was to evaluate the transcriptional expression of molecules associated with the metabolism of high-density lipoproteins and with the inflammatory response mediated by the NLRP3 inflammasome in patients infected with HIV-1. This is a cross-sectional study, which included 23 HIV-1 patients without antiretroviral treatment, with different stages of progression, 7 of which are controllers (Viral load <2000 copies/mL) and 16 progressors (Viral load >2000 copies/mL), in addition to 7 healthy controls. In peripheral blood mononuclear cells, the levels of transcriptional expression of ABCA-1, ABCA-3, Caspase-5 and TXNIP were quantified by RT-PCR. The association of these parameters with laboratory and demographic variables was evaluated and it was found that HIV-1 progressing individuals showed significantly lower levels of TXNIP and ABCA-3, suggesting that during HIV-1 infection there is an alteration in the expression of these molecules. Given the complexity of the immuno-metabolic interactions during HIV-1 infection, additional studies are needed to establish the precise mechanisms involved in these alterations

Evaluation of Differences in Metabolic and Immunologic Markers and Cardiovascular Risk in HIV-1 Patients / Evaluación de la relación entre marcadores metabólicos, inmunológicos y de riesgo cardiovascular en pacientes con VIH-1 / Avaliação da relação entre marcadores metabólicos, imunológicos e de risco cardiovascular em pacientes com HIV-1

Introduction:hiv infection induces an exacerbated chronic inflammatory response, which triggers met-abolic disorders and cardiovascular diseases; however, there are individuals, known as hiv controllers, who do not have typical progression markers. As cardiovascular risk tests are not accurate on hiv-1 infected patients, the study of metabolic and inflammatory parameters in individuals with different patterns of progression could contribute to the definition of predictors of cardiovascular disease in this population. The aim of this study was to compare hiv controllers and hiv progressors (with and without antiretroviral therapy) as well as with healthy controls in order to explore differences and correlations in metabolic and inflammatory biomarkers associated with cardiovascular risk. Materials and methods:This was a cross-sectional analytical study which included 63 individuals infected with hiv-1 classified as hiv controllers or progressors (with or without antiretroviral therapy), and a healthy control group. The following parameters were determined: carotid intima-media thickness (cimt); cardiovascular risk scores; lipid profile, fasting glucose, high-sensitivity crp, D-dimer, sCD14, sCD163, il-6, and il-18. Data were compared with Anova or Kruskal­Wallis, and correlations were evaluated by the Spearman coef-ficient. Results: While there were no significant differences in Framingham, dad or cimt values, hiv con-trollers exhibited lower triglycerides levels when compared with hiv progressors. No differences were observed in markers, such as high-sensitivity crp, il-6, il-18, and sCD163, among the groups. The median hdl value was higher in hiv progressors on antiretroviral therapy, and cimt in hiv controllers was nega-tively correlated with sCD14. Conclusion:hiv controllers have a different cardiovascular profile than hivprogressors according to their values in metabolic and immunological biomarkers

Introducción: la infección por vih-1 induce una respuesta inflamatoria crónica exacerbada que desencadena alteraciones metabólicas y cardiovasculares; sin embargo, algunos individuos "controladores" no presentan los marcadores de progresión típicos. Dado que las pruebas que evaluan el riesgo cardiovascular carecen de precisión en pacientes con vih-1, el estudio de parámetros inflamatorios en individuos con diferente progresión podría aportar a la definición de predictores de enfermedad cardiovascular en esta población. El objetivo es explorar diferencias y correlaciones en biomarcadores metabólicos e inflamatorios asociados con riesgo cardiovascular, comparando individuos controladores y progresores con y sin terapia antiviral. Materiales y métodos: estudio analítico transversal con 63 individuos infectados por vih-1, clasificados en controladores y progresores (con terapia antiviral y sin esta), y controles sanos. Se midió el grosor de la íntima media carotidea (cimt), puntajes de riesgo cardiovascular y cuantificación de perfil lipídico, glucemia en ayunas, pcr ultrasensible, dímero D, sCD14, sCD163, il-6 e il-18. Se realizó comparación por Anova o Kruskal-Wallis y correlación por coeficiente de Spearman. Resultados: no hubo diferencias significativas en índices de Framingham, dad o cimt, pero los individuos controladores presen-taron menores valores de triglicéridos, comparados con los progresores. No se observaron diferencias en pcr ultrasensible, il-6, il-18, y sCD163, entre los grupos estudiados. La mediana del hdl fue mayor en los progresores con terapia antiviral y el cimt en los controladores se correlacionó negativamente con sCD14. Conclusión: los individuos controladores presentan un perfil cardiovascular diferente a los individuos progresores, de acuerdo con los biomarcadores metabólicos e inmunológicos evaluados

Introdução: a infecção pelo hiv-1 induz resposta inflamatória crônica exacerbada, que desencadeia alte-rações metabólicas e doenças cardiovasculares; no entanto, existem indivíduos, chamados controlado-res, que não possuem os marcadores de progressão típicos. Tendo em vista que os testes que avaliam o risco cardiovascular carecem de precisão em pacientes com hiv-1, o estudo de parâmetros metabólicos e inflamatórios em indivíduos com diferentes padrões de progressão pode contribuir para a definição de preditores de doença cardiovascular nessa população. O objetivo é explorar diferenças e correlações em biomarcadores metabólicos e inflamatórios associados ao risco cardiovascular, comparando indiví-duos controladores e progressores submetidos ou não à terapia antiviral. Materiais e métodos: Estudo analítico transversal que incluiu 63 indivíduos infectados pelo hiv-1, classificados como controladores e progressores (com e sem terapia antiviral), além de grupos controle saudáveis. Realizou-se a medição da espessura da íntima média da carótida (cimt), pontuações de risco cardiovascular; e quantificação do perfil lipídico, glicemia em jejum, pcr ultrassensível, dímero d, sCD14, sCD163, il-6 e il-18. A comparação foi feita por Anova ou teste de Kruskal-Wallis e a correlação pelo coeficiente de Spearman. Resultados.Embora não tenha havido diferenças significativas nos índices de Framingham, dad ou cimt, os indivíduos controladores apresentaram valores de triglicerídeos mais baixos, em comparação com os progressores. Não foram observadas diferenças em marcadores como pcr ultrassensível, il-6, il-18 e sCD163, entre os grupos estudados. O hdl médio foi maior em indivíduos progressores em terapia antiviral, e o cimtem indivíduos controladores foi negativamente correlacionado com o sCD14. Conclusão: os indivíduos controladores apresentam um perfil cardiovascular diferente dos indivíduos progressores, de acordo com os biomarcadores metabólicos e imunológicos avaliados

Factores inmunológicos relacionados con VIH-1 en pacientes colombianos / Immunological Factors Related to HIV-1 in Colombian Patients / Fatores imunológicos relacionados com HIV-1 em pacientes colombianos

Resumen Introducción : los inflamasomas dirigen la maduración de las citoquinas IL-1b e IL-18, las cuales contribuyen en la patogénesis de la infección por VIH-1. Dada la complejidad de la infección, se hace necesaria la búsqueda de marcadores que permitan identificar nuevos blancos terapéuticos o hacer seguimiento del estado inmunológico de los pacientes. Por lo tanto, el objetivo del presente trabajo fue explorar el efecto independiente de los principales componentes inflamatorios sobre la infección por VIH-1. Materiales y métodos : estudio analítico con 36 pacientes VIH+ y 36 controles sanos, pareados por edad y sexo. Se cuantificó la carga viral, los linfocitos T CD4+/CD8+, el perfil lipídico, la proteína C reactiva y las concentraciones séricas de IL-1-ß, IL-6 e IL-18. El HIRNA de los genes relacionados con los inflamasomas fue cuantificado por RT-PCR en tiempo real. El análisis estadístico se basó en medidas de resumen, pruebas de hipótesis y regresión logística binaria multivariante. Resultados : se encontraron menores valores de HDL y HIRNA IL-18 y mayores de HIRNA NLRPI y HIRNA ASC en los pacientes con VIH-1, comparados con los controles. Los valores de HDL y HIRNA IL-18 se correlacionaron con los recuentos de linfocitos. En el análisis multivariado se encontró que la relación CD4/CD8, el mRNA IL-18 y el HIRNA ASC pueden constituir las principales variables que tienen un potencial explicativo sobre la infección por VIH-1 en la población de estudio. Conclusión : se evidenció la importancia de estudiar los inflamasomas, dado que en la población de estudio constituyen potenciales blancos terapéuticos para disminuir la respuesta inflamatoria.

Abstract Introduction : Inflammasomes direct the maturation of the cytokines IL-1ß and IL-18, which contribute to the pathogenesis of HIV-1 infection. Given its complexity, it is necessary to search for markers that can identify new therapeutic targets or monitor the immunological status of patients. Therefore, the objective of the present work was to explore the independent effect of the main inflammatory components on HIV-1 infection. Materials and Methods : Researchers conducted an analytical study with 36 HIV+ patients and 36 healthy controls, matched by age and sex. Viral load, CD4+/CD8+ T lymphocytes, lipid profile, C-reactive protein and serum concentrations of IL-1ß, IL-6, and IL-18 were quantified. RT-PCR in real time quantified the ITIRNA of the genes related to the inflammasomes. The statistical analysis based on summary measures, hypothesis tests, and multivariate binary logistic regression. Results : Lower values of HDL and ITIRNA IL-18 and higher ITIRNA NLRPI and ITVRNA ASC presented in patients with HIV-1 compared with controls. The values of HDL and ITIRNA IL-18 correlated with lymphocyte counts. The multivariate analysis shows that the CD4 / CD8 ratio, the IL-18 ITIRNA and the ASC ITIRNA can be the main variables that have an explanatory potential on HIV-1 infection in the study population. Conclusion : The importance of studying inflammasomes was evidenced, given that in the study population they are potential therapeutic targets to reduce the inflammatory response.

Resumo Introdução : os inflamassomas dirigem a maduração das citocinas IL-1ß e IL-18; as quais contribuem nas patogêneses da infeção por HIV-1. Dada a complexidade da infeção se faz necessária a busca de marcadores que permitam identificar novos alvos terapêuticos ou fazer seguimento do estado imunológico dos pacientes. Portanto, o objetivo do presente trabalho foi explorar o efeito independente os principais componentes inflamatórios sobre a infeção por HIV-1. Materiais e métodos : estudo analítico com 36 pacientes HIV+ e 36 controles saudáveis, pareados por idade e sexo. Se quantificou a carga viral, os linfócitos T CD4+/CD8+, o perfil lipídico, a proteína C reativa e as concentrações séricas de IL-1ß, IL-6 e IL-18. O ITIRNA dos genes relacionados com os inflamassomas foi quantificado por RT-PCR em tempo real. A análise estatística se baseou em medidas de resumo, provas de hipótese e regressão logística binaria multivariado. Resultados : se encontraram menores valores de HDL e TÍTRNA IL-18 e maiores de TÍIRNA NLRPI e TÍTRNA ASC nos pacientes com HIV-1, comparados com os controles. Os valores de HDL e TÍTRNA IL-18 se correlacionaram com os recontos de linfócitos. Na análise multivariada encontrou-se que a relação CD4/CD8, o TÍIRNA IL-18 e o TÍTRNA ASC podem constituir as principais variáveis que têm um potencial explicativo sobre a infeção por HIV-1 na população de estudo. Conclusão : se evidenciou a importância de estudar os inflamassomas, dado que na população de estudo constituem potenciais brancos terapêuticos para diminuir a resposta inflamatória.

Inflammatory status and severity of disease in dengue patients are associated with lipoprotein alterations.

INTRODUCTION: The triggering of severe dengue has been associated with an exacerbated inflammatory process characterized by the production of pro-inflammatory cytokines such as IL-1ß/IL-18, which are the product of inflammasome activation. Furthermore, alteration in the levels of high-density (HDL) and low-density lipoproteins (LDL) has been observed; and HDL are known to have immunomodulatory properties, including the regulation of inflammasomes. While HDL would be expected to counteract hyperactivation of the inflammasome, the relationship between HDL and dengue severity, has not previously been explored. METHODOLOGY: We conducted a cross-sectional study of 30 patients with dengue and 39 healthy controls matched by sex and age. Lipid profile and levels of C-reactive protein were quantified. Serum levels of IL-1ß, IL-6, IL-10, IL-18, and TNF-α, were assessed by ELISA. Expression of inflammasome-related genes in PBMC was quantified by qPCR. RESULTS: Dengue patients presented an alteration in the parameters of the lipid profile, with a significant decrease in HDL levels, which was more pronounced in dengue patients with warning signs. Moreover, a decrease in the expression of the inflammasome-related genes NLRP1, NLRC4, caspase-1, IL-1ß and IL-18 was observed, as well as an increase in serum levels of C-reactive protein and IL-10 in dengue patients versus healthy donors. Significant positive correlations between LDL levels and the relative expression of NLRP3, NLRC4, IL-1ß and IL-18, were found. CONCLUSION: The results suggest that there is a relationship between the alteration of LDL and HDL with the imbalance in the inflammatory response, which could be associated with the severity of dengue.

Lower High-Density Lipoproteins Levels During Human Immunodeficiency Virus Type 1 Infection Are Associated With Increased Inflammatory Markers and Disease Progression.

INTRODUCTION: High-density lipoproteins (HDL) are responsible for the efflux and transport of cholesterol from peripheral tissues to the liver. In addition, HDL can modulate various immunological mechanisms, including the inflammatory response. Inflammasomes are multiprotein complexes that have been reported to be activated during human immunodeficiency virus type 1 (HIV-1) infection, thus contributing to immune hyperactivation, which is the main pathogenic mechanism of HIV-1 progression. However, the relationship between HDL and inflammasomes in the context of HIV-1 infection is unclear. Therefore, this research aims to explore the association between HDL and the components of the inflammatory response during HIV-1 infection. METHODOLOGY: A cross-sectional study, including 36 HIV-1-infected individuals without antiretroviral treatment and 36 healthy controls matched by sex and age, was conducted. Viral load, CD4+ T-cell counts, serum HDL, and C-reactive protein (CRP) were quantified. Serum cytokine levels, including IL-1ß, IL-6, and IL-18, were assessed by ELISA. The inflammasome-related genes in peripheral blood mononuclear cells were determined by quantitative real-time PCR. RESULTS: HIV-1-infected individuals showed a significant decrease in HDL levels, particularly those subjects with higher viral load and lower CD4+ T-cell counts. Moreover, upregulation of inflammasome-related genes (NLRP3, AIM2, ASC, IL-1ß, and IL-18) was observed, notably in those HIV-1-infected individuals with higher viral loads (above 5,000 copies/mL). Serum levels of IL-6 and CRP were also elevated in HIV-1-infected individuals. Significant negative correlations between HDL and the mRNA of NLRP3, AIM2, ASC, IL-1ß, and IL-18, as well as viral load and CRP were observed in HIV-1-infected individuals. Likewise, a significant positive correlation between HDL and CD4+ T-cell counts was found. CONCLUSION: In summary, our results indicate that HDL might modulate the expression of several key components of the inflammasomes during HIV-1 infection, suggesting a novel role of HDL in modifying the inflammatory state and consequently, the progression of HIV-1 infection.

Inflamación y respuesta inmune innata: participación de las lipoproteínas de alta densidad / Inflammation and innate immune response: role of high-density lipoprotein / Inflamação e resposta imune inata: participação das lipoproteínas de altadensidade

RESUMEN Las lipoproteínas de alta densidad (HDL) tienen como función transportar el exceso de colesterol desde los tejidos hacia el hígado, para ser excretado; y de este modo contribuyen al control de las enfermedades cardiovasculares. Además, las HDL pueden modular la respuesta inmune, por sus propiedades anti-inflamatorias, antioxidantes y anti-apoptóticas, entre otras. A nivel celular, las HDL pueden modificar las balsas lipídicas, las cuales son determinantes en la activación de la respuesta inmune frente a patógenos o agentes extraños. En algunas patologías como la sepsis, las HDL participan mediando la eliminación del lipopolisacárido (LPS) a través de su captura y posterior eliminación en el hígado; esto conlleva a una modulación negativa de la expresión del TLR4, principal receptor del LPS. También se ha reportado que las HDL modulan la respuesta inflamatoria a través de la regulación de la activación de la cascada del complemento y la expresión de pentraxina 3. Finalmente, la función y los niveles de las HDL se han encontrado particularmente alterados en algunas patologías infecciosas, ateroesclerosis y sepsis, lo que se ha asociado con el progreso o la severidad de la enfermedad.

SUMMARY The main function of high-density lipoproteins (HDL) is to transport the excess of cholesterol from tissues to the liver, where it is excreted, thus decreasing the risk of atherosclerotic plaques development and cardiovascular diseases establishment. Besides, HDL participates in different processes of the immune response, as its components have anti-inflammatory, anti-oxidative and antiapoptotic activities, among others. At cellular level, these lipoproteins have the ability to modify lipid rafts, critical micro-domains that participate in signaling pathways in response to pathogens. Likewise, it has been reported that HDL have a great impact in sepsis, as they eliminate the excess of LPS in blood and transport it to the liver for its elimination, and downregulate the expression of TLR4, main receptor of this molecule. Also, HDL can modulate humoral innate immune responses through regulating the activation of the complement pathway and the expression of pentraxin 3, resulting in the modulation of inflammatory processes. In fact, it has been reported that in several infectious diseases, atherosclerosis and sepsis, the level and function of HDL are altered, which associates with the progress of the diseases.

RESUMO As lipoproteínas de alta densidade (HDL) têm a fun- ção de transportar o excesso de colesterol desde os tecidos até ofígado para aqui ser excretado e dessa forma contribuem no controlo das doenças cardiovasculares. Além disso, as HDL podemmodular a resposta imune devido as suas propriedades anti-inflamatórias, antioxidantes e antiapopticas, entreoutras. Anívelcelular, asHDLpodemmodificar os rafts lipídicos, que são essências para a ativa- ção da resposta imune contra patógenos ouagentes estranhos. Nalgumas patologias como a septicemia, as HDL participam mediando a eliminação do lipopolissacarídeo (LPS) através da sua captura e posterior eliminação no fígado. Isto leva a uma modulação negativa da expressão de TLR4, orecetor principal do LPS. Também foi reportado que as HDL modulam a resposta inflamatória através da regulação da ativaçãoda cascata do sistema do complemento e a expressão de pentraxina 3. Por último, a função e os níveis das HDL têm sido especialmente encontrados alterados nalgumas doenças infeciosas, em aterosclerose e em septicemia, o qual esta associado aevolução ou a gravidade da doença.