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ABSTRACT: CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, because it improves survival and outcome of patients who received hematopoietic stem cell transplant compared with the continuous infusion of cytarabine plus daunorubicin (referred to as "7 + 3" combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily affects the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 vs "7 + 3" combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and "7 + 3" combination on mucosal barrier function, gut microbial composition and function, and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with "7 + 3" combination, protected from gut dysbiosis, mucosal damage, and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-interleukin-22 (IL-22)-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.
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Microbioma Gastrointestinal , Leucemia Mieloide Aguda , Adulto , Humanos , Antifúngicos/uso terapêutico , Disbiose/etiologia , Daunorrubicina , Leucemia Mieloide Aguda/tratamento farmacológico , Citarabina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , HomeostaseRESUMO
The progress in human disease treatment can be greatly advanced through the implementation of nanomedicine. This approach involves targeted and cell-specific therapy, controlled drug release, personalized dosage forms, wearable drug delivery, and companion diagnostics. By integrating cutting-edge technologies with drug delivery systems, greater precision can be achieved at the tissue and cellular levels through the use of stimuli-responsive nanoparticles, and the development of electrochemical sensor systems. This precision targeting - by virtue of nanotechnology - allows for therapy to be directed specifically to affected tissues while greatly reducing side effects on healthy tissues. As such, nanomedicine has the potential to transform the treatment of conditions such as cancer, genetic diseases, and chronic illnesses by facilitating precise and cell-specific drug delivery. Additionally, personalized dosage forms and wearable devices offer the ability to tailor treatment to the unique needs of each patient, thereby increasing therapeutic effectiveness and compliance. Companion diagnostics further enable efficient monitoring of treatment response, enabling customized adjustments to the treatment plan. The question of whether all the potential therapeutic approaches outlined here are viable alternatives to current treatments is also discussed. In general, the application of nanotechnology in the field of biomedicine may provide a strong alternative to existing treatments for several reasons. In this review, we aim to present evidence that, although in early stages, fully merging advanced technology with innovative drug delivery shows promise for successful implementation across various disease areas, including cancer and genetic or chronic diseases.
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Produtos Biológicos , Neoplasias , Humanos , Medicina de Precisão , Sistemas de Liberação de Medicamentos , Nanomedicina , Neoplasias/tratamento farmacológicoRESUMO
Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1α (hypoxia-inducible factor 1α) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection in vivo and human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1ß heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.
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Fibrose Cística , Receptores de Hidrocarboneto Arílico , Humanos , Camundongos , Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Hipóxia/metabolismo , Transdução de Sinais , Inflamação , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
The pathogenesis of coronavirus disease 2019 (COVID-19) is associated with a hyperinflammatory response. The mechanisms of SARS-CoV-2-induced inflammation are scantly known. Methylglyoxal (MG) is a glycolysis-derived byproduct endowed with a potent glycating action, leading to the formation of advanced glycation end products (AGEs), the main one being MG-H1. MG-H1 exerts strong pro-inflammatory effects, frequently mediated by the receptor for AGEs (RAGE). Here, we investigated the involvement of the MG-H1/RAGE axis as a potential novel mechanism in SARS-CoV-2-induced inflammation by resorting to human bronchial BEAS-2B and alveolar A549 epithelial cells, expressing different levels of the ACE2 receptor (R), exposed to SARS-CoV-2 spike protein 1 (S1). Interestingly, we found in BEAS-2B cells that do not express ACE2-R that S1 exerted a pro-inflammatory action through a novel MG-H1/RAGE-based pathway. MG-H1 levels, RAGE and IL-1ß expression levels in nasopharyngeal swabs from SARS-CoV-2-positive and -negative individuals, as well as glyoxalase 1 expression, the major scavenging enzyme of MG, seem to support the results obtained in vitro. Altogether, our findings reveal a novel mechanism involved in the inflammation triggered by S1, paving the way for the study of the MG-H1/RAGE inflammatory axis in SARS-CoV-2 infection as a potential therapeutic target to mitigate COVID-19-associated pathogenic inflammation.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Glicoproteína da Espícula de Coronavírus , Aldeído Pirúvico/farmacologia , Aldeído Pirúvico/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Enzima de Conversão de Angiotensina 2 , Inflamação/metabolismoRESUMO
It is becoming increasingly clear that the communities of microorganisms that populate the surfaces exposed to the external environment, termed microbiota, are key players in the regulation of pathogen-host cross talk affecting the onset as well as the outcome of infectious diseases. We have performed a multicenter, prospective, observational study in which nasal and oropharyngeal swabs were collected for microbiota predicting the risk of invasive fungal infections (IFIs) in patients with hematological malignancies. Here, we demonstrate that the nasal and oropharyngeal microbiota are different, although similar characteristics differentiate high-risk from low-risk samples at both sites. Indeed, similar to previously published results on the oropharyngeal microbiota, high-risk samples in the nose were characterized by low diversity, a loss of beneficial bacteria, and an expansion of potentially pathogenic taxa, in the presence of reduced levels of tryptophan (Trp). At variance with oropharyngeal samples, however, low Trp levels were associated with defective host-derived kynurenine production, suggesting reduced tolerance mechanisms at the nasal mucosal surface. This was accompanied by reduced levels of the chemokine interleukin-8 (IL-8), likely associated with a reduced recruitment of neutrophils and impaired fungal clearance. Thus, the nasal and pharyngeal microbiomes of hematological patients provide complementary information that could improve predictive tools for the risk of IFI in hematological patients.
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Infecções Fúngicas Invasivas , Microbiota , Bactérias , Humanos , Nariz/microbiologia , Estudos ProspectivosRESUMO
The microbiome, i.e., the communities of microbes that inhabit the surfaces exposed to the external environment, participates in the regulation of host physiology, including the immune response against pathogens. At the same time, the immune response shapes the microbiome to regulate its composition and function. How the crosstalk between the immune system and the microbiome regulates the response to fungal infection has remained relatively unexplored. We have previously shown that strict anaerobes protect from infection with the opportunistic fungus Aspergillus fumigatus by counteracting the expansion of pathogenic Proteobacteria. By resorting to immunodeficient mouse strains, we found that the lung microbiota could compensate for the lack of B and T lymphocytes in Rag1-/- mice by skewing the composition towards an increased abundance of protective anaerobes such as Clostridia and Bacteroidota. Conversely, NSG mice, with major defects in both the innate and adaptive immune response, showed an increased susceptibility to infection associated with a low abundance of strict anaerobes and the expansion of Proteobacteria. Further exploration in a murine model of chronic granulomatous disease, a primary form of immunodeficiency characterized by defective phagocyte NADPH oxidase, confirms the association of lung unbalance between anaerobes and Proteobacteria and the susceptibility to aspergillosis. Consistent changes in the lung levels of short-chain fatty acids between the different strains support the conclusion that the immune system and the microbiota are functionally intertwined during Aspergillus infection and determine the outcome of the infection.
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Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Pulmão/microbiologia , Imunidade Adaptativa , Animais , Aspergilose/microbiologia , Aspergillus fumigatus/fisiologia , Ácidos Graxos Voláteis/imunologia , Interações Hospedeiro-Patógeno , Imunidade Inata , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , MicrobiotaRESUMO
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.
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Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteínas Recombinantes/farmacologia , Superóxido Dismutase/metabolismo , Animais , Células Cultivadas , Fibrose Cística/etiologia , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Modelos Animais de Doenças , Doença Granulomatosa Crônica/etiologia , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Phagocytes fight fungi using canonical and noncanonical, also called LC3-associated phagocytosis (LAP), autophagy pathways. However, the outcomes of autophagy/LAP in shaping host immune responses appear to greatly vary depending on fungal species and cell types. By allowing efficient pathogen clearance and/or degradation of inflammatory mediators, autophagy proteins play a broad role in cellular and immune homeostasis during fungal infections. Indeed, defects in autophagic machinery have been linked with aberrant host defense and inflammatory states. Thus, understanding the molecular mechanisms underlying the relationship between the different forms of autophagy may offer a way to identify drugable molecular signatures discriminating between selective recognition of cargo and host protection. In this regard, IFN-γ and anakinra are teaching examples of successful antifungal agents that target the autophagy machinery. This article provides an overview of the role of autophagy/LAP in response to fungi and in their infections, regulation, and therapeutic exploitation.
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Autofagia/fisiologia , Fagocitose/fisiologia , Animais , Humanos , Interferon gama/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Fagócitos/metabolismo , Fagócitos/fisiologiaRESUMO
Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis.
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Fibrose Cística/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Humanos , Indóis/metabolismo , Lactobacillus/metabolismoRESUMO
Mast cells are increasingly being recognized as crucial cells in the response of the organism to environmental agents. Interestingly, the ability of mast cells to sense and respond to external cues is modulated by the microenvironment that surrounds mast cells and influences their differentiation. The scenario that is emerging unveils a delicate equilibrium that balances the effector functions of mast cells to guarantee host protection without compromising tissue homeostasis. Among the environmental components able to mold mast cells and fine-tune their effector functions, the microorganisms that colonize the human body, collectively known as microbiome, certainly play a key role. Indeed, microorganisms can regulate not only the survival, recruitment, and maturation of mast cells but also their activity by setting the threshold required for the exploitation of their different effector functions. Herein, we summarize the current knowledge about the mechanisms underlying the ability of the microorganisms to regulate mast cell physiology and discuss potential deviations that result in pathological consequences. We will discuss the pivotal role of the aryl hydrocarbon receptor in sensing the environment and shaping mast cell adaptation at the host-microbe interface.
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Mastócitos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Microbiota/fisiologiaRESUMO
Patients with cystic fibrosis (PwCF) have recently experienced an unprecedented breakthrough with the adoption of modulator therapy in clinical practice. This remarkable achievement has led to the reconsideration of disease management as the increased life expectancy has gradually shifted the attention over a spectrum of extra-pulmonary manifestations that become prevalent in the aging population. It comes to be that complementary approaches that target patient co-morbidities are needed for the optimal clinical management of PwCF. A strategy would be to adjuvate the cystic fibrosis transmembrane conductance regulator (CFTR) in performing its functions in the different organs in which it is expressed. Solute carrier family 26 (SLC26) members appear ideal in this context. Indeed, they not only cooperate with CFTR in the organ-dependent regulation of ion fluxes but physically interact with it to reciprocally modulate their function. In this opinion, we summarize available evidence pointing to a physical and functional interaction between CFTR and SLC26 members, with a particular focus on SLC26A6 for its wider expression and broader anion selectivity, and then discuss how restoring the physical interaction between CFTR and SLC26A6 might be beneficial in the treatment of PwCF in the era of modulator therapy.
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As a result of a long evolutionary history, serotonin plays a variety of physiological roles, including neurological, cardiovascular, gastrointestinal, and endocrine functions. While many of these activities can be accommodated within the serotoninergic activity, recent findings have revealed an unsuspected role of serotonin in orchestrating host and microbial dialogue at the tryptophan dining table, to the benefit of local and systemic homeostasis. Herein we review the dual role of serotonin at the host-microbe interface and discuss how unraveling the interconnections among the host and microbial pathways of tryptophan degradation may help to accommodate the versatility of serotonin in physiology and pathology.
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Humans interact with a multitude of microorganisms in various ecological relationships, ranging from commensalism to pathogenicity. The same applies to fungi, long recognized for their pathogenic roles in infection-such as in invasive fungal diseases caused, among others, by Aspergillus fumigatus and Candida spp.-and, more recently, for their beneficial activities as an integral part of the microbiota. Indeed, alterations in the fungal component of the microbiota, or mycobiota, have been associated with inflammatory, infectious and metabolic diseases, and cancer. Whether acting as opportunistic pathogens or symbiotic commensals, fungi possess a complex enzymatic repertoire that intertwines with that of the host. In this metabolic cross-talk, fungal enzymes may be unique, thus providing novel metabolic opportunities to the host, or, conversely, produce toxic metabolites. Indeed, administration of fungal probiotics and fungi-derived products may be beneficial in inflammatory and infectious diseases, but fungi may also produce a plethora of toxic secondary metabolites, collectively known as mycotoxins. Fungal enzymes may also be homologues to human enzymes, but nevertheless embedded in fungal-specific metabolic networks, determined by all the interconnected enzymes and molecules, quantitatively and qualitatively specific to the network, such that the activity and metabolic effects of each enzyme remain unique to fungi. In this Opinion, we explore the concept that targeting this fungal metabolic unicity, either in opportunistic pathogens or commensals, may be exploited to develop novel therapeutic strategies. In doing so, we present our recent experience in different pathological settings that ultimately converge on relevant trans-kingdom metabolic differences.
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The Sertoli cells (SeCs) of the seminiferous tubules secrete a multitude of immunoregulatory and trophic factors to provide immune protection and assist in the orderly development of germ cells. Grafts of naked or encapsulated SeCs have been proved to represent an interesting therapeutic option in a plethora of experimental models of diseases. However, whether SeCs have immunosuppressive or immunomodulatory effects, which is imperative for their clinical translatability, has not been demonstrated. We directly assessed the immunopotential of intraperitoneally grafted microencapsulated porcine SeCs (MC-SeCs) in murine models of fungal infection (Aspergillus fumigatus or Candida albicans) or cancer (Lewis lung carcinoma/LLC or B16 melanoma cells). We found that MC-SeCs (i) provide antifungal resistance with minimum inflammatory pathology through the activation of the tolerogenic aryl hydrocarbon receptor/indoleamine 2,3-dioxygenase pathway; (ii) do not affect tumor growth in vivo; and (iii) reduce the LLC cell metastatic cancer spread associated with restricted Vegfr2 expression in primary tumors. Our results point to the fine immunoregulation of SeCs in the relative absence of overt immunosuppression in both infection and cancer conditions, providing additional support for the potential therapeutic use of SeC grafts in human patients.
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Carcinoma Pulmonar de Lewis , Células de Sertoli , Masculino , Humanos , Suínos , Animais , Camundongos , Células de Sertoli/metabolismo , Túbulos Seminíferos/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Imunossupressores/uso terapêutico , Tolerância ImunológicaRESUMO
Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.
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Candida albicans , Doença Celíaca , Homeostase , Mastócitos , Doença Celíaca/imunologia , Doença Celíaca/microbiologia , Doença Celíaca/metabolismo , Humanos , Candida albicans/patogenicidade , Candida albicans/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Microbioma Gastrointestinal/imunologia , Disbiose/imunologia , Candidíase/imunologia , Candidíase/microbiologia , Animais , Candida/patogenicidade , Candida/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismoRESUMO
BACKGROUND: The recent Coronavirus Disease 2019 (COVID-19) pandemic has dramatically exposed our gap in understanding the pathogenesis of airborne infections. Within such a context, it is increasingly clear that the nasal cavity represents a critical checkpoint not only in the initial colonization phase but also in shaping any infectious sequelae. This is particularly relevant to COVID-19 in that the nasal cavity is characterized by high-level expression of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) receptor, Angiotensin-Converting Enzyme 2 (ACE2), all along the respiratory tract. As part of the nasal mucosa, commensal microbes harbored by the nasal cavity likely are far more than just innocent bystanders in the interaction between SARS-CoV-2 and the local microenvironment. Yet the role of the qualitative composition of the nasal microbiome is unclear, as is its function, whether protective or not. METHODS: In this study, individuals undergoing SARS-CoV-2 molecular testing at the Hospital of Perugia (Italy) were recruited, with their residual material from the nasopharyngeal swabs being collected for microbiome composition analysis and short-chain fatty acid (SCFA) measurements (by 16S rRNA sequencing and gas chromatography-mass spectrometry), respectively. RESULTS: After stratification by age, gender, and viral load, the composition of the nasopharyngeal microbiome appeared to be influenced by age and gender, and SARS-CoV-2 infection further determined compositional changes. Notwithstanding this variability, a restricted analysis of female subjects-once SARS-CoV-2-infected-unraveled a shared expansion of Lachnospirales-Lachnospiraceae, irrespective of the viral load and age. This was associated with a reduction in the branched SCFA isobutanoic acid, as well as in the SCFAs with longer chains. CONCLUSIONS: Our results indicate that the nasopharyngeal microbiome is influenced by age, gender, and viral load, with consistent patterns of microbiome changes being present across specific groups. This may help in designing a personalized medicine approach in COVID-19 patients with specific patterns of nasal microbial communities.
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COVID-19 , Microbiota , Humanos , Feminino , SARS-CoV-2 , RNA Ribossômico 16S/genética , NasofaringeRESUMO
Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA.
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Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.
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Esclerose Múltipla , Triptofano , Humanos , Cinurenina/metabolismo , Ligantes , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Triptofano Hidroxilase/metabolismoRESUMO
Developing therapeutics for inflammatory diseases is challenging due to physiological mucosal barriers, systemic side effects, and the local microbiota. In the search for novel methods to overcome some of these problems, drug delivery systems that improve tissue-targeted drug delivery and modulate the microbiota are highly desirable. Microbial metabolites are known to regulate immune responses, an observation that has resulted in important conceptual advances in areas such as metabolite pharmacology and metabolite therapeutics. Indeed, the doctrine of "one molecule, one target, one disease" that has dominated the pharmaceutical industry in the 20th century is being replaced by developing therapeutics which simultaneously manipulate multiple targets through novel formulation approaches, including the multitarget-directed ligands. Thus, metabolites may not only represent biomarkers for disease development, but also, being causally linked to human diseases, an unexploited source of therapeutics. We have shown the successful exploitation of this approach: by deciphering how signaling molecules, such as the microbial metabolite, indole-3-aldehyde, and the repurposed drug anakinra, interact with the aryl hydrocarbon receptor may pave the way for novel therapeutics in inflammatory human diseases, for the realization of which drug delivery platforms are instrumental.
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Biological membrane-engineered lipid nanoparticles (LNP) have shown enormous potential as vehicles for drug delivery due to their outstanding biomimetic properties. To make these nanoparticles more adaptable to complex biological systems, several methods and cellular sources have been adopted to introduce biomembrane-derived moieties onto LNP and provide the latter with more functions while preserving their intrinsic nature. In this review, we focus on LNP decoration with specific regard to mRNA therapeutics and vaccines. The bio-engineering approach exploits a variety of biomembranes for functionalization, such as those derived from red blood cells, white blood cells, cancer cells, platelets, exosomes, and others. Biomembrane engineering could greatly enhance efficiency in targeted drug delivery, treatment, and diagnosis of cancer, inflammation, immunological diseases, and a variety of pathologic conditions. These membrane-modification techniques are expected to advance biomembrane-derived LNP into wider applications in the future.