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1.
Elife ; 92020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134383

RESUMO

Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.


Assuntos
Mycobacterium tuberculosis/fisiologia , Receptores Depuradores Classe B/fisiologia , Tonsila Faríngea/citologia , Tonsila Faríngea/microbiologia , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/classificação , Nariz , Sistemas de Secreção Tipo VII/fisiologia
2.
Cell ; 181(2): 293-305.e11, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142653

RESUMO

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.


Assuntos
Tosse/fisiopatologia , Glicolipídeos/metabolismo , Nociceptores/fisiologia , Fatores de Virulência/metabolismo , Adulto , Animais , Linhagem Celular , Tosse/etiologia , Tosse/microbiologia , Feminino , Glicolipídeos/fisiologia , Cobaias , Interações Hospedeiro-Patógeno , Humanos , Lipídeos/fisiologia , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Tuberculose/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/fisiopatologia , Fatores de Virulência/fisiologia
3.
Cell Rep ; 16(5): 1253-1258, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27452467

RESUMO

The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell-depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb.


Assuntos
Células Epiteliais/virologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/virologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/virologia , Feminino , Humanos , Linfonodos/virologia , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/virologia
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