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1.
Viruses ; 15(12)2023 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-38140641

RESUMO

Recognition of viruses invading the central nervous system (CNS) by pattern recognition receptors (PRRs) is crucial to elicit early innate responses that stem dissemination. These innate responses comprise both type I interferon (IFN-I)-mediated defenses as well as signals recruiting leukocytes to control the infection. Focusing on insights from the neurotropic mouse CoV model, this review discusses how early IFN-I, fibroblast, and myeloid signals can influence protective anti-viral adaptive responses. Emphasis is placed on three main areas: the importance of coordinating the distinct capacities of resident CNS cells to induce and respond to IFN-I, the effects of select IFN-stimulated genes (ISGs) on host immune responses versus viral control, and the contribution of fibroblast activation and myeloid cells in aiding the access of T cells to the parenchyma. By unraveling how the dysregulation of early innate components influences adaptive immunity and viral control, this review illustrates the combined effort of resident CNS cells to achieve viral control.


Assuntos
Infecções por Coronavirus , Coronavirus , Encefalomielite , Interferon Tipo I , Camundongos , Animais , Sistema Nervoso Central , Imunidade Inata
2.
ASN Neuro ; 15: 17590914221146365, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36591943

RESUMO

The central nervous system (CNS) can be preconditioned to resist damage by peripheral pretreatment with low-dose gram-negative bacterial endotoxin lipopolysaccharide (LPS). Underlying mechanisms associated with transient protection of the cerebral cortex against traumatic brain injury include increased neuronal production of antiapoptotic and neurotrophic molecules, microglial-mediated displacement of inhibitory presynaptic terminals innervating the soma of cortical projection neurons, and synchronized firing of cortical projection neurons. However, the cell types and signaling responsible for these neuronal and microglial changes are unknown. A fundamental question is whether LPS penetrates the CNS or acts on the luminal surface of brain endothelial cells, thereby triggering an indirect parenchymal neuroprotective response. The present study shows that a low-dose intraperitoneal LPS treatment increases brain endothelial cell activation markers CD54, but does not open the blood-brain barrier or alter brain endothelial cell tight junctions as assessed by electron microscopy. NanoString nCounter transcript analyses of CD31-positive brain endothelial cells further revealed significant upregulation of Cxcl10, C3, Ccl2, Il1ß, Cxcl2, and Cxcl1, consistent with identification of myeloid differentiation primary response 88 (MyD88) as a regulator of these transcripts by pathway analysis. Conditional genetic endothelial cell gene ablation approaches demonstrated that both MyD88-dependent Toll-like receptor 4 (TLR4) signaling and Cxcl10 expression are essential for LPS-induced neuroprotection and microglial activation. These results suggest that C-X-C motif chemokine ligand 10 (CXCL10) production by endothelial cells in response to circulating TLR ligands may directly or indirectly signal to CXCR3 on neurons and/or microglia. Targeted activation of brain endothelial receptors may thus provide an attractive approach for inducing transient neuroprotection.


Assuntos
Lipopolissacarídeos , Fator 88 de Diferenciação Mieloide , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neuroproteção , Células Endoteliais , Camundongos Knockout , Microglia/metabolismo , Camundongos Endogâmicos C57BL
3.
Immunol Rev ; 311(1): 75-89, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35984298

RESUMO

A diverse number of DNA and RNA viruses have the potential to invade the central nervous system (CNS), causing inflammation and injury to cells that have a limited capacity for repair and regeneration. While rare, viral encephalitis in humans is often fatal and survivors commonly suffer from permanent neurological sequelae including seizures. Established treatment options are extremely limited, predominantly relying on vaccines, antivirals, or supportive care. Many viral CNS infections are characterized by the presence of antiviral antibodies in the cerebral spinal fluid (CSF), indicating local maintenance of protective antibody secreting cells. However, the mechanisms maintaining these humoral responses are poorly characterized. Furthermore, while both viral and autoimmune encephalitis are associated with the recruitment of diverse B cell subsets to the CNS, their protective and pathogenic roles aside from antibody production are just beginning to be understood. This review will focus on the relevance of B cell responses to viral CNS infections, with an emphasis on the importance of intrathecal immunity and the potential contribution to autoimmunity. Specifically, it will summarize the newest data characterizing B cell activation, differentiation, migration, and localization in clinical samples as well as experimental models of acute and persistent viral encephalitis.


Assuntos
Viroses do Sistema Nervoso Central , Encefalite Viral , Antivirais , Linfócitos B , Sistema Nervoso Central , Viroses do Sistema Nervoso Central/patologia , Encefalite Viral/patologia , Humanos
4.
PLoS Negl Trop Dis ; 12(11): e0006880, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30418969

RESUMO

The recent emergence of Zika virus (ZIKV) in the Americas coincident with increased caseloads of microcephalic infants and Guillain-Barre syndrome has prompted a flurry of research on ZIKV. Much of the research is difficult to compare or repeat because individual laboratories use different virus isolates, growth conditions, and quantitative assays. Here we obtained three readily available contemporary ZIKV isolates and the prototype Ugandan isolate. We generated stocks of each on Vero mammalian cells (ZIKVmam) and C6/36 mosquito cells (ZIKVmos), determined titers by different assays side-by-side, compared growth characteristics using one-step and multi-step growth curves on Vero and C6/36 cells, and examined plaque phenotype. ZIKV titers consistently peaked earlier on Vero cells than on C6/36 cells. Contemporary ZIKV isolates reached peak titer most quickly in a multi-step growth curve when the amplifying cell line was the same as the titering cell line (e.g., ZIKVmam titered on Vero cells). Growth of ZIKVmam on mosquito cells was particularly delayed. These data suggest that the ability to infect and/or replicate in insect cells is limited after growth in mammalian cells. In addition, ZIKVmos typically had smaller, more homogenous plaques than ZIKVmam in a standard plaque assay. We hypothesized that the plaque size difference represented early adaptation to growth in mammalian cells. We plaque purified representative-sized plaques from ZIKVmos and ZIKVmam. ZIKVmos isolates maintained the initial phenotype while plaques from ZIKVmam isolates became larger with passaging. Our results underscore the importance of the cells used to produce viral stocks and the potential for adaptation with minimal cell passages. In addition, these studies provide a foundation to compare current and emerging ZIKV isolates in vitro and in vivo.


Assuntos
Adaptação Fisiológica , Aedes/citologia , Zika virus/crescimento & desenvolvimento , Zika virus/fisiologia , Aedes/virologia , Animais , Linhagem Celular , Chlorocebus aethiops , Humanos , Técnicas In Vitro , Fenótipo , Células Vero , Replicação Viral , Zika virus/classificação , Zika virus/isolamento & purificação
5.
PLoS Negl Trop Dis ; 11(2): e0005394, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28187142

RESUMO

Half of the human population is at risk of infection by an arthropod-borne virus. Many of these arboviruses, such as West Nile, dengue, and Zika viruses, infect humans by way of a bite from an infected mosquito. This infectious inoculum is insect cell-derived giving the virus particles distinct qualities not present in secondary infectious virus particles produced by infected vertebrate host cells. The insect cell-derived particles differ in the glycosylation of virus structural proteins and the lipid content of the envelope, as well as their induction of cytokines. Thus, in order to accurately mimic the inoculum delivered by arthropods, arboviruses should be derived from arthropod cells. Previous studies have packaged replicon genome in mammalian cells to produce replicon particles, which undergo only one round of infection, but no studies exist packaging replicon particles in mosquito cells. Here we optimized the packaging of West Nile virus replicon genome in mosquito cells and produced replicon particles at high concentration, allowing us to mimic mosquito cell-derived viral inoculum. These particles were mature with similar genome equivalents-to-infectious units as full-length West Nile virus. We then compared the mosquito cell-derived particles to mammalian cell-derived particles in mice. Both replicon particles infected skin at the inoculation site and the draining lymph node by 3 hours post-inoculation. The mammalian cell-derived replicon particles spread from the site of inoculation to the spleen and contralateral lymph nodes significantly more than the particles derived from mosquito cells. This in vivo difference in spread of West Nile replicons in the inoculum demonstrates the importance of using arthropod cell-derived particles to model early events in arboviral infection and highlights the value of these novel arthropod cell-derived replicon particles for studying the earliest virus-host interactions for arboviruses.


Assuntos
Aedes/virologia , Infecções por Arbovirus/virologia , Arbovírus/fisiologia , Insetos Vetores/virologia , Replicon , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Animais , Arbovírus/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Estruturais Virais/genética , Proteínas Estruturais Virais/metabolismo , Montagem de Vírus , Cultura de Vírus , Vírus do Nilo Ocidental/crescimento & desenvolvimento , Vírus do Nilo Ocidental/fisiologia
6.
Skin Pharmacol Physiol ; 28(4): 177-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25620035

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory disorder of skin and joints for which conventional treatments that are effective in clearing the moderate-to-severe disease are limited due to long-term safety issues. This necessitates exploring the usefulness of botanical agents for treating psoriasis. We previously showed that delphinidin, a diet-derived anthocyanidin endowed with antioxidant and anti-inflammatory properties, induces normal epidermal keratinocyte differentiation and suggested its possible usefulness for the treatment of psoriasis [1]. OBJECTIVES: To investigate the effect of delphinidin (0-20 µM; 2-5 days) on psoriatic epidermal keratinocyte differentiation, proliferation and inflammation using a three-dimensional reconstructed human psoriatic skin equivalent (PSE) model. METHODS: PSEs and normal skin equivalents (NSEs) established on fibroblast-contracted collagen gels with respective psoriatic and normal keratinocytes and treated with/without delphinidin were analyzed for histology, expression of markers of differentiation, proliferation and inflammation using histomorphometry, immunoblotting, immunochemistry, qPCR and cultured supernatants for cytokine with a Multi-Analyte ELISArray Kit. RESULTS: Our data show that treatment of PSE with delphinidin induced (1) cornification without affecting apoptosis and (2) the mRNA and protein expression of markers of differentiation (caspase-14, filaggrin, loricrin, involucrin). It also decreased the expression of markers of proliferation (Ki67 and proliferating cell nuclear antigen) and inflammation (inducible nitric oxide synthase and antimicrobial peptides S100A7-psoriasin and S100A15-koebnerisin, which are often induced in psoriatic skin). ELISArray showed increased release of psoriasis-associated keratinocyte-derived proinflammatory cytokines in supernatants of the PSE cultures, and this increase was significantly suppressed by delphinidin. CONCLUSIONS: These observations provide a rationale for developing delphinidin for the management of psoriasis.


Assuntos
Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Queratinócitos/efeitos dos fármacos , Modelos Biológicos , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Caspases/genética , Caspases/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Proteínas Filagrinas , Humanos , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/genética , Pele/metabolismo
7.
Exp Dermatol ; 22(5): 342-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23614741

RESUMO

Delphinidin (Del), [3,5,7,3'-,4'-,5'-hexahydroxyflavylium], an anthocyanidin and a potent antioxidant abundantly found in pigmented fruits and vegetables exhibits proapoptotic effects in many cancer cells. Here, we determined the effect of Del on growth, apoptosis and differentiation of normal human epidermal keratinocytes (NHEKs) in vitro in submerged cultures and examined its effects in a three-dimensional (3D) epidermal equivalent (EE) model that permits complete differentiation reminiscent of in vivo skin. Treatment of NHEKs with Del (10-40 µm; 24-48 h) significantly enhanced keratinocyte differentiation. In Del-treated cells, there was marked increase in human involucrin (hINV) promoter activity with simultaneous increase in the mRNA and protein expressions of involucrin and other epidermal differentiation markers including procaspase-14 and transglutaminase-1 (TGM1), but without any effect on TGM2. Del treatment of NHEKs was associated with minimal decrease in cell viability, which was not associated with apoptosis as evident by lack of modulation of caspases, apoptosis-related proteins including Bcl-2 family of proteins and poly(ADP-ribose) polymerase cleavage. To establish the in vivo relevance of our observations in submerged cultures, we then validated these effects in a 3D EE model, where Del was found to significantly enhance cornification and increase the protein expression of cornification markers including caspase-14 and keratin 1. For the first time, we show that Del induces epidermal differentiation using an experimental system that closely mimics in vivo human skin. These observations suggest that Del could be a useful agent for dermatoses associated with epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation observed in skin diseases like psoriasis and ichthyoses.


Assuntos
Antocianinas/farmacologia , Antioxidantes/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epidérmicas , Prepúcio do Pênis/citologia , Frutas/química , Expressão Gênica/efeitos dos fármacos , Humanos , Recém-Nascido , Masculino , Técnicas de Cultura de Órgãos/métodos , Regiões Promotoras Genéticas/fisiologia , Precursores de Proteínas/genética , Verduras/química
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