RESUMEN

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On the one hand, TMEM176B promotes antigen cross-presentation to CD8+ T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, it inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. We speculated that formulating BayK8644 in PEGylated chitosan nanoparticles (NP-PEG-BayK8644) should slowly release the compound and by that mean avoid cross-presentation inhibition (which happens with a fast 30 min kinetics) while still triggering inflammasome activation. Chitosan nanocarriers were successfully obtained, exhibiting a particle size within the range of 200 nm; they had a high positive surface charge and a 99 % encapsulation efficiency. In in vitro studies, NP-PEG-BayK8644 did not inhibit antigen cross-presentation by DCs, unlike the free compound. The NP-PEG-BayK8644 activated the inflammasome in a Tmem176b-dependent manner in DCs. We administered either empty (eNP-PEG) or NP-PEG-BayK8644 to mice with established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and improved mice survival compared to both eNP-PEG and free BayK8644 in melanoma and lymphoma models. This effect was associated with enhanced inflammasome activation by DCs in the tumor-draining lymph node and infiltration of the tumor by CD8+ T cells. Thus, encapsulation of BayK8644 in chitosan NPs improves the anti-tumoral properties of the compound by avoiding inhibition of antigen cross-presentation.

Asunto(s)

Inmunidad Adaptativa , Quitosano , Células Dendríticas , Inmunidad Innata , Nanopartículas , Quitosano/química , Quitosano/farmacología , Animales , Nanopartículas/química , Ratones , Inmunidad Adaptativa/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Proteínas de la Membrana/inmunología , Inflamasomas/metabolismo , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones Endogámicos C57BL , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Polietilenglicoles/química , Polietilenglicoles/farmacología

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-1 infection can activate the expression of human endogenous retroviruses (HERVs), particularly HERV-K (HML-2). HIV controllers (HICs) are rare people living with HIV (PLWHs) who naturally control HIV-1 replication and overexpress some cellular restriction factors that negatively regulate the LTR-driven transcription of HIV-1 proviruses. OBJECTIVES: To understand the ability of HICs to control the expression of endogenous retroviruses. METHODS: We measured endogenous retrovirus type K6 (ERVK-6) RNA expression in peripheral blood mononuclear cells (PBMCs) of HICs (n = 23), antiretroviral (ART)-suppressed subjects (n = 8), and HIV-1-negative (NEG) individuals (n = 10) and correlated the transcript expression of ERVK-6 with multiple HIV-1 cellular restriction factors. FINDINGS: Our study revealed that ERVK-6 RNA expression in PBMCs from HICs was significantly downregulated compared with that in both the ART and NEG control groups. Moreover, we detected that ERVK-6 RNA levels in PBMCs across all groups were negatively correlated with the expression levels of p21 and MCPIP1, two cellular restriction factors that limit the activation of macrophages and T cells by downregulating the activity of NF-kB. MAIN CONCLUSIONS: These findings support the hypothesis that HICs activate innate antiviral mechanisms that may simultaneously downregulate the transcription of both exogenous (HIV-1) and endogenous (ERVK-6) retroviruses. Future studies with larger cohorts should be performed to confirm this hypothesis and to explore the role of p21 and MCPIP1 in regulating HERV-K expression in physiological and pathological conditions.

Asunto(s)

Retrovirus Endógenos , Infecciones por VIH , VIH-1 , ARN Viral , Ribonucleasas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Retrovirus Endógenos/genética , Retrovirus Endógenos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , VIH-1/genética , VIH-1/inmunología , Inmunidad Innata/genética , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ribonucleasas/genética , Ribonucleasas/metabolismo , ARN Viral/genética , Factores de Transcripción/genética , Replicación Viral/genética

RESUMEN

During virus infection, many host proteins are redirected from their normal cellular roles to restrict and terminate infection. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are cellular RNA-binding proteins critical to host nucleic acid homeostasis, but can also be involved in the viral infection process, affecting virus replication, assembly and propagation. It has become evident that hnRNPs play important roles in modulation of host innate immunity, which provides critical initial protection against infection. These novel findings can potentially lead to the leveraging of hnRNPs in antiviral therapies. We review hnRNP involvement in antiviral innate immunity, in humans, mice and other animals, and discuss hnRNP targeting as a potential novel antiviral therapeutic.

Asunto(s)

Ribonucleoproteínas Nucleares Heterogéneas , Inmunidad Innata , Virosis , Humanos , Animales , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Virosis/inmunología , Replicación Viral , Ratones , Interacciones Huésped-Patógeno/inmunología

RESUMEN

Microglia are specialized immune cells that reside in the central nervous system (CNS) and play a crucial role in maintaining the homeostasis of the brain microenvironment. While traditionally regarded as a part of the innate immune system, recent research has highlighted their role in adaptive immunity. The CNS is no longer considered an immune-privileged organ, and increasing evidence suggests bidirectional communication between the immune system and the CNS. Microglia are sensitive to systemic immune signals and can respond to systemic inflammation by producing various inflammatory cytokines and chemokines. This response is mediated by activating pattern recognition receptors (PRRs), which recognize pathogen- and danger-associated molecular patterns in the systemic circulation. The microglial response to systemic inflammation has been implicated in several neurological conditions, including depression, anxiety, and cognitive impairment. Understanding the complex interplay between microglia and systemic immunity is crucial for developing therapeutic interventions to modulate immune responses in the CNS.

Asunto(s)

Inmunidad Innata , Microglía , Microglía/inmunología , Microglía/metabolismo , Humanos , Animales , Inmunidad Innata/inmunología , Inflamación/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Inmunidad Adaptativa/inmunología , Encéfalo/inmunología

RESUMEN

BACKGROUND: In this study, a probiotic mixture (Honeybeeotic) consisting of seven bacterial strains isolated from a unique population of honeybees (Apis mellifera ligustica) was used. That honeybee population was located in the Roti Abbey locality of the Marche Region in Italy, an area isolated from human activities, and genetic contamination from other honeybee populations. The aim was to investigate the effects of this probiotic mixture on the innate immunity and intestinal microbiome of healthy common honeybees in two hives of the same apiary. Hive A received a diet of 50% glucose syrup, while hive B received the same syrup supplemented with the probiotics, both administered daily for 1 month. To determine whether the probiotic altered the immune response, phenoloxidase activity and hemolymph cellular subtype count were investigated. Additionally, metagenomic approaches were used to analyze the effects on gut microbiota composition and function, considering the critical role the gut microbiota plays in modulating host physiology. RESULTS: The results revealed differences in hemocyte populations between the two hives, as hive A exhibited higher counts of oenocytoids and granulocytes. These findings indicated that the dietary supplementation with the probiotic mixture was safe and well-tolerated. Furthermore, phenoloxidase activity significantly decreased in hive B (1.75 ± 0.19 U/mg) compared to hive A (3.62 ± 0.44 U/mg, p < 0.005), suggesting an improved state of well-being in the honeybees, as they did not require activation of immune defense mechanisms. Regarding the microbiome composition, the probiotic modulated the gut microbiota in hive B compared to the control, retaining core microbiota components while causing both positive and negative variations. Notably, several genes, particularly KEGG genes involved in amino acid metabolism, carbohydrate metabolism, and branched-chain amino acid (BCAA) transport, were more abundant in the probiotic-fed group, suggesting an effective nutritional supplement for the host. CONCLUSIONS: This study advocated that feeding with this probiotic mixture induces beneficial immunological effects and promoted a balanced gut microbiota with enhanced metabolic activities related to digestion. The use of highly selected probiotics was shown to contribute to the overall well-being of the honeybees, improving their immune response and gut health.

Asunto(s)

Microbioma Gastrointestinal , Hemolinfa , Monofenol Monooxigenasa , Probióticos , Animales , Abejas/citología , Abejas/efectos de los fármacos , Abejas/enzimología , Abejas/microbiología , Suplementos Dietéticos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Hemocitos , Hemolinfa/citología , Inmunidad Innata , Italia , Monofenol Monooxigenasa/metabolismo , Probióticos/administración & dosificación

RESUMEN

Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.

Asunto(s)

Citocinas , Deshidroepiandrosterona , Hidrocortisona , Macrófagos , Metformina , Mycobacterium tuberculosis , Metformina/farmacología , Humanos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos/inmunología , Mycobacterium tuberculosis/efectos de los fármacos , Hidrocortisona/metabolismo , Deshidroepiandrosterona/farmacología , Citocinas/metabolismo , Inmunidad Innata/efectos de los fármacos , Células THP-1 , Interacciones Huésped-Patógeno , Células Cultivadas , Hipoglucemiantes/farmacología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/microbiología , Mediadores de Inflamación/metabolismo

RESUMEN

Since the discovery of specific immune memory in invertebrates, researchers have investigated its immune response to diverse microbial and environmental stimuli. Nevertheless, the extent of the immune system's interaction with metabolism, remains relatively enigmatic. In this mini review, we propose a comprehensive investigation into the intricate interplay between metabolism and specific immune memory. Our hypothesis is that cellular endocycles and epigenetic modifications play pivotal roles in shaping this relationship. Furthermore, we underscore the importance of the crosstalk between metabolism and specific immune memory for understanding the evolutionary costs. By evaluating these costs, we can gain deeper insights into the adaptive strategies employed by invertebrates in response to pathogenic challenges. Lastly, we outline future research directions aimed at unraveling the crosstalk between metabolism and specific immune memory. These avenues of inquiry promise to illuminate fundamental principles governing host-pathogen interactions and evolutionary trade-offs, thus advancing our understanding of invertebrate immunology.

Asunto(s)

Epigénesis Genética , Interacciones Huésped-Patógeno , Memoria Inmunológica , Invertebrados , Animales , Invertebrados/inmunología , Interacciones Huésped-Patógeno/inmunología , Evolución Biológica , Inmunidad Innata

RESUMEN

Rainbow trout is an important fish species for Peruvian artisanal aquaculture, comprising over 60 % of the total aquaculture production. However, their industry has been highly affected by several bacterial agents such as Yersinia ruckeri. This pathogen is the causative agent of Enteric Redmouth Disease, and causes high mortality in fingerlings and chronic infection in adult rainbow trout. To date, the immune response of rainbow trout against Y. ruckeri has been well studied in laboratory-controlled infection studies (i.e. intraperitoneal infection, bath immersion), however, the immune response during natural infection has not been explored. To address this, in this study, 35 clinically healthy O. mykiss without evidence of lesions or changes in behavior and 32 rainbow trout naturally infected by Y. ruckeri, were collected from semi-intensive fish farms located in the Central Highlands of Peru. To evaluate the effect on the immune response, RT-qPCR, western blotting, and ELISA were conducted using head kidney, spleen, and skin tissues to evaluate the relative gene expression and protein levels. Our results show a significant increase in the expression of the pro-inflammatory cytokines il1b, tnfa, and il6, as well as ifng in all three tissues, as well as increases in IL-1ß and IFN-γ protein levels. The endogenous pathway of antigen presentation showed to play a key role in defense against Y. ruckeri, due to the upregulation of mhc-I, tapasin, and b2m transcripts, and the significant increase of Tapasin protein levels in infected rainbow trout. None of the genes associated with the exogenous pathway of antigen presentation showed a significant increase in infected fish, suggesting that this pathway is not involved in the response against this intracellular pathogen. Finally, the transcripts of immunoglobulins IgM and IgT did not show a modulation, nor were the protein levels evaluated in this study.

Asunto(s)

Inmunidad Adaptativa , Enfermedades de los Peces , Inmunidad Innata , Oncorhynchus mykiss , Yersiniosis , Yersinia ruckeri , Animales , Oncorhynchus mykiss/inmunología , Yersinia ruckeri/fisiología , Yersiniosis/veterinaria , Yersiniosis/inmunología , Enfermedades de los Peces/inmunología , Inmunidad Innata/genética , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Perú

RESUMEN

Systemic candidiasis remains a significant public health concern worldwide, with high mortality rates despite available antifungal drugs. Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that Candida albicans EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with C. albicans EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal C. albicans inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant C. albicans strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with O- and N-linked mannans and the presence of ß-1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.IMPORTANCESystemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that Candida albicans EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with Candida. This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.

Asunto(s)

Candida albicans , Candidiasis , Células Dendríticas , Vesículas Extracelulares , Vacunas Fúngicas , Receptores de Reconocimiento de Patrones , Receptor Toll-Like 4 , Animales , Candida albicans/inmunología , Vesículas Extracelulares/inmunología , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Ratones , Candidiasis/inmunología , Candidiasis/prevención & control , Candidiasis/microbiología , Vacunas Fúngicas/inmunología , Vacunas Fúngicas/administración & dosificación , Células Dendríticas/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Ratones Endogámicos C57BL , Femenino , Inmunidad Innata , Modelos Animales de Enfermedad

RESUMEN

Legionella species are Gram-negative intracellular bacteria that evolved in soil and freshwater environments, where they infect and replicate within various unicellular protozoa. The primary virulence factor of Legionella is the expression of a type IV secretion system (T4SS), which contributes to the translocation of effector proteins that subvert biological processes of the host cells. Because of its evolution in unicellular organisms, T4SS effector proteins are not adapted to subvert specific mammalian signaling pathways and immunity. Consequently, Legionella pneumophila has emerged as an interesting infection model for investigating immune responses against pathogenic bacteria in multicellular organisms. This review highlights recent advances in our understanding of mammalian innate immunity derived from studies involving L. pneumophila. This includes recent insights into inflammasome-mediated mechanisms restricting bacterial replication in macrophages, mechanisms inducing cell death in response to infection, induction of effector-triggered immunity, activation of specific pulmonary cell types in mammalian lungs, and the protective role of recruiting monocyte-derived cells to infected lungs.

Asunto(s)

Inmunidad Innata , Legionella pneumophila , Enfermedad de los Legionarios , Legionella pneumophila/inmunología , Legionella pneumophila/patogenicidad , Humanos , Animales , Enfermedad de los Legionarios/inmunología , Enfermedad de los Legionarios/microbiología , Fagocitos/inmunología , Fagocitos/microbiología , Sistemas de Secreción Tipo IV/inmunología , Sistemas de Secreción Tipo IV/genética , Sistemas de Secreción Tipo IV/metabolismo , Inflamasomas/inmunología , Inflamasomas/metabolismo , Monocitos/inmunología , Monocitos/microbiología , Factores de Virulencia/inmunología , Factores de Virulencia/metabolismo , Macrófagos/inmunología , Macrófagos/microbiología , Interacciones Huésped-Patógeno/inmunología

RESUMEN

One hundred years have passed since the death of Élie Metchnikoff (1845-1916). He was the first to observe the uptake of particles by cells and realized the importance of this process, named phagocytosis, for the host response to injury and infection. He also was a strong advocate of the role of phagocytosis in cellular immunity, and with this, he gave us the basis for our modern understanding of inflammation and the innate immune response. Phagocytosis is an elegant but complex process for the ingestion and elimination of pathogens, but it is also important for the elimination of apoptotic cells and hence fundamental for tissue homeostasis. Phagocytosis can be divided into four main steps: (i) recognition of the target particle, (ii) signaling to activate the internalization machinery, (iii) phagosome formation, and (iv) phagolysosome maturation. In this chapter, we present a general view of our current knowledge on phagocytosis performed mainly by professional phagocytes through antibody and complement receptors and discuss aspects that remain incompletely understood.

Asunto(s)

Fagocitosis , Fagosomas , Humanos , Animales , Fagosomas/metabolismo , Fagocitos/inmunología , Fagocitos/metabolismo , Transducción de Señal , Inmunidad Innata

Asunto(s)

Inmunidad Innata , Vasculitis , Humanos , Vasculitis/inmunología , Animales

RESUMEN

BACKGROUND: The impact of Schistosoma mansoni infection over the immune response and the mechanisms involved in pathogenesis are not yet completely understood. OBJECTIVES: This study aimed to evaluate the expression of innate immune receptors in three distinct mouse lineages (BALB/c, C57BL/6 and Swiss) during experimental S. mansoni infection with LE strain. METHODS: The parasite burden, intestinal tissue oogram and presence of hepatic granulomas were evaluated at 7- and 12-weeks post infection (wpi). The mRNA expression for innate Toll-like receptors, Nod-like receptors, their adaptor molecules, and cytokines were determined at 2, 7 and 12 wpi in the hepatic tissue by real-time quantitative polymerase chain reaction (qPCR). FINDINGS: Swiss mice showed 100% of survival, had lower parasite burden and intestinal eggs, while infected BALB/c and C57BL/6 presented 80% and 90% of survival, respectively, higher parasite burden and intestinal eggs. The three mouse lineages displayed distinct patterns in the expression of innate immune receptors, their adaptor molecules and cytokines, at 2 and 7 wpi. MAIN CONCLUSIONS: Our results suggest that the pathogenesis of S. mansoni infection is related to a dynamic early activation of innate immunity receptors and cytokines important for the control of developing worms.

Asunto(s)

Citocinas , Inmunidad Innata , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Esquistosomiasis mansoni , Animales , Esquistosomiasis mansoni/inmunología , Inmunidad Innata/inmunología , Citocinas/inmunología , Ratones , Schistosoma mansoni/inmunología , Modelos Animales de Enfermedad , Femenino , Receptores Toll-Like/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Recuento de Huevos de Parásitos , Masculino , ARN Mensajero , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología

RESUMEN

Innate immune system activation is crucial in the inflammatory response, but uncontrolled activation can lead to autoimmune diseases. Cellular exhaustion and senescence are two processes that contribute to innate immune tolerance breakdown. Exhausted immune cells are unable to respond adequately to specific antigens or stimuli, while senescent cells have impaired DNA replication and metabolic changes. These processes can impair immune system function and disrupt homeostasis, leading to the emergence of autoimmunity. However, the influence of innate immune exhaustion and senescence on autoimmune disorders is not well understood. This review aims to describe the current findings on the role of innate immune exhaustion and senescence in autoimmunity, focusing on the cellular and molecular changes involved in each process. Specifically, the article explores the markers and pathways associated with immune exhaustion, such as PD-1 and TIM-3, and senescence, including Β-galactosidase (ß-GAL), lamin B1, and p16ink4a, and their impact on autoimmune diseases, namely type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and immune-mediated myopathies. Understanding the mechanisms underlying innate immune exhaustion and senescence in autoimmunity may provide insights for the development of novel therapeutic strategies.

Asunto(s)

Enfermedades Autoinmunes , Senescencia Celular , Inmunidad Innata , Humanos , Inmunidad Innata/inmunología , Enfermedades Autoinmunes/inmunología , Senescencia Celular/inmunología , Autoinmunidad/inmunología , Agotamiento del Sistema Inmunológico

RESUMEN

Pathogenic bacteria have several mechanisms to evade the host's immune response and achieve an efficient infection. Bacterial extracellular vesicles (EVs) are a relevant cellular communication mechanism, since they can interact with other bacterial cells and with host cells. In this review, we focus on the EVs produced by some World Health Organization (WHO) priority Gram-negative and Gram-positive pathogenic bacteria; by spore-producing bacteria; by Mycobacterium tuberculosis (a bacteria with a complex cell wall); and by Treponema pallidum (a bacteria without lipopolysaccharide). We describe the classification and the general properties of bacterial EVs, their role during bacterial infections and their effects on the host immune response. Bacterial EVs contain pathogen-associated molecular patterns that activate innate immune receptors, which leads to cytokine production and inflammation, but they also contain antigens that induce the activation of B and T cell responses. Understanding the many effects of bacterial EVs on the host's immune response can yield new insights on the pathogenesis of clinically important infections, but it can also lead to the development of EV-based diagnostic and therapeutic strategies. In addition, since EVs are efficient activators of both the innate and the adaptive immune responses, they constitute a promising platform for vaccine development.

Asunto(s)

Vesículas Extracelulares , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Humanos , Animales , Inmunidad Innata , Interacciones Huésped-Patógeno/inmunología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Bacterias/inmunología

RESUMEN

Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.

Asunto(s)

Citocinas , Reposicionamiento de Medicamentos , Inhibidores de Histona Desacetilasas , Inmunidad Innata , Infecciones por Mycobacterium no Tuberculosas , Inmunidad Innata/efectos de los fármacos , Humanos , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Inhibidores de Histona Desacetilasas/farmacología , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/inmunología , Mycobacterium/inmunología , Mycobacterium/efectos de los fármacos

RESUMEN

BACKGROUND: The Tripartite motif (TRIM) family includes more than 80 distinct human genes. Their function has been implicated in regulating important cellular processes, including intracellular signaling, transcription, autophagy, and innate immunity. During viral infections, macrophages are key components of innate immunity that produce interferons (IFNs) and IL27. We recently published that IL27 and IFNs induce transcriptional changes in various genes, including those involved in JAK-STAT signaling. Furthermore, IL27 and IFNs share proinflammatory and antiviral pathways in monocyte-derived macrophages (MDMs), resulting in both common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs) encoding antiviral proteins. Interestingly, many TRIM proteins have been recognized as ISGs in recent years. Although it is already very well described that TRIM expression is induced by IFNs, it is not fully understood whether TRIM genes are induced in macrophages by IL27. Therefore, in this study, we examined the effect of stimulation with IL27 and type I, II, and III IFNs on the mRNA expression profiles of TRIM genes in MDMs. METHODS: We used bulk RNA-seq to examine the TRIM expression profile of MDMs treated with IFNs or IL27. Initially, we characterized the expression patterns of different TRIM subfamilies using a heatmap. Subsequently, a volcano plot was employed to identify commonly differentially expressed TRIM genes. Additionally, we conducted gene ontology analysis with ClueGO to explore the biological processes of the regulated TRIMs, created a gene-gene interaction network using GeneMANIA, and examined protein-protein interactions with the STRING database. Finally, RNA-seq data was validated using RT-qPCR. Furthermore, the effect of IL27 on Mayaro virus replication was also evaluated. RESULTS: We found that IL27, similar to IFNs, upregulates several TRIM genes' expression in human macrophages. Specifically, we identified three common TRIM genes (TRIM19, 21, and 22) induced by IL27 and all types of human IFNs. Additionally, we performed the first report of transcriptional regulation of TRIM19, 21, 22, and 69 genes in response to IL27. The TRIMs involved a broad range of biological processes, including defense response to viruses, viral life cycle regulation, and negative regulation of viral processes. In addition, we observed a decrease in Mayaro virus replication in MDMs previously treated with IL27. CONCLUSIONS: Our results show that IL27, like IFNs, modulates the transcriptional expression of different TRIM-family members involved in the induction of innate immunity and an antiviral response. In addition, the functional analysis demonstrated that, like IFN, IL27 reduced Mayaro virus replication in MDMs. This implies that IL27 and IFNs share many similarities at a functional level. Moreover, identifying distinct TRIM groups and their differential expressions in response to IL27 provides new insights into the regulatory mechanisms underlying the antiviral response in human macrophages.

Asunto(s)

Interferones , Macrófagos , Proteínas de Motivos Tripartitos , Replicación Viral , Humanos , Macrófagos/virología , Macrófagos/inmunología , Proteínas de Motivos Tripartitos/genética , Interferones/inmunología , Regulación de la Expresión Génica , Inmunidad Innata , Interleucinas/genética , Interleucinas/inmunología , Interleucinas/metabolismo , Transducción de Señal

RESUMEN

The innate immune response in Salmo salar, mediated by pattern recognition receptors (PRRs), is crucial for defending against pathogens. This study examined DDX41 protein functions as a cytosolic/nuclear sensor for cyclic dinucleotides, RNA, and DNA from invasive intracellular bacteria. The investigation determined the existence, conservation, and functional expression of the ddx41 gene in S. salar. In silico predictions and experimental validations identified a single ddx41 gene on chromosome 5 in S. salar, showing 83.92% homology with its human counterpart. Transcriptomic analysis in salmon head kidney confirmed gene transcriptional integrity. Proteomic identification through mass spectrometry characterized three unique peptides with 99.99% statistical confidence. Phylogenetic analysis demonstrated significant evolutionary conservation across species. Functional gene expression analysis in SHK-1 cells infected by Piscirickettsia salmonis and Renibacterium salmoninarum indicated significant upregulation of DDX41, correlated with increased proinflammatory cytokine levels and activation of irf3 and interferon signaling pathways. In vivo studies corroborated DDX41 activation in immune responses, particularly when S. salar was challenged with P. salmonis, underscoring its potential in enhancing disease resistance. This is the first study to identify the DDX41 pathway as a key component in S. salar innate immune response to invading pathogens, establishing a basis for future research in salmonid disease resistance.

Asunto(s)

Enfermedades de los Peces , Inmunidad Innata , Filogenia , Piscirickettsia , Infecciones por Piscirickettsiaceae , Renibacterium , Salmo salar , Animales , Piscirickettsia/genética , Inmunidad Innata/genética , Salmo salar/microbiología , Salmo salar/genética , Salmo salar/inmunología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/genética , Infecciones por Piscirickettsiaceae/microbiología , Infecciones por Piscirickettsiaceae/inmunología , Infecciones por Piscirickettsiaceae/genética , Infecciones por Piscirickettsiaceae/veterinaria , Renibacterium/genética , Renibacterium/inmunología , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Proteínas de Peces/inmunología , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Evolución Molecular

RESUMEN

Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.

Asunto(s)

Sistema Nervioso , Neurogénesis , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Animales , Sistema Nervioso/metabolismo , Sistema Nervioso/inmunología , Inmunidad Innata , Neuronas/metabolismo , Neuronas/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Transducción de Señal

RESUMEN

The protein scaffold that includes the caspases is ancient and found in all domains of life. However, the stringent specificity that defines the caspase biologic function is relatively recent and found only in multicellular animals. During the radiation of the Chordata, members of the caspase family adopted roles in immunity, events coinciding with the development of substrates that define the modern innate immune response. This review focuses on the switch from the non-inflammatory cellular demise of apoptosis to the highly inflammatory innate response driven by distinct members of the caspase family, and the interplay between these two regulated cell death pathways.

Asunto(s)

Caspasas , Inmunidad Innata , Piroptosis , Humanos , Caspasas/metabolismo , Animales , Evolución Molecular , Apoptosis