Mycobacterium-Infected Dendritic Cells Disseminate Granulomatous Inflammation

Abstract

The disappearance and reformation of granulomas during tuberculosis has been described using PET/CT/X-ray in both human clinical settings and animal models, but the mechanisms of granuloma reformation during active disease remains unclear. Granulomas can recruit inflammatory dendritic cells (iDCs) that can regulate local T-cell responses and can carry bacteria into the lymph nodes, which is crucial for generating systemic T-cell responses against mycobacteria. Here, we report that a subset of mycobacterium-infected iDCs are associated with bacteria-specific T-cells in infected tissue, outside the granuloma, and that this results in the formation of new and/or larger multi-focal lesions. Mycobacterium-infected iDCs express less CCR7 and migrate less efficiently compared to the non-infected iDCs, which may support T-cell capture in granulomatous tissue. Capture may reduce antigen availability in the lymph node, thereby decreasing systemic priming, resulting in a possible regulatory loop between systemic T-cell responses and granuloma reformation. T-cell/infected iDCs clusters outside the granuloma can be detected during the acute and chronic phase of BCG and Mtb infection. Our studies suggest a direct role for inflammatory dendritic cells in the dissemination of granulomatous inflammation.

VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection

“…These inflammatory effector cells have a limited lifespan, and so continuous cell replacement and granuloma reformation is needed to maintain granulomas long-term. (Harding et al, 2015b). In fact, more than a third of monocytes are replaced within in a week in a granuloma transplantation model, and dendritic cells and (Schreiber et al, 2011b) and lymphocytes (Schreiber et al, 2011a) have a similar turnover rate.…”

“…Granuloma transplantation was performed as previously described (Harding et al, 2015b;Schreiber et al, 2011b). Mice were anesthetized with a ketamine/xylazine mixture and given meloxicam subcutaneously for post-operative pain management.…”

Mycobacterium tuberculosis: Rewiring host cell signaling to promote infection

“…Additionally, the mycobacterial serine hydrolase Hip1 reduced surface expression of MHC class II and the costimulatory molecules CD40 and CD86, as well as a number of pro‐inflammatory cytokines . Several groups have also reported that infection of DCs with M. tuberculosis reduces their expression integrins and chemokine receptors, therefore hindering their migration to lymph nodes and delaying the onset of adaptive immunity . It is also thought that the cross‐presentation of M. tuberculosis antigens is prevented by the inhibition of apoptosis of infected phagocytes, as discussed below.…”

A Novel In Vitro Mouse Model to Study Mycobacterium tuberculosis Dissemination Across Brain Vessels: A Combination Granuloma and Blood‐Brain Barrier Mouse Model

“…Previous data from our group showed that after in vivo BCG infection, primary granulomas are formed from where immune cells carrying live bacteria exit. These cells were identified as CD11c+ DCs (Harding et al, 2015), which arrest with CD4+ T cells in the body at different distances from the primary focus, forming new secondary granulomas and promoting dissemination. Concurrently, the migratory capacity of infected cells isolated from liver granulomas were studied and revealed that phagocytic cells carrying mycobacteria are hindered in motion (Harding et al, 2015).…”

“…Mycobacterium tuberculosis (Mtb) primarily infects the lung, resulting in pulmonary granuloma formation, but disseminating bacteria can spread to the central nervous system (CNS) and form lesions in the parenchyma, causing serious neurological symptoms and high mortality (Jain et al, 2018). Previous studies from our laboratory have shown that dendritic cells (DCs) in vivo are capable of escaping primary granulomas and contribute to Mtb dissemination (Harding, Rayasam, Schreiber, Fabry, & Sandor, 2015); however, the mechanism by which Mtb then enters the CNS is not yet clear. The model presented here allows us to test different mechanisms, including the "Trojan horse" theory, which favors Mtb dissemination into the CNS via cellular transport.…”