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The aim of this study was to analyze molecules associated with regulatory immune response in unvaccinated, recovered COVID-19 patients with and without diabetes mellitus (DM) and hypertension (HTN). We determined anti-SARS-CoV-2 nucleocapsid IgG in plasma by electrochemiluminescence immunoassay. The levels of sCD40, TGF-ß, IL-10, and sCTLA-4 were assessed by ELISA in the serum of the subjects, as well as in healthy donors. We observed that only half of the subjects in the non-comorbid group produced antibodies, whereas all subjects in comorbid groups were IgG-positive for the anti-SARS-CoV-2 nucleocapsid. High levels of sCTL-4 were observed in the non-comorbid group, and the level of IL-10 was observed to increase in seropositive subjects without comorbidities. TGF-ß concentration was similar in all groups studied. Finally, sCD40 decreased in the comorbid group. In conclusion, our results suggest that comorbidities such as DM and HTN alter the production of co-stimulatory inhibitory molecules sCTLA-4 and sCD40 in subjects recovering from mild COVID-19. The alterations observed here were independent of seropositivity, suggesting an effective humoral immune response against COVID-19 separate from the levels of co-stimulatory inhibitory molecules.
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Epidemiological studies have associated long-term exposure to environmental air pollution particulate matter (PM) with the development of diverse health problems. They include infectious respiratory diseases related to the deregulation of some innate immune response mechanisms, such as the host defense peptides' expression. Herein, we evaluated in BALB/c mice the effect of long-standing exposure (60 days) to urban-PM from the south of Mexico City, with aerodynamic diameters below 2.5 µm (PM2.5) and 10 µm (PM10) on the lung's gene expression and production of three host defense peptides (HDPs); murine beta-defensin-3, -4 (mBD-3, mBD-4) and cathelin-related antimicrobial peptide (CRAMP). We also evaluated mRNA levels of Il1b and Il10, two cytokines related to the expression of host defense peptides. Exposure to PM2.5 and PM10 differentially induced lung inflammation, being PM2.5, which caused higher inflammation levels, probably associated with a differential deposition on the airways, that facilitate the interaction with alveolar macrophages. Inflammation levels were associated with an early upregulation of the three HDPs assessed and an increment in Il1b mRNA levels. Interestingly, after 28 days of exposure, Il10 mRNA upregulation was observed and was associated with the downregulation of HDPs and Il1b mRNA levels. The upregulation of Il10 mRNA and suppression of HDPs might facilitate microbial colonization and the development of diseases associated with long-term exposure to PM.
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Contaminantes Atmosféricos/toxicidad , Catelicidinas/metabolismo , Interleucina-1beta/metabolismo , Material Particulado/toxicidad , Neumonía/patología , beta-Defensinas/metabolismo , Animales , Catelicidinas/genética , Interleucina-1beta/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Neumonía/etiología , Neumonía/metabolismo , beta-Defensinas/genéticaRESUMEN
INTRODUCTION: The use of probiotics has been broadly popularized due to positive effects in the attenuation of aberrant immune responses such as asthma. Allergic asthma is a chronic respiratory disease characterized by airway inflammation and remodelling. OBJECTIVE: This study was aimed to evaluate the effect of oral administration of Lactococcus lactis NZ9000 on asthmatic airway inflammation and lung tissue remodelling in rats and its relation to the maintenance of an adequate intestinal barrier. METHODS: Wistar rats were ovalbumin (OVA) sensitized and challenged and orally treated with L. lactis. Lung inflammatory infiltrates and cytokines were measured, and remodelling was evaluated. Serum OVA-specific immunoglobulin (Ig) E levels were assessed. We also evaluated changes on intestinal environment and on systemic immune response. RESULTS: L. lactis diminished the infiltration of proinflammatory leucocytes, mainly eosinophils, in the bronchoalveolar compartment, decreased lung IL-4 and IL-5 expression, and reduced the level of serum allergen-specific IgE. Furthermore, L. lactis prevented eosinophil influx, collagen deposition, and goblet cell hyperplasia in lung tissue. In the intestine, L. lactis-treated asthmatic rats increased Peyer's patch and goblet cell quantity and mRNA expression of IgA, MUC-2, and claudin. Additionally, intestinal morphological alterations were normalized by L. lactis administration. Splenocyte proliferative response to OVA was abolished, and serum levels of transforming growth factor (TGF)-ß were increased by L. lactis treatment. CONCLUSIONS: These findings suggest that L. lactis is a potential candidate for asthma prevention, and the effect is mediated by the improvement of intestinal barrier function and systemic TGF-ß production.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Asma/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lactococcus lactis/fisiología , Probióticos/administración & dosificación , Factor de Crecimiento Transformador beta/biosíntesis , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Animales , Asma/etiología , Asma/prevención & control , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Ovalbúmina/inmunología , RatasRESUMEN
Exposure to air pollution particulate matter (PM) and tuberculosis (TB) are two of the leading global public health challenges affecting low and middle income countries. An estimated 4.26 million premature deaths are attributable to household air pollution and an additional 4.1 million to outdoor air pollution annually. Mycobacterium tuberculosis (M.tb) infects a large proportion of the world's population with the risk for TB development increasing during immunosuppressing conditions. There is strong evidence that such immunosuppressive conditions develop during household air pollution exposure, which increases rates of TB development. Exposure to urban air pollution has been shown to alter the outcome of TB therapy. Here we examined whether in vitro exposure to urban air pollution PM alters human immune responses to M.tb. PM2.5 and PM10 (aerodynamic diameters <2.5µm, <10µm) were collected monthly from rainy, cold-dry and warm-dry seasons in Iztapalapa, a highly populated TB-endemic municipality of Mexico City with elevated outdoor air pollution levels. We evaluated the effects of seasonality and size of PM on cytotoxicity and antimycobacterial host immunity in human peripheral blood mononuclear cells (PBMC) from interferon gamma (IFN-γ) release assay (IGRA)+ and IGRA- healthy study subjects. PM10 from cold-dry and warm-dry seasons induced the highest cytotoxicity in PBMC. With the exception of PM2.5 from the cold-dry season, pre-exposure to all seasonal PM reduced M.tb phagocytosis by PBMC. Furthermore, M.tb-induced IFN-γ production was suppressed in PM2.5 and PM10-pre-exposed PBMC from IGRA+ subjects. This observation coincides with the reduced expression of M.tb-induced T-bet, a transcription factor regulating IFN-γ expression in T cells. Pre-exposure to PM10 compared to PM2.5 led to greater loss of M.tb growth control. Exposure to PM2.5 and PM10 collected in different seasons differentially impairs M.tb-induced human host immunity, suggesting biological mechanisms underlying altered M.tb infection and TB treatment outcomes during air pollution exposures.
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Contaminantes Atmosféricos/toxicidad , Citotoxicidad Inmunológica/efectos de los fármacos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Material Particulado/toxicidad , Adolescente , Adulto , Anciano , Ciudades , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Interacciones Microbiota-Huesped/efectos de los fármacos , Interacciones Microbiota-Huesped/inmunología , Humanos , Técnicas In Vitro , Interferón gamma/biosíntesis , Interleucina-1beta/biosíntesis , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Masculino , México , Persona de Mediana Edad , Mycobacterium tuberculosis/crecimiento & desarrollo , Tamaño de la Partícula , Fagocitosis/efectos de los fármacos , Estaciones del Año , Proteínas de Dominio T Box/inmunología , Salud Urbana , Adulto JovenRESUMEN
Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses against Mycobacterium tuberculosis has been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 µm (PM2.5) and 10 µm (PM10) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM2.5 or PM10 deregulated the ability of the A549 cells to express the antimicrobial peptides human ß-defensin 2 (HBD-2) and HBD-3 upon infection with M. tuberculosis and increased intracellular M. tuberculosis growth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhanced M. tuberculosis growth represent mechanisms by which exposure to air pollution PM may increase the risk of M. tuberculosis infection and the development of TB.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/análisis , Mycobacterium tuberculosis/fisiología , Material Particulado/toxicidad , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Contaminantes Atmosféricos/química , Línea Celular Tumoral , ADN Complementario/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad Innata , México , Material Particulado/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , beta-Defensinas/genética , beta-Defensinas/metabolismoRESUMEN
Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15-30 µg/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.
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Péptidos Catiónicos Antimicrobianos/farmacología , Antituberculosos/farmacología , Inmunidad Innata/efectos de los fármacos , Neumonía/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Animales , Péptidos Catiónicos Antimicrobianos/síntesis química , Antituberculosos/síntesis química , Carga Bacteriana/efectos de los fármacos , Línea Celular , Citocinas/biosíntesis , Citocinas/inmunología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Inmunomodulación/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/patología , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/inmunología , Neumonía/complicaciones , Neumonía/microbiología , Neumonía/patología , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
Tuberculosis (TB) is a major worldwide health problem in part due to the lack of development of new treatments and the emergence of new strains such as multidrug-resistant (MDR) and extensively drug-resistant strains that are threatening and impairing the control of this disease. In this study, the efficacy of natural and synthetic cationic antimicrobial (host defence) peptides that have been shown often to possess broad-spectrum antimicrobial activity was tested. The natural antimicrobial peptides human LL-37 and mouse CRAMP as well as synthetic peptides E2, E6 and CP26 were tested for their activity against Mycobacterium tuberculosis both in in vitro and in vivo models. The peptides had moderate antimicrobial activities, with minimum inhibitory concentrations ranging from 2 µg/mL to 10 µg/mL. In a virulent model of M. tuberculosis lung infection, intratracheal therapeutic application of these peptides three times a week at doses of ca. 1mg/kg led to significant 3-10-fold reductions in lung bacilli after 28-30 days of treatment. The treatments worked both against the drug-sensitive H37Rv strain and a MDR strain. These results indicate that antimicrobial peptides might constitute a novel therapy against TB.