To address the question of how Mtb crosses the airway mucosa to establish infection, we are testing the hypothesis that a rare epithelial cell called a microfold or M-cell mediates Mtb transmission (Fig. 2).
In the oropharynx and respiratory tree, Mtb encounters mucosa associated lymphoid tissue (MALT) such as nasal associated lymphatic tissue (NALT), tonsils and adenoids. Specialized M-cells overlying MALT transcytose antigens from the apical to the basolateral compartment. Whether Mtb leverage M-cells to initiate infection is unknown. We recently established a mouse intranasal infection model and found that cervical lymph node dissemination by Mtb occurred without contacting alveolar macrophages. Mice genetically lacking M-cells or depleted of M-cells had reduced Mtb invasion and dissemination to draining lymph nodes. M-cell depletion delayed mouse mortality in a low-dose aerosol infection, indicating a vital role for M-cells in respiratory Mtb disease.
Our ongoing experiments are aimed at identifying how Mtb adheres and traffics through M-cells, and the consequences of M-cell transcytosis for innate and adaptive immunity. We have preliminary data that a cell surface receptor on M-cells mediates transcytosis, and are characterizing this interaction with Mtb in vitro and in vivo. We are also determining how M-cell transcytosis influences the subsequent interaction of Mtb with macrophages and dendritic cells. Finally, since M-cells overlie human tonsils, we are establishing an M-cell translocation assay in human tonsillar explants to assess the role of M-cells, Mtb receptors, and transcytosis in primary human tissue. The identified mechanisms will fundamentally advance the fields of microbiology and host defense, and provide new approaches towards reducing Mtb infectivity.