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2.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34353890

RESUMO

Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity.


Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , COVID-19/imunologia , COVID-19/terapia , Inibidores Enzimáticos/farmacologia , Elastase de Leucócito/antagonistas & inibidores , SARS-CoV-2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/efeitos dos fármacos , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Imunidade nas Mucosas/efeitos dos fármacos , Imunidade nas Mucosas/imunologia , Imunoglobulina A/imunologia , Elastase de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/imunologia , Suínos , Células Th1/imunologia
3.
Cells ; 10(8)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34440903

RESUMO

Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.


Assuntos
COVID-19/imunologia , Imunidade Inata/imunologia , COVID-19/fisiopatologia , Citocinas , Progressão da Doença , Humanos , Inflamação
4.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445642

RESUMO

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis-the engulfment and elimination of dying cells and cell debris-are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance.


Assuntos
Apoptose , Imunidade Inata/imunologia , Fagócitos/fisiologia , Fagocitose , Animais , Caenorhabditis elegans , Humanos , Transdução de Sinais
5.
mBio ; 12(4): e0178121, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34372695

RESUMO

The 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2',5'-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2',5'-PEs. 2',5'-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3',5'-oligoribonucleotides, they all cleaved 2',5'-oligoadenylates efficiently but with variable activity against other 2',5'-oligonucleotides. The 2',5'-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2',5'-p3A3) producing mono- or diadenylates with 2',3'-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2',5'-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2',5'-PEs, specifically degrade 2',5'-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2',5'- and not 3',5'-phosphodiester bonds, producing cleavage products with cyclic 2',3'-phosphate termini. Our study defines 2',5'-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Nucleotídeos de Adenina/metabolismo , Endorribonucleases/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Vírus da Hepatite Murina/enzimologia , Oligorribonucleotídeos/metabolismo , Rotavirus/enzimologia , Animais , Humanos , Imunidade Inata/imunologia , Interferons/imunologia , Camundongos
6.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372568

RESUMO

Influenza viruses are still a serious threat to human health. Cytokines are essential for cell-to-cell communication and viral clearance in the immune system, but excessive cytokines can cause serious immune pathology. Deaths caused by severe influenza are usually related to cytokine storms. The recent literature has described the mechanism behind the cytokine-storm network and how it can exacerbate host pathological damage. Biological factors such as sex, age, and obesity may cause biological differences between different individuals, which affects cytokine storms induced by the influenza virus. In this review, we summarize the mechanism behind influenza virus cytokine storms and the differences in cytokine storms of different ages and sexes, and in obesity.


Assuntos
Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/fisiopatologia , Influenza Humana/imunologia , Fatores Etários , Citocinas/imunologia , Humanos , Imunidade Inata/imunologia , Influenza Humana/fisiopatologia , Influenza Humana/virologia , Obesidade/virologia , Orthomyxoviridae/imunologia , Orthomyxoviridae/patogenicidade , Fatores Sexuais
7.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372572

RESUMO

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases.


Assuntos
Desaminases APOBEC/genética , Desaminases APOBEC/metabolismo , Viroses/genética , Citidina Desaminase/genética , Citosina Desaminase/genética , HIV-1/fisiologia , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Polimorfismo Genético/genética , Isoformas de Proteínas/genética , Viroses/metabolismo , Replicação Viral/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360659

RESUMO

Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.


Assuntos
Aterosclerose/patologia , Plaquetas/patologia , Imunidade Inata/imunologia , Neoplasias/patologia , Ativação Plaquetária , Receptores Imunológicos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Plaquetas/imunologia , Plaquetas/metabolismo , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo
9.
Sci Rep ; 11(1): 15107, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34302024

RESUMO

COVID-19 outbreak brings intense pressure on healthcare systems, with an urgent demand for effective diagnostic, prognostic and therapeutic procedures. Here, we employed Automated Machine Learning (AutoML) to analyze three publicly available high throughput COVID-19 datasets, including proteomic, metabolomic and transcriptomic measurements. Pathway analysis of the selected features was also performed. Analysis of a combined proteomic and metabolomic dataset led to 10 equivalent signatures of two features each, with AUC 0.840 (CI 0.723-0.941) in discriminating severe from non-severe COVID-19 patients. A transcriptomic dataset led to two equivalent signatures of eight features each, with AUC 0.914 (CI 0.865-0.955) in identifying COVID-19 patients from those with a different acute respiratory illness. Another transcriptomic dataset led to two equivalent signatures of nine features each, with AUC 0.967 (CI 0.899-0.996) in identifying COVID-19 patients from virus-free individuals. Signature predictive performance remained high upon validation. Multiple new features emerged and pathway analysis revealed biological relevance by implication in Viral mRNA Translation, Interferon gamma signaling and Innate Immune System pathways. In conclusion, AutoML analysis led to multiple biosignatures of high predictive performance, with reduced features and large choice of alternative predictors. These favorable characteristics are eminent for development of cost-effective assays to contribute to better disease management.


Assuntos
COVID-19/diagnóstico , COVID-19/metabolismo , Imunidade Inata/imunologia , Aprendizado de Máquina , SARS-CoV-2/metabolismo , Biomarcadores/sangue , COVID-19/genética , COVID-19/patologia , Simulação por Computador , Bases de Dados Factuais , Bases de Dados Genéticas , Bases de Dados de Proteínas , Perfilação da Expressão Gênica , Humanos , Imunidade Inata/genética , Interferon gama/sangue , Metabolômica , Prognóstico , Proteômica , Curva ROC , SARS-CoV-2/genética , Índice de Gravidade de Doença , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Software
10.
Cell Mol Immunol ; 18(9): 2128-2139, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34290398

RESUMO

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin ß7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.


Assuntos
COVID-19/imunologia , Células Dendríticas/imunologia , SARS-CoV-2/imunologia , Células Cultivadas , Feminino , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interferon-alfa/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Índice de Gravidade de Doença
11.
Adv Drug Deliv Rev ; 176: 113900, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34324884

RESUMO

The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.


Assuntos
Amplificação de Genes/imunologia , Imunidade Inata/imunologia , Imunoterapia/métodos , RNA Mensageiro/imunologia , Vacinas Sintéticas/imunologia , Animais , COVID-19/genética , COVID-19/imunologia , COVID-19/prevenção & controle , Amplificação de Genes/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/tendências , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética
12.
Nat Cell Biol ; 23(7): 718-732, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34239064

RESUMO

Patients with Coronavirus disease 2019 exhibit low expression of interferon-stimulated genes, contributing to a limited antiviral response. Uncovering the underlying mechanism of innate immune suppression and rescuing the innate antiviral response remain urgent issues in the current pandemic. Here we identified that the dimerization domain of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is required for SARS2-NP to undergo liquid-liquid phase separation with RNA, which inhibits Lys63-linked poly-ubiquitination and aggregation of MAVS and thereby suppresses the innate antiviral immune response. Mice infected with an RNA virus carrying SARS2-NP exhibited reduced innate immunity, an increased viral load and high morbidity. Notably, we identified SARS2-NP acetylation at Lys375 by host acetyltransferase and reported frequently occurring acetylation-mimicking mutations of Lys375, all of which impaired SARS2-NP liquid-liquid phase separation with RNA. Importantly, a peptide targeting the dimerization domain was screened out to disrupt the SARS2-NP liquid-liquid phase separation and demonstrated to inhibit SARS-CoV-2 replication and rescue innate antiviral immunity both in vitro and in vivo.


Assuntos
Proteínas do Nucleocapsídeo/imunologia , Proteínas do Nucleocapsídeo/metabolismo , SARS-CoV-2/genética , Animais , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Camundongos , Proteínas do Nucleocapsídeo/genética , Vírus de RNA/genética , SARS-CoV-2/fisiologia
13.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299236

RESUMO

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn's disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.


Assuntos
Imunidade Inata/imunologia , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Imunidade Adaptativa/imunologia , Animais , Colite , Colite Ulcerativa , Doença de Crohn , Trato Gastrointestinal , Homeostase/fisiologia , Humanos , Tolerância Imunológica , Inflamação , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Microbiota , Células Th17
14.
Curr Rheumatol Rep ; 23(8): 63, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34216297

RESUMO

PURPOSE: Myositis as a rare manifestation of COVID-19 is only recently being reported. This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era. RECENT FINDINGS: COVID-19 is associated with a viral myositis attributable to direct myocyte invasion or induction of autoimmunity. COVID-19-induced myositis may be varied in presentation, from typical dermatomyositis to rhabdomyolysis, and a paraspinal affliction with back pain. It may or may not present with acute exponential elevations of enzyme markers such as creatine kinase (CK). Virus-mediated muscle inflammation is attributed to ACE2 (angiotensin-converting enzyme) receptor-mediated direct entry and affliction of muscle fibers, leading on to innate and adaptive immune activation. A greater recognition of the stark similarity between anti-MDA5-positive myositis with COVID-19 has thrown researchers into the alley of exploration - finding common etiopathogenic basis as well as therapeutic strategies. For patients with established myositis, chronic care was disrupted during the pandemic with several logistic challenges and treatment dilemmas leading to high flare rates. Teleconsultation bridged the gap while ushering in an era of patient-led care with the digital transition to tools of remote disease assessment. COVID-19 has brought along greater insight into unique manifestations of COVID-19-related myositis, ranging from direct virus-induced muscle disease to triggered autoimmunity and other etiopathogenic links to explore. A remarkable shift in the means of delivering chronic care has led patients and caregivers worldwide to embrace a virtual shift with teleconsultation and opened doorways to a new era of patient-led care.


Assuntos
COVID-19/fisiopatologia , Miosite/fisiopatologia , Rabdomiólise/fisiopatologia , Imunidade Adaptativa/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Autoanticorpos/imunologia , Dor nas Costas/etiologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/metabolismo , Creatina Quinase/metabolismo , Dermatomiosite/etiologia , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Dermatomiosite/fisiopatologia , Humanos , Imunidade Inata/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Miastenia Gravis/etiologia , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Miastenia Gravis/fisiopatologia , Miosite/etiologia , Miosite/imunologia , Miosite/metabolismo , Músculos Paraespinais/fisiopatologia , Receptores de Coronavírus/metabolismo , Rabdomiólise/etiologia , Rabdomiólise/imunologia , Rabdomiólise/metabolismo , SARS-CoV-2
16.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299065

RESUMO

One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)-the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to detect TLR9 mRNA and protein respectively in the lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) ipsilateral and contralateral to a sterile unilateral sciatic nerve compression or transection. The unilateral sciatic nerve lesions led to bilateral increases in levels of both TLR9 mRNA and protein not only in the lumbar but also in the remote cervical DRG compared with naive or sham-operated controls. This upregulation of TLR9 was linked to activation of the Nuclear Factor kappa B (NFκB) and nuclear translocation of the Signal Transducer and Activator of Transcription 3 (STAT3), implying innate neuronal immune reaction and a pro-regenerative state in uninjured primary sensory neurons of the cervical DRG. The relationship of TLR9 to the induction of a pro-regenerative state in the cervical DRG neurons was confirmed by the shorter lengths of regenerated axons distal to ulnar nerve crush following a previous sciatic nerve lesion and intrathecal chloroquine injection compared with control rats. The results suggest that a systemic innate immune reaction not only triggers the regenerative state of axotomized DRG neurons but also induces a pro-regenerative state further along the neural axis after unilateral nerve injury.


Assuntos
Gânglios Espinais/citologia , Imunidade Inata/imunologia , Neurônios/citologia , Neurônios/imunologia , Fator de Transcrição STAT3/metabolismo , Neuropatia Ciática/terapia , Receptor Toll-Like 9/metabolismo , Animais , Masculino , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Receptor Toll-Like 9/genética
17.
J Interferon Cytokine Res ; 41(7): 244-257, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280026

RESUMO

Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV-2), which initiated as an endemic from China, converted into a pandemic disease worldwide within a couple of months' time. This has led researchers from all over the world to come together to find and develop possible curative or preventive strategies, including vaccine development, drug repurposing, plasma therapy, drug discovery, and cytokine-based therapies. Herein, we are providing, a summarized overview of immunopathology of the SARS-CoV-2 along with various therapeutic strategies undertaken to COVID-19 with a vision for their possible outcome. High levels of proinflammatory cytokines such as interleukin (IL)-7, G-CSF, IP-10, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-2 in severe cases of COVID-19 have been observed. Immune responses play significant roles in the determination of SARS-CoV-2 pathogenesis. Thus, exploring the underlying mechanism of the immune system response to SARS-CoV-2 infection would help in the prediction of disease course and selection of intensive care and therapeutic strategy. As an effort toward developing possible therapeutics for COVID-19, we highlighted different types of vaccines, which are under clinical trials, and also discussed the impact of genome variability on efficacy of vaccine under development.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , SARS-CoV-2/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Vacinas contra COVID-19/uso terapêutico , Controle de Doenças Transmissíveis/métodos , Controle de Doenças Transmissíveis/estatística & dados numéricos , Saúde Global/estatística & dados numéricos , Humanos , Sistema Imunitário/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Mutação , Pandemias/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética
18.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200555

RESUMO

Lipopolysaccharides (LPSs) are bacterial surface glycolipids, produced by Gram-negative bacteria. LPS is known to determine acute inflammatory reactions, particularly in the context of sepsis. However, LPS can also trigger chronic inflammation. In this case, the source of LPS is not an external infection, but rather an increase in endogenous production, which is usually sustained by gut microbiota (GM), and LPS contained in food. The first site in which LPS can exert its inflammatory action is the gut: both GM and gut-associated lymphoid tissue (GALT) are influenced by LPS and shift towards an inflammatory pattern. The changes in GM and GALT induced by LPS are quite similar to the ones seen in IBD: GM loses diversity, while GALT T regulatory (Tregs) lymphocytes are reduced in number, with an increase in Th17 and Th1 lymphocytes. Additionally, the innate immune system is triggered, through the activation of toll-like receptor (TLR)-4, while the epithelium is directly damaged, further triggering inflammation. In this review, we will discuss the importance of the crosstalk between LPS, GM, and GALT, and discuss the possible implications.


Assuntos
Microbioma Gastrointestinal , Imunidade Inata/imunologia , Doenças Inflamatórias Intestinais/patologia , Lipopolissacarídeos/farmacologia , Animais , Humanos , Doenças Inflamatórias Intestinais/etiologia
19.
Cytokine ; 146: 155637, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34242899

RESUMO

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Interferon gama/imunologia , Antivirais/imunologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , Interferon gama/uso terapêutico , Receptores de Interferon/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Transdução de Sinais/imunologia
20.
Nat Commun ; 12(1): 3739, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145258

RESUMO

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.


Assuntos
Aspergillus fumigatus/imunologia , Aspergilose Pulmonar Invasiva/imunologia , Neutrófilos/imunologia , Componente Amiloide P Sérico/genética , Animais , Células Cultivadas , Variação Genética/genética , Humanos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/imunologia , Aspergilose Pulmonar Invasiva/patologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologia
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