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.

NK cells from Men Who Have Sex with Men at high risk for HIV-1 infection exhibit higher effector capacity.

Despite being under constant exposure to HIV-1, some individuals do not show serological or clinical evidence of infection and are known as HESN (HIV-Exposed Seronegative). Multiple studies in different HESN cohorts have linked the NK cells as a correlate of resistance; however, little is known about the role of these cells in Men Who Have Sex with Men (MSM) with high risk sexual behaviors. We evaluated a general overview of activation and effector features of NK cells of MSM co-cultured with LT CD4+ HIV+ in which MSM at high risk of HIV-1 infection (HR-MSM) exhibit higher capacity to eliminate infected cells, reduced percentages of CD69+ cells when compared to MSM at low risk of infection (LR-MSM). In addition, we found that, despite the lower levels of CD69+ NK cells on HR-MSM group, within this population, higher percentages of CD69+ IFN-γ+ and CD69+ NKG2D+ NK cells were found together with higher levels of RANTES and Granzyme B production with higher antiviral capacity, resulting in a lower concentration of p24 protein and p24+ CD4+ T cells. Altogether, this information suggests that NK cells of MSM could impact the capacity to face the viral infection.

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.

Molecular mechanisms by which the HIV-1 latent reservoir is established and therapeutic strategies for its elimination.

The human immunodeficiency virus type 1 (HIV-1) reservoir, composed of cells harboring the latent, integrated virus, is not eliminated by antiretroviral therapy. It therefore represents a significant barrier to curing the infection. The biology of HIV-1 reservoirs, the mechanisms of their persistence, and effective strategies for their eradication are not entirely understood. Here, we review the molecular mechanisms by which HIV-1 reservoirs develop, the cells and compartments where the latent virus resides, and advancements in curative therapeutic strategies. We first introduce statistics and relevant data on HIV-1 infection, aspects of pathogenesis, the role of antiretroviral therapy, and the general features of the latent HIV reservoir. Then, the article is built on three main pillars: The molecular mechanisms related to latency, the different strategies for targeting the reservoir to obtain a cure, and the current progress in immunotherapy to counteract said reservoirs.

Recent advances in CD8+ T cell-based immune therapies for HIV cure.

Achieving a cure for HIV infection is a global priority. There is substantial evidence supporting a central role for CD8+ T cells in the natural control of HIV, suggesting the rationale that these cells may be exploited to achieve remission or cure of this infection. In this work, we review the major challenges for achieving an HIV cure, the models of HIV remission, and the mechanisms of HIV control mediated by CD8+ T cells. In addition, we discuss strategies based on this cell population that could be used in the search for an HIV cure. Finally, we analyze the current challenges and perspectives to translate this basic knowledge toward scalable HIV cure strategies.

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.

Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy.

BACKGROUND: Although combined antiretroviral therapy (cART) has decreased the mortality associated with HIV infection, complete immune reconstitution is not achieved despite viral suppression. Alterations of CD8+ T cells and some of their subpopulations, such as interleukin (IL)-17-producing cells, are evidenced in treated individuals and are associated with systemic inflammation and adverse disease outcomes. We sought to evaluate if different CD8+ T cell subsets are differentially normalized during a clinical follow-up of people living with HIV (PLWH) receiving suppressive cART. METHODS: We explored the changes in the frequencies, activation/exhaustion phenotypes (HLA-DR, CD38, PD-1, and TIM-3), and function (total and HIV-specific cells expressing CD107a, perforin, granzyme B, interferon [IFN]-γ and IL-17) of CD8+ T cells from early-treated PLWH receiving cART in a 1-year follow-up, using a multidimensional flow cytometry approach. RESULTS: Despite continuous cART-induced viral suppression and recovery of CD4+ T cells, after a 1-year follow-up, the CD8+ T cell counts, CD4:CD8 ratio, PD-1 expression, and IL-17 production by CD8+ T cells exhibited incomplete normalization compared with seronegative controls. However, the proportion of CD8+ T cells with an exhausted phenotype (co-expressing PD-1 andTIM-3), and cells co-expressing cytotoxic molecules (Perforin and Granzyme B), reached normalization. CONCLUSIONS: Although suppressive cART achieves normalization of CD4+ T cell counts, only particular subsets of CD8+ T cells are more rapidly normalized in PLWH receiving cART, which could be routinely used as biomarkers for therapy efficiency in these patients.

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.

Particulate matter (PM10) induces in vitro activation of human neutrophils, and lung histopathological alterations in a mouse model.

The epidemiological association between exposure to particulate matter (PM10) and various respiratory and cardiovascular problems is well known, but the mechanisms driving these effects remain unclear. Neutrophils play an essential role in immune defense against foreign agents and also participate in the development of inflammatory responses. However, the role of these cells in the PM10 induced inflammatory response is not yet fully established. Thus, this study aims to evaluate the effect of PM10 on the neutrophil-mediated inflammatory response. For this, neutrophils from healthy adult human donors were in vitro exposed to different concentrations of PM10. The cell viability and cytotoxic activity were evaluated by MTT. LDH, propidium iodide and reactive oxygen species (ROS) were quantified by flow cytometry. Interleukin 8 (IL-8) expression, peptidyl arginine deiminase 4 (PAD4), myeloperoxidase (MPO), and neutrophil elastase (NE) expression were measured by RT-PCR. IL-8 was also quantified by ELISA. Fluorescence microscopy was used to evaluate neutrophil extracellular traps (NETs) release. The in vivo inflammatory responses were assessed in BALB/c mice exposed to PM10 by histopathology and RT-PCR. The analysis shows that PM10 exposure induced a cytotoxic effect on neutrophils, evidenced by necrosis and LDH release at high PM10 concentrations. ROS production, IL-8, MPO, NE expression, and NETs release were increased at all PM10 concentrations assessed. Neutrophil infiltration in bronchoalveolar lavage fluid (BALF), histopathological changes with inflammatory cell infiltration, and CXCL1 expression were observed in PM10-treated mice. The results suggest that lung inflammation in response to PM10 could be mediated by neutrophils activation. In this case, these cells migrate to the lungs and release pro-inflamatory mediators, including ROS, IL-8, and NETs. Thus, contributing to the exacerbation of respiratory pathologies, such as allergies, infectious and obstructive diseases.

Humoral Response to BNT162b2 Vaccine Against SARS-CoV-2 Variants Decays After Six Months.

SARS-CoV-2 vaccines have shown very high effectiveness in real-world scenarios. However, there is compelling evidence for a fast-paced waning of immunity. The increasing number of new variants that could alter the severity, transmissibility, and potential to evade the immune response raised significant concern. Therefore, elucidating changes in the humoral immune response against viral variants induced by vaccines over time is crucial for improving immunization protocols. We carried out a 6-month longitudinal prospective study in which 60 individuals between 21 and 71 years of age who have received the complete scheme of the BNT162b2 vaccine were followed to determine titers of serum neutralizing activity. The neutralizing capacity was measured at one, three, and six-months post-vaccination by plaque reduction neutralization assay using SARS-CoV-2 B.1 (D614G) and the Gamma, Alpha, Delta, and Mu variants. Data were analyzed using GraphPad 5.0. Neutralizing activity against five different SARS-CoV-2 variants was detected in the serum samples of all vaccinated participants to a different extent after one month, with a progressive decrease according to age and gender. Overall, after one month of vaccination, the neutralizing titer was lower for all evaluated variants when compared to B.1, most remarkable against Delta and Mu, with a reduction of 83.1% and 92.3%, respectively. In addition, the Titer at 3- or 6-months follow-up decreased dramatically for all variants. Our results support the decaying of serum neutralizing activity, both over time and across SARS-CoV-2 variants, being more significant in older men. Since Delta and Mu appear to evade the neutralizing activity, these and further new variants of immune escape mutations should be considered for novel vaccine formulations.

Neutralizing antibody titers to Omicron six months after vaccination with BNT162b2 in Colombia.

The emergence of the Omicron variant has generated concerns about the efficacy of COVID-19 vaccines. We evaluated the serum neutralizing activity of antibodies against the Omicron (lineage BA.1.1) by plaque reduction neutralizing test, as well as its correlation with age and gender, in a Colombian cohort six months after being vaccinated with BNT162b2 (Pfizer/BioNTech). Compared to all other variants analyzed, a significantly lower neutralizing activity (p<0.001) was observed against Omicron. Interestingly, older individuals exhibited lower titers against Omicron than those younger than 40. No statistical differences in neutralizing activity were observed according to gender. Our results showed that two doses of BNT162b2 might not provide robust protection against the Omicron variant over time. It is necessary to consider including changes in the composition of the vaccines to protect against new emerging variants of SARS-CoV-2 and campaigns to implement additional booster vaccinations.

A specific structure and high richness characterize intestinal microbiota of HIV-exposed seronegative individuals.

Intestinal microbiota facilitates food breakdown for energy metabolism and influences the immune response, maintaining mucosal homeostasis. Overall, HIV infection is associated with intestinal dysbiosis and immune activation, which has been related to seroconversion in HIV-exposed individuals. However, it is unclear whether microbiota dysbiosis is the cause or the effect of immune alterations and disease progression or if it could modulate the risk of acquiring the HIV infection. We characterize the intestinal microbiota and determine its association with immune regulation in HIV-exposed seronegative individuals (HESN), HIV-infected progressors (HIV+), and healthy control (HC) subjects. For this, feces and blood were collected. The microbiota composition of HESN showed a significantly higher alpha (p = 0.040) and beta diversity (p = 0.006) compared to HC, but no differences were found compared to HIV+. A lower Treg percentage was observed in HESN (1.77%) than HC (2.98%) and HIV+ (4.02%), with enrichment of the genus Butyrivibrio (p = 0.029) being characteristic of this profile. Moreover, we found that Megasphaera (p = 0.017) and Victivallis (p = 0.0029) also are enriched in the microbiota composition in HESN compared to HC and HIV+ subjects. Interestingly, an increase in Succinivibrio and Prevotella, and a reduction in Bacteroides genus, which is typical of HIV-infected individuals, were observed in both HESN and HIV+, compared to HC. Thus, HESNs have a microbiota profile, similar to that observed in HIV+, most likely because HESN are cohabiting with their HIV+ partners.

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.

Ichthyosis: case report in a Colombian man with genetic alterations in ABCA12 and HRNR genes.

BACKGROUND: Ichthyosis is a heterogeneous group of diseases caused by genetic disorders related to skin formation. They are characterized by generalized dry skin, scaling, hyperkeratosis and frequently associated with erythroderma. Among its different types, harlequin ichthyosis (HI) stands out due to its severity. HI is caused by mutations in the ABCA12 gene, which encodes essential proteins in epidermal lipid transport, and it helps maintain the homeostasis of the stratum corneum of the epidermis. However, due to the wide spectrum of genetic alterations that can cause ichthyosis, holistic medical care, and genetic studies are required to improve the diagnosis and outcomes of these diseases. CASE PRESENTATION: Here, we presented the case of a 19 years old male patient who was a premature infant and exhibited clinical features consistent with HI, including bright yellow hyperkeratotic plates with erythematous fissures that covered his entire body like a collodion baby. Currently, he exhibited erythroderma, photosensitivity, ectropion, auricular pavilion alterations, and musculoskeletal disorders, such as equinovarus feet, fingers, hands, and hypoplastic feet with contractures in flexion and marked difficulty in fine motor skills. In addition, he presented dyschromatopsia, Achilles reflex hyporeflexia, slight speech, dental alteration and deficient cognitive performance. After the genetic sequencing, variants were found in ABCA12 and HRNR which are related to several skin diseases, including ichthyosis. CONCLUSIONS: Although in clinical practice, ichthyosis is a common entity, a severe type of ichthyosis is presented, highlighting the importance of appropriate genetic diagnosis, given the broad spectrum of genetic alterations with similar phenotypic and clinical characteristics. These pathologies must be known to guarantee initial support measures to prevent complications and offer multidisciplinary management to those patients.

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

Inflammatory effects of particulate matter air pollution.

Air pollution is an important cause of non-communicable diseases globally with particulate matter (PM) as one of the main air pollutants. PM is composed of microscopic particles that contain a mixture of chemicals and biological elements that can be harmful to human health. The aerodynamic diameter of PM facilitates their deposition when inhaled. For instance, coarse PM having a diameter of < 10 µm is deposited mainly in the large conducting airways, but PM of < 2.5 µm can cross the alveolar-capillary barrier, traveling to other organs within the body. Epidemiological studies have shown the association between PM exposure and risk of disease, namely those of the respiratory system such as lung cancer, asthma, and chronic obstructive pulmonary disease (COPD). However, cardiovascular and neurological diseases have also been reported, including hypertension, atherosclerosis, acute myocardial infarction, stroke, loss of cognitive function, anxiety, and Parkinson's and Alzheimer's diseases. Inflammation is a common hallmark in the pathogenesis of many of these diseases associated with exposure to a variety of air pollutants, including PM. This review focuses on the main effects of PM on human health, with an emphasis on the role of inflammation.

Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases.

Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.