RESUMO
Recently, we showed a natural reprogramming process during infection with Mycobacterium leprae (ML), the causative organism of human leprosy. ML hijacks the notable plasticity of adult Schwann cells in the peripheral nervous system (PNS), bacteria's preferred nonimmune niche, to reprogram infected cells to progenitor/stem cell-like cells (pSLCs). Whereas ML appear to use this reprogramming process as a sophisticated bacterial strategy to spread infection to other tissues, understanding the mechanisms may shed new insights into the basic biology of cellular reprogramming and the development of new approaches for generating pSLC for therapeutic purposes as well as targeting bacterial infectious diseases at an early stage. Toward these goals, we extended our studies to identify other players that might be involved in this complex host cell reprogramming. Here we show that ML activates numerous immune-related genes mainly involved in innate immune responses and inflammation during early infection before downregulating Schwann cell lineage genes and reactivating developmental transcription factors. We validated these findings by demonstrating the ability of infected cells to secrete soluble immune factor proteins at early time points and their continued release during the course of reprogramming. By using time-lapse microscopy and a migration assay with reprogrammed Schwann cells (pSLCs) cultured with macrophages, we show that reprogrammed cells possess the ability to attract macrophages, providing evidence for a functional role of immune gene products during reprogramming. These findings suggest a potential role of innate immune response and the related signaling pathways in cellular reprogramming and the initiation of neuropathogenesis during ML infection.
Assuntos
Desdiferenciação Celular/imunologia , Regulação para Baixo/imunologia , Imunidade Inata , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Células de Schwann/imunologia , Animais , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Hanseníase/patologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos ICR , Células de Schwann/microbiologia , Células de Schwann/patologiaRESUMO
Differentiated cells possess a remarkable genomic plasticity that can be manipulated to reverse or change developmental commitments. Here, we show that the leprosy bacterium hijacks this property to reprogram adult Schwann cells, its preferred host niche, to a stage of progenitor/stem-like cells (pSLC) of mesenchymal trait by downregulating Schwann cell lineage/differentiation-associated genes and upregulating genes mostly of mesoderm development. Reprogramming accompanies epigenetic changes and renders infected cells highly plastic, migratory, and immunomodulatory. We provide evidence that acquisition of these properties by pSLC promotes bacterial spread by two distinct mechanisms: direct differentiation to mesenchymal tissues, including skeletal and smooth muscles, and formation of granuloma-like structures and subsequent release of bacteria-laden macrophages. These findings support a model of host cell reprogramming in which a bacterial pathogen uses the plasticity of its cellular niche for promoting dissemination of infection and provide an unexpected link between cellular reprogramming and host-pathogen interaction.
Assuntos
Interações Hospedeiro-Patógeno , Hanseníase/microbiologia , Hanseníase/patologia , Mycobacterium leprae , Células de Schwann/patologia , Células-Tronco/patologia , Animais , Movimento Celular , Sobrevivência Celular , Epigênese Genética , Transição Epitelial-Mesenquimal , Granuloma/microbiologia , Humanos , Hanseníase/genética , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Nus , Nervos Periféricos/patologia , Células de Schwann/microbiologiaRESUMO
The clinical characteristics of five (22%) of 23 patients with Guillain-Barré syndrome (GBS), whose serum contained immunoglobulin G (IgG) antibodies to the ganglioside N-acetylgalactosaminyl GD1a (GalNAc-GD1a), included pure motor weakness of the axonal type. These patients had a relatively good prognosis, but displayed higher serum tumor necrosis factor-alpha (TNF-alpha) titers than the other GBS patients. We examined the effect of serum from these patients with IgG anti-GalNAc-GD1a antibodies on neurites from cultured rat dorsal root ganglia (DRG) and found it to damage the myelin in well-elongated DRG neurites and monolayer cultures of Schwann cells and neurons. In the regeneration model, serum from these patients delayed neurite extension and inhibited Schwann cell proliferation. Neurons in cultured monolayers showed vacuolation and decreased rapidly in number. Schwann cells were also vacuolated and readily detached from the substratum. The effects of IgG anti-GalNAc-GD1a antibodies purified from one of the patients, rabbit serum after immunization with GalNAc-GD1a, and recombinant TNF-alpha were also examined. IgG anti-GalNAc-GD1a antibodies mainly inhibited the regeneration and preservation of neurons, while TNF-alpha mainly induced morphological changes in well-proliferated Schwann cells and myelin.
Assuntos
Anticorpos Anti-Idiotípicos/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gangliosídeos/imunologia , Fator de Necrose Tumoral alfa/toxicidade , Adolescente , Adulto , Animais , Animais Recém-Nascidos , Criança , Cromatografia em Camada Fina/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Imunofluorescência/métodos , Gânglios Espinais/citologia , Gangliosídeos/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Proteínas de Neurofilamentos/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Proteínas S100/metabolismo , Células de Schwann/efeitos dos fármacos , Fatores de TempoRESUMO
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) play central roles in the metabolism of ethanol and its metabolite, acetaldehyde, in the liver. In ADH2, one nucleotide replacement causes either a super-active beta 2 subunit encoded by the ADH2*2 allele or a less active beta 1 subunit (ADH2*1 allele). In the same way, a G/A replacement at codon 487 of the ALDH2 gene produces an inactive form of the enzyme. Because the geno-types of these genes may explain individual differences in concentration and elimination of ethanol and acetaldehyde in the blood after drinking, they could be used as models to elucidate the contribution of these substances to the development of addiction and various types of organ damage. We have examined the influence of genetic variations of these enzymes on alcohol-related disorders in the Japanese. The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol-induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence. Possible mechanisms of altered risk for these disorders are discussed.
Assuntos
Álcool Desidrogenase/genética , Transtornos Relacionados ao Uso de Álcool/genética , Aldeído Desidrogenase/genética , Variação Genética/genética , Fenótipo , Álcool Desidrogenase/metabolismo , Transtornos Relacionados ao Uso de Álcool/enzimologia , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Etanol/metabolismo , Frequência do Gene/genética , HumanosRESUMO
Most of the peripheral neuropathies in Sjögren's syndrome (SS) are sensory- or autonomic-dominant. In this report, we present two cases of a rare type of neuropathy, motor dominant neuropathy, in SS. One showed signs similar to those of Guillain-Barré syndrome, and the other showed signs characteristic of chronic inflammatory demyelinating polyradiculoneuropathy. These patients received i.v. immunoglobulin therapy. To our knowledge, this is the first report indicating that i.v. immunoglobulin has beneficial effects on motor dominant neuropathy in SS.