RESUMEN
Surfactant Protein A (SP-A) is an innate immune modulator produced by the lung with known protective effects against bacteria and viruses. Its role in asthma, an inflammatory lung disease that affects 10% of the world's population, is not entirely known. In this review, we demonstrate that SP-A confers protection against exposure to interleukin-13, a type 2 cytokine integral to eosinophilic asthma, in a mouse model of SP-A deficiency, a house dust mite model of asthma, and in human bronchial epithelial cells from participants with asthma. We also show that small peptides derived from SP-A, such as the major allele of single nucleotide polymorphism (SNP) rs1965708, which includes the carbohydrate recognition domain of SP-A2 at position 223, reduce airway hyperresponsiveness, airway eosinophils, and mucus in a mouse model of asthma. These data suggest that SP-A has beneficial effects relevant to asthma and that an SP-A peptide may have a new therapeutic use in asthma.
Asunto(s)
Asma , Modelos Animales de Enfermedad , Inmunidad Innata , Proteína A Asociada a Surfactante Pulmonar , Asma/inmunología , Asma/tratamiento farmacológico , Animales , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína A Asociada a Surfactante Pulmonar/inmunología , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Interleucina-13/metabolismo , Interleucina-13/inmunología , Interleucina-13/genética , Pulmón/inmunología , Pulmón/metabolismo , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Pyroglyphidae/inmunologíaRESUMEN
Human papillomavirus (HPV) infection poses a significant health challenge, particularly in low- and middle-income countries (LMIC), where limited healthcare access and awareness hinder vaccine accessibility. To identify alternative HPV targeting interventions, we previously reported on surfactant protein A (SP-A) as a novel molecule capable of recognising HPV16 pseudovirions (HPV16-PsVs) and reducing infection in a murine cervicovaginal HPV challenge model. Building on these findings, our current study aimed to assess SP-A's suitability as a broad-spectrum HPV-targeting molecule and its impact on innate immune responses. We demonstrate SP-A's ability to agglutinate and opsonise multiple oncogenic HPV-PsVs types, enhancing their uptake and clearance by RAW264.7 murine macrophages and THP-1 human-derived immune cells. The SP-A opsonisation of HPV not only led to increased lysosomal accumulation in macrophages and HaCaT keratinocytes but also resulted in a decreased infection of HaCaT cells, which was further decreased when co-cultured with innate immune cells. An analysis of human innate immune cell cytokine profiles revealed a significant inflammatory response upon SP-A exposure, potentially contributing to the overall inhibition of HPV infection. These results highlight the multi-layered impact of SP-A on HPV, innate immune cells and keratinocytes and lay the basis for the development of alternative prophylactic interventions against diverse HPV types.
Asunto(s)
Macrófagos , Infecciones por Papillomavirus , Proteína A Asociada a Surfactante Pulmonar , Humanos , Animales , Ratones , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína A Asociada a Surfactante Pulmonar/inmunología , Células RAW 264.7 , Macrófagos/inmunología , Macrófagos/metabolismo , Inmunidad Innata , Queratinocitos/metabolismo , Queratinocitos/virología , Queratinocitos/inmunología , Citocinas/metabolismo , Células HaCaT , Células THP-1 , FemeninoRESUMEN
Influenza A virus infection (IAV) often leads to acute lung injury that impairs breathing and can lead to death, with disproportionate mortality in children and the elderly. Surfactant Protein A (SP-A) is a calcium-dependent opsonin that binds a variety of pathogens to help control pulmonary infections by alveolar macrophages. Alveolar macrophages play critical roles in host resistance and susceptibility to IAV infection. The effect of SP-A on IAV infection and antiviral response of macrophages, however, is not understood. Here, we report that SP-A attenuates IAV infection in a dose-dependent manner at the level of endosomal trafficking, resulting in infection delay in a model macrophage cell line. The ability of SP-A to suppress infection was independent of its glycosylation status. Binding of SP-A to hemagglutinin did not rely on the glycosylation status or sugar binding properties of either protein. Incubation of either macrophages or IAV with SP-A slowed endocytic uptake rate of IAV. SP-A interfered with binding to cell membrane and endosomal exit of the viral genome as indicated by experiments using isolated cell membranes, an antibody recognizing a pH-sensitive conformational epitope on hemagglutinin, and microscopy. Lack of SP-A in mice enhanced IFNß expression, viral clearance and reduced mortality from IAV infection. These findings support the idea that IAV is an opportunistic pathogen that co-opts SP-A to evade host defense by alveolar macrophages. Our study highlights novel aspects of host-pathogen interactions that may lead to better understanding of the local mechanisms that shape activation of antiviral and inflammatory responses to viral infection in the lung.
Asunto(s)
Virus de la Influenza A , Macrófagos , Infecciones por Orthomyxoviridae , Proteína A Asociada a Surfactante Pulmonar , Animales , Ratones , Hemaglutininas , Macrófagos/inmunología , Macrófagos/virología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Infecciones por Orthomyxoviridae/inmunologíaRESUMEN
OBJECTIVES: Human milk reduces the incidence of necrotizing enterocolitis (NEC). Prior studies have demonstrated that exogenous surfactant protein-A (SP-A) modulates intestinal inflammation, reduces NEC-like pathology in SP-A-deficient (SPAKO) pups, and may contribute to breast milk's immunomodulatory potential. We hypothesize that SP-A is present in milk and impacts inflammatory responses in the terminal ileum of neonatal mice. METHODS: Human milk was collected at postpartum days 1-3 and 28. Mouse milk was collected at postpartum days 1-10. SP-A was detected in milk through immunoprecipitation and western blot analysis. The impact of murine wild-type (WT) milk on SPAKO pup ileum was evaluated in a model of intestinal inflammation via cross-rearing experiments. Terminal ileum was evaluated for inflammatory cytokine and toll-like receptor 4 (TLR4) mRNA expression via quantitative real-time RT-PCR. RESULTS: SP-A was detected in human milk and wild type (WT) mouse milk, but not in SPAKO mouse milk. Expression of TLR4, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α was decreased in SPAKO pups reared with WT dams compared to SPAKO pups reared with SPAKO dams, with a peak effect at day of life 14. When inflammation was induced using a lipopolysaccharide-induced model of inflammation, expression of TLR4, IL-1ß, IL-6, CXCL-1, and TNF-α was significantly lower in SPAKO pups reared with WT dams compared to SPAKO pups reared with SPAKO dams. CONCLUSIONS: SP-A is present in human and murine milk and plays a role in lowering inflammation in murine pup terminal ileum. Both baseline inflammation and induced inflammatory responses are reduced via exposure to SP-A in milk with the effect amplified in inflammatory conditions.
Asunto(s)
Enterocolitis Necrotizante , Leche Humana , Proteína A Asociada a Surfactante Pulmonar , Receptor Toll-Like 4 , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/inmunología , Femenino , Humanos , Agentes Inmunomoduladores/farmacología , Recién Nacido , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-6 , Ratones , Leche Humana/efectos de los fármacos , Leche Humana/inmunología , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/inmunología , Tensoactivos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The human SFTPA1 and SFTPA2 genes encode the surfactant protein A1 (SP-A1) and SP-A2, respectively, and they have been identified with significant genetic and epigenetic variability including sequence, deletion/insertions, and splice variants. The surfactant proteins, SP-A1 and SP-A2, and their corresponding variants play important roles in several processes of innate immunity as well in surfactant-related functions as reviewed elsewhere [1]. The levels of SP-A have been shown to differ among individuals both under baseline conditions and in response to various agents or disease states. Moreover, a number of agents have been shown to differentially regulate SFTPA1 and SFTPA2 transcripts. The focus in this review is on the differential regulation of SFTPA1 and SFTPA2 with primary focus on the role of 5' and 3' untranslated regions (UTRs) and flanking sequences on this differential regulation as well molecules that may mediate the differential regulation.
Asunto(s)
Variación Genética/inmunología , Inmunidad Innata/inmunología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Transcriptoma/inmunología , Regiones no Traducidas 3'/genética , Regiones no Traducidas 3'/inmunología , Regiones no Traducidas 5'/genética , Regiones no Traducidas 5'/inmunología , Secuencia de Bases , Variación Genética/genética , Humanos , Inmunidad Innata/genética , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Homología de Secuencia de Ácido Nucleico , Transcriptoma/genéticaRESUMEN
Lung surfactant protein A (SP-A) is critical for immunomodulation. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) drive T follicular helper (Tfh) cells differentiation in allergic asthma. We employed wild-type (WT) and SP-A-/- mice injected with TSLP and ovalbumin (OVA)-activated DCs and challenged with OVA. Compared with WT mice, we showed that allergic inflammation was dramatically increased in SP-A-/- mice. In parallel, both IL-4-producing CD45RA-CXCR5+PD-1+CD4+ cells (Tfh2) and IgE were markedly increased in SP-A-/- mice. Further study showed that SP-A prohibited TSLP activated-DCs from expressing OX40L. When we blocked OX40L-OX40 and IL-4R signaling, the differentiation of Tfh2 and IgE responses in SP-A-/- mice was significantly inhibited. In severe asthma patients, SP-A is dysfunctional in modulating the TSLP-DCs-mediated differentiation of Tfh cells. This study suggests that SP-A acts as a modulator of Tfh differentiation and IgE generation in asthma.
Asunto(s)
Asma/inmunología , Citocinas/inmunología , Inmunoglobulina E/biosíntesis , Proteína A Asociada a Surfactante Pulmonar/inmunología , Células T Auxiliares Foliculares/inmunología , Adulto , Anciano , Animales , Asma/metabolismo , Diferenciación Celular/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Femenino , Humanos , Inmunoglobulina E/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
Protein-protein interactions in adsorbed multilayer of an immuno-specific system of proteins that include staphylococcal protein A (SpA), bovine serum albumin (BSA), anti-chicken immunoglobulin Y (ac-IgG), chicken serum IgG (cs-IgG), and rabbit serum IgG (rs-IgG) on polystyrene (PS) were studied using attenuated total reflection-Fourier transform infrared spectroscopy. A systematic analysis allowed a direct qualitative and quantitative determination of protein interactions at each step of specific and nonspecific binding conditions at the molecular level. The study also provided information about (1) the adsorption behavior of the proteins, (2) the role of SpA in enabling correct orientation of the adsorbed IgG and maintaining the stability of the adsorbed SpA/ac-IgG system on the PS surface, (3) the function of BSA as both blocking reagent and promoter of specific and selective binding, and (4) the bioactivity conserved accommodation of SpA molecules on the PS surface. Furthermore, the unique characteristics of cs-IgG such as passive toward SpA adsorption and exposure of the multivalence state at nonspecific binding conditions was revealed spectroscopically. The present investigation provides a platform for further extension of the adopted methodology to a more complex system of immuno-detection for highly sensitive and rapid diagnostics.
Asunto(s)
Proteínas/inmunología , Coloración y Etiquetado , Adsorción , Simulación por Computador , Inmunoglobulina G/inmunología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Albúmina Sérica Bovina/inmunología , Espectroscopía Infrarroja por Transformada de Fourier , VibraciónRESUMEN
Human surfactant protein-A2 (hSP-A2) is a component of pulmonary surfactant that plays an important role in the lung's immune system by interacting with viruses, bacteria, and fungi to facilitate pathogen clearance and by downregulating inflammatory responses after an allergic challenge. Genetic variation in SP-A2 at position Gln223Lys is present in up to â¼30% of the population and has been associated with several lung diseases, such as asthma, pulmonary fibrosis, and lung cancer (M. M. Pettigrew, J. F. Gent, Y. Zhu, E. W. Triche, et al., BMC Med Genet 8:15, 2007, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-8-15; Y. Wang, P. J. Kuan, C. Zing, J. T. Cronkhite, et al., Am J Hum Genet 84:52-59, 2009, https://www.cell.com/ajhg/fulltext/S0002-9297(08)00595-8). Previous work performed by our group showed differences in levels of SP-A binding to non-live mycoplasma membrane fractions that were dependent on the presence of a lysine (K) or a glutamine (Q) at amino acid position 223 in the carbohydrate region of SP-A2. On the basis of these differences, we have derived 20-amino-acid peptides flanking this region of interest in order to test the ability of each to regulate various immune responses to live Mycoplasma pneumoniae in SP-A knockout mice and RAW 264.7 cells. In both models, the 20-mer containing 223Q significantly decreased both tumor necrosis factor alpha (TNF-α) mRNA levels and protein levels in comparison to the 20-mer containing 223K during M. pneumoniae infection. While neither of the 20-mer peptides (223Q and 223K) had an effect on p38 phosphorylation during M. pneumoniae infection, the 223Q-20mer peptide significantly reduced NF-κB p65 phosphorylation in both models. Taken together, our data suggest that small peptides derived from the lectin domain of SP-A2 that contain the major allelic variant (223Q) maintain activity in reducing TNF-α induction during M. pneumoniae infection.
Asunto(s)
Antiinflamatorios/farmacología , Interacciones Microbiota-Huesped/inmunología , Mycoplasma pneumoniae/inmunología , Péptidos/farmacología , Neumonía por Mycoplasma/tratamiento farmacológico , Proteína A Asociada a Surfactante Pulmonar/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adhesinas Bacterianas/genética , Adhesinas Bacterianas/inmunología , Animales , Antiinflamatorios/síntesis química , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Interacciones Microbiota-Huesped/genética , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycoplasma pneumoniae/efectos de los fármacos , Mycoplasma pneumoniae/patogenicidad , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/microbiología , Péptidos/síntesis química , Neumonía por Mycoplasma/genética , Neumonía por Mycoplasma/inmunología , Neumonía por Mycoplasma/microbiología , Dominios Proteicos , Proteína A Asociada a Surfactante Pulmonar/química , Proteína A Asociada a Surfactante Pulmonar/deficiencia , Proteína A Asociada a Surfactante Pulmonar/genética , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/inmunología , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunologíaRESUMEN
Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.
Asunto(s)
Antivirales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Proteína A Asociada a Surfactante Pulmonar/fisiología , Proteína B Asociada a Surfactante Pulmonar/fisiología , Animales , Antivirales/inmunología , Colectinas/deficiencia , Humanos , Factores Inmunológicos/inmunología , Inflamación/tratamiento farmacológico , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Proteína B Asociada a Surfactante Pulmonar/inmunología , Proteína B Asociada a Surfactante Pulmonar/uso terapéutico , Receptores Depuradores/inmunología , Virosis/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19RESUMEN
In humans there are two surfactant protein A (SP-A) functional genes SFTPA1 and SFTPA2 encoding innate immune molecules, SP-A1 and SP-A2, respectively, with numerous genetic variants each. SP-A interacts and regulates many of the functions of alveolar macrophages (AM). It is shown that SP-A variants differ in their ability to regulate the AM miRNome in response to oxidative stress (OxS). Because humans have both SP-A gene products, we were interested to determine the combined effect of co-expressed SP-A1/SP-A2 (co-ex) in response to ozone (O3) induced OxS on AM miRNome. Human transgenic (hTG) mice, carrying both SP-A1/SP-A2 (6A2/1A0, co-ex) and SP-A- KO were utilized. The hTG and KO mice were exposed to filtered air (FA) or O3 and miRNA levels were measured after AM isolation with or without normalization to KO. We found: (i) The AM miRNome of co-ex males and females in response to OxS to be largely downregulated after normalization to KO, but after Bonferroni multiple comparison analysis only in females the AM miRNome remained significantly different compared to control (FA); (ii) The targets of the significantly changed miRNAs were downregulated in females and upregulated in males; (iii) Several of the validated mRNA targets were involved in pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation; (iv) The AM of SP-A2 male, shown, previously to have major effect on the male AM miRNome in response to OxS, shared similarities with the co-ex, namely in pathways involved in the pro-inflammatory response and anti-apoptosis but also exhibited differences with the cell-cycle, growth, and proliferation pathway being involved in co-ex and ROS homeostasis in SP-A2 male. We speculate that the presence of both gene products vs. single gene products differentially impact the AM responses in males and females in response to OxS.
Asunto(s)
Inflamación/inmunología , MicroARNs/genética , Estrés Oxidativo/inmunología , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/inmunología , Animales , Ciclo Celular/fisiología , Proliferación Celular/fisiología , Femenino , Humanos , Macrófagos Alveolares/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ozono/toxicidad , Factores SexualesAsunto(s)
Oído Medio/inmunología , Inmunidad Innata , Otitis Media/inmunología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Animales , Modelos Animales de Enfermedad , Oído Medio/metabolismo , Oído Medio/microbiología , Oído Medio/patología , Trompa Auditiva/inmunología , Trompa Auditiva/metabolismo , Femenino , Infecciones por Haemophilus/genética , Infecciones por Haemophilus/inmunología , Infecciones por Haemophilus/metabolismo , Infecciones por Haemophilus/patología , Haemophilus influenzae/crecimiento & desarrollo , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Otitis Media/metabolismo , Otitis Media/microbiología , Otitis Media/patología , Fagocitosis/genética , Fagocitosis/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína A Asociada a Surfactante Pulmonar/genéticaRESUMEN
PURPOSE OF REVIEW: The aim of this review is to describe the co-occurrence of chronic rhinosinusitis (CRS) with other inflammatory illnesses of the lower respiratory system characterised by airway obstruction and hyperresponsiveness, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) in the context of the unified airway disease (UAD). We also sought to discuss the novel role of surfactant proteins as mediators of innate immunity in the sinonasal epithelium and their potential as therapeutic interventions. RECENT FINDINGS: Different epidemiological and physiological studies in CRS and asthma have outlined that there are common clustering patterns in the phenotypes/endotypes of both diseases, reinforcing the notion of the UAD. Also, surfactant proteins A (SP-A) and SP-D have now emerged as novel innate immunity molecules in bacterial sinusitis and allergic fungal sinusitis patients, respectively. SUMMARY: CRS and asthma coexist and are interconnected. Therefore, management of CRS and asthma must be jointly carried out as one functional entity. SP-A and SP-D bridge the innate and adaptive immunity mechanisms of the sinonasal epithelium to bring together a well-orchestrated mechanism that effectively fights pathogens. The use of SP-A to ameliorate the innate immune responses in CRS is a new concept and is likely to lead to new horizons in CRS therapeutic regimens.  .
Asunto(s)
Enfermedad Crónica , Inmunidad Innata/inmunología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Asma/inmunología , Fibrosis Quística/inmunología , HumanosRESUMEN
As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro-oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the lung mucosa of the elderly.
Asunto(s)
Pulmón/inmunología , Pulmón/microbiología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Tuberculosis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Inflamación/microbiología , Lisosomas/inmunología , Lisosomas/microbiología , Macrófagos/inmunología , Macrófagos/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Fagosomas/inmunología , Fagosomas/microbiología , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Tuberculosis/microbiología , Adulto JovenRESUMEN
Molecular allergology research has provided valuable information on the structure and function of single allergenic molecules. There are several allergens in food and inhalant allergen sources that are able to interact with lipid ligands via different structural features: hydrophobic pockets, hydrophobic cavities, or specialized domains. For only a few of these allergens information on their associated ligands is already available. Several of the allergens are clinically relevant, so that it is highly probable that the individual structural features with which they interact with lipids have a direct effect on their allergenic potential, and thus on allergy development. There is some evidence for a protective effect of lipids delaying the enzymatic digestion of the peanut (Arachis hypogaea) allergen Ara h 8 (hydrophobic pocket), probably allowing this molecule to get to the intestinal immune system intact (sensitization). Oleosins from different food allergen sources are part of lipid storage organelles and potential marker allergens for the severity of the allergic reaction. House dust mite (HDM), is more often associated with allergic asthma than other sources of inhalant allergens. In particular, lipid-associated allergens from Dermatophagoides pteronyssinus which are Der p 2, Der p 5, Der p 7, Der p 13, Der p 14, and Der p 21 have been reported to be associated with severe allergic reactions and respiratory symptoms such as asthma. The exact mechanism of interaction of these allergens with lipids still has to be elucidated. Apart from single allergens glycolipids have been shown to directly induce allergic inflammation. Several-in parts conflicting-data exist on the lipid (and allergen) and toll-like receptor interactions. For only few single allergens mechanistic studies were performed on their interaction with the air-liquid interface of the lungs, in particular with the surfactant components SP-A and SP-D. The increasing knowledge on protein-lipid-interaction for lipophilic and hydrophobic food and inhalant allergens on the basis of their particular structure, of their capacity to be integral part of membranes (like the oleosins), and their ability to interact with membranes, surfactant components, and transport lipids (like the lipid transfer proteins) are essential to eventually clarify allergy and asthma development.
Asunto(s)
Alérgenos/metabolismo , Antígenos de Plantas/metabolismo , Asma/inmunología , Proteínas Portadoras/metabolismo , Hipersensibilidad/inmunología , Lípidos/inmunología , Proteínas de Plantas/metabolismo , Alérgenos/inmunología , Animales , Antígenos de Plantas/inmunología , Proteínas Portadoras/inmunología , Humanos , Metabolismo de los Lípidos , Proteínas de Plantas/inmunología , Plantas , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína D Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/metabolismoRESUMEN
Interaction between surfactant protein-A (SP-A) and toll-like receptor (TLR)4 plays a critical role in host defense. In this work, we studied the host defense function of SPA4 peptide (amino acids GDFRYSDGTPVNYTNWYRGE), derived from the TLR4-interacting region of SP-A, against Pseudomonas aeruginosa. We determined the binding of SPA4 peptide to live bacteria, and its direct antibacterial activity against P. aeruginosa. Pro-phagocytic and anti-inflammatory effects were investigated in JAWS II dendritic cells and primary alveolar macrophages. The biological relevance of SPA4 peptide was evaluated in a mouse model of acute lung infection induced by intratracheal challenge with P. aeruginosa. Our results demonstrate that the SPA4 peptide does not interact with or kill P. aeruginosa when cultured outside the host. The SPA4 peptide treatment induces the uptake and localization of bacteria in the phagolysosomes of immune cells. At the same time, the secreted amounts of TNF-α are significantly reduced in cell-free supernatants of SPA4 peptide-treated cells. In cells overexpressing TLR4, the TLR4-induced phagocytic response is maintained, but the levels of TLR4-stimulated TNF-α are reduced. Furthermore, our results demonstrate that the therapeutic administration of SPA4 peptide reduces bacterial burden, inflammatory cytokines and chemokines, intracellular signaling, and lactate levels, and alleviates lung edema and tissue damage in P. aeruginosa-infected mice. Together, our results suggest that the treatment with SPA4 peptide can help control the bacterial burden, inflammation, and tissue injury in a P. aeruginosa lung infection model.
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Fragmentos de Péptidos/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Proteína A Asociada a Surfactante Pulmonar/uso terapéutico , Receptor Toll-Like 4/metabolismo , Animales , Carga Bacteriana , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Fagocitosis/efectos de los fármacos , Fagosomas/efectos de los fármacos , Fagosomas/inmunología , Fagosomas/microbiología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Unión Proteica , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/inmunologíaRESUMEN
Innate recognition of viruses is an essential part of the immune response to viral pathogens. This is integral to the maintenance of healthy lungs, which are free from infection and efficient at gaseous exchange. An important component of innate immunity for identifying viruses is the family of C-type collagen-containing lectins, also known as collectins. These secreted, soluble proteins are pattern recognition receptors (PRRs) which recognise pathogen-associated molecular patterns (PAMPs), including viral glycoproteins. These innate immune proteins are composed of trimerized units which oligomerise into higher-order structures and facilitate the clearance of viral pathogens through multiple mechanisms. Similarly, many viral surface proteins form trimeric configurations, despite not showing primary protein sequence similarities across the virus classes and families to which they belong. In this review, we discuss the role of the lung collectins, i.e., surfactant proteins A and D (SP-A and SP-D) in viral recognition. We focus particularly on the structural similarity and complementarity of these trimeric collectins with the trimeric viral fusion proteins with which, we hypothesise, they have elegantly co-evolved. Recombinant versions of these innate immune proteins may have therapeutic potential in a range of infectious and inflammatory lung diseases including anti-viral therapeutics.
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Colectinas , Inmunidad Innata , Proteína A Asociada a Surfactante Pulmonar , Proteína D Asociada a Surfactante Pulmonar , Receptores de Reconocimiento de Patrones , Proteínas Virales de Fusión/inmunología , Animales , Colectinas/química , Colectinas/inmunología , Humanos , Pulmón/inmunología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/terapia , Enfermedades Pulmonares/virología , Multimerización de Proteína , Proteína A Asociada a Surfactante Pulmonar/química , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/química , Proteína D Asociada a Surfactante Pulmonar/inmunología , Receptores de Reconocimiento de Patrones/química , Receptores de Reconocimiento de Patrones/inmunología , Proteínas Virales de Fusión/química , Virus/inmunologíaRESUMEN
Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). We genotyped a total of 17 SP SNPs from 72 case-trio pedigree (SFTPA1 (5), SFTPA2 (4), SFTPB (4), SFTPC (2), and SFTPD (2)), and identified SP SNP associations by applying quantitative genetic principles. The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity.
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Fibrosis Quística/genética , Polimorfismo de Nucleótido Simple , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Adulto , Niño , Preescolar , Fibrosis Quística/inmunología , Fibrosis Quística/patología , Femenino , Humanos , Masculino , Proteína A Asociada a Surfactante Pulmonar/inmunología , Proteína C Asociada a Surfactante Pulmonar/inmunologíaRESUMEN
The goal of the present study was to investigate the role of M1 macrophages in acute lung injury (ALI). To address this, we used lipopolysaccharide (LPS)-treated wild-type and CD11b-DTR mice, and examined their M1 macrophage levels, and the extent of their inflammation and pulmonary injuries. In addition, we evaluated pulmonary function by measuring the expressions of SP-A and SP-B in infiltrated M1 macrophages. Finally, we co-cultured the mouse type II-like alveolar epithelial cells (AT-II) and mouse pulmonary microvascular endothelial cells (PMECs) with M1 macrophages in the presence of TNF-α or H2O2 and assessed them for viability and apoptosis. After LPS treatment, we observed that the number of pulmonary M1/M2 macrophages and the serum levels of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and reactive oxygen species (ROS) significantly increased. Furthermore, the increase in cytokines was accompanied with the initiation of lung injury indicated by the decreased levels of SP-A and SP-B. In macrophage-depleted CD11b-DTR mice, ALI was attenuated, serum levels of IL-1ß, TNF-α and ROS were reduced, and lung levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were decreased. After administering TNF-α and H2O2, the proapoptotic effect of M1 macrophages on AT-II or PMECs significantly increased, the cell viabilities significantly decreased, and apoptosis significantly increased. Our results suggest that M1 macrophages are recruited to the lungs where they significantly contribute to an increase in TNF-α and ROS production, thus initiating ALI.
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Lesión Pulmonar Aguda/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Citocinas/inmunología , Lipopolisacáridos/toxicidad , Macrófagos/patología , Masculino , Ratones , Proteína A Asociada a Surfactante Pulmonar/inmunologíaRESUMEN
BACKGROUND: Surfactant Protein-A (SP-A) is a major protein component of surfactant and plays a role in surfactant-related functions and innate immunity. Human SP-A consists of two functional genes, SFTPA1 and SFTPA2, encoding SP-A1 and SP-A2 proteins, respectively and each is identified with numerous genetic variants. These differentially enhance bacterial phagocytosis, with SP-A2 variants being more effective than SP-A1. METHODS: Lung functions of humanized transgenic (hTG) mice that carry different SP-A1 and SP-A2 variants or both variants SP-A1/SP-A2 (6A2/1A0, co-ex), as well as SP-A knockout (KO), were studied. The animals were connected to a flexiVent system to obtain forced oscillation technique (FOT) measurements and the data were analyzed using various models. Lung function was assessed after infection (baseline) and following inhaled methacholine concentrations (0-50 mg/mL). RESULTS: Here, we investigated the role of SP-A variants on airway function after Klebsiella pneumoniae (Kp) infection (baseline) and following inhaled methacholine. We found that: 1) in the absence of methacholine no significant differences were observed between SP-A1 and SP-A2 variants and/or SP-A knockout (KO) except for sex differences in most of the parameters studied. 2) In response to methacholine, i) sex differences were observed that were reverse of those observed in the absence of methacholine; ii) SP-A2 (1A3) gene variant in males exhibited increased total and central airway resistance (Rrs and Rn) versus all other variants; iii) In females, SP-A2 (1A3) and SP-A1 (6A2) variants had similar increases in total and central airway resistance (Rrs and Rn) versus all other variants; iv) Allele-specific differences were observed, a) with SP-A2 (1A3) exhibiting significantly higher lung functions versus SP-A2 (1A0) in both sexes, except for Crs, and b) SP-A1 (6A2, 6A4) had more diverse changes in lung function in both sexes. CONCLUSION: We conclude that, in response to infection and methacholine, SP-A variants differentially affect lung function and exhibit sex-specific differences consistent with previously reported findings of functional differences of SP-A variants. Thus, the observed changes in respiratory function mechanics provide insight into the role and importance of genetic variation of innate immune molecules, such as SP-A, on mechanical consequences of lung function after infection and inhaled substances.