Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection
Year: 2015
Type: article
Abstract: Background. Although Mycobacterium tuberculosis (Mtb) transmission requires an obligate airborne route once inhaled the precise mechanisms used by Mtb to penetrate the mucosa remain unknown. The prevailing paradigm is that infection is initiated when patrolling alveolar macrophages within the terminal alveolus ingest inhaled mycobacteria. However, definitive data for this model is lacking, and a significant number of lymphatic or disseminated cases of tuberculosis occur in the absence of obvious pulmonary disease. Amongst the epithelial cells of the upper airway a specialized epithelial cell known as a microfold cell (M-cell) exists overlying nasal associated lymphatic tissue (NALT), the tonsils of Waldeyer's ring and bronchus associated lymphatic tissue. M-cells can transcytose mucosal antigens from the apical to the basolateral domain, yet a functional or genetic analysis of M-cell translocation of Mtb has not been reported. Methods. We studied mice genetically deficient in M-cells (SpiB−/−) or wild-type mice depleted of M-cells via anti-RANKL antibody treatment. We established a novel mouse intranasal infection model to initiate Mtb infection via M-cells. We used an in vitro M-cell mediated translocation assay, an Mtb eccD1mutant lacking its Type VII secretion system, and a fluorescent bead translocation assay. Results. Intranasal Mtb infection in SpiB−/− mice resulted in reduced invasion and dissemination to draining lymph nodes. Transient depletion of M-cells also reduced mycobacterial dissemination in both intranasal and low-dose aerosol infection models. Using in vitro assays we found that translocation across M-cells was rapid, temperature-dependent and required eccD1. Mtb translocation across NALT required the Type VII secretion system, and its secreted effector ESAT-6 was sufficient to mediate translocation of inert beads across M-cells in vitro. Finally, M-cell depletion immediately before Mtb aerosol infection significantly delayed mortality in mice. Conclusion. We conclude that M-cells are a vital portal of entry for Mtb. We propose a revised paradigm for Mtb infection that incorporates M-cell mediated entry to facilitate dissemination to lymph nodes. M-cell entry may therefore account for scrofula and other lymphatic forms of disease that together represent more than 10% of all tuberculosis cases annually. Disclosures. All authors: No reported disclosures.
Source: Open Forum Infectious Diseases
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,053
OpenAlex ID: W2475191266