Mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination

Abstract

The mechanisms by which the airborne pathogen Mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (TB) in humans, remains poorly understood. Herein, we used a transcriptomic approach to investigate the host cell gene expression profile in M. tuberculosis–infected human macrophages (ΜΦ). We identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significantly modified during infection, and we show that the potent angiogenic factor VEGF is secreted by M. tuberculosis-infected ΜΦ, in an RD1-dependent manner. In vivo these factors promote the formation of blood vessels in murine models of the disease. Inhibiting angiogenesis, via VEGF inactivation, abolished mycobacterial spread from the infection site. In accordance with our in vitro and in vivo results, we show that the level of VEGF in TB patients is elevated and that endothelial progenitor cells are mobilized from the bone marrow. These results strongly strengthen the most recent data suggesting that mycobacteria take advantage of the formation of new blood vessels to disseminate.

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

“…Previously, it has been shown that upregulation of vascular endothelial growth factor (VEGF) had a promoting effect on macrophage‐mediated extra pulmonary dissemination of M. tuberculosis (Polena et al, 2016). To examine the role of VEGF in our zebrafish model, we systemically infected Tg(kdrl:mCherry) is5 embryos with M. marinum .…”

“…The observed colocalisation of intensified kdrl/vegfr2 signal with M. marinum ‐ loaded phagocytes in larval brain blood vessels in our study suggests an interaction between infected macrophages and the blood vessel wall and a role for VEGF in this process. It has been shown that macrophages secrete VEGF after infection with M. tuberculosis in an ESX‐1‐dependent manner, which in turn interacts with VEGFR2 specifically (Polena et al, 2016). This mechanism is essential for angiogenetic vessel growth and bacterial expansion and dissemination.…”

“…In line with this hypothesis, M. tuberculosis was found to cross an epithelial barrier with significantly higher efficiency when phagocytosed by monocytes than when mycobacteria alone were introduced in an in vitro system (Bermudez, Sangari, Kolonoski, Petrofsky, & Goodman, 2002). Furthermore, macrophages played an essential role in early dissemination and establishment of extra‐pulmonary foci (Clay et al, 2011; Polena et al, 2016). However, the ability of M. tuberculosis to invade brain endothelial cells in vitro has been described as well (Be, Bishai, & Jain, 2012; Chen, Sakamoto, Quinn, Chen, & Fu, 2015; Jain, Paul‐Satyaseela, Lamichhane, Kim, & Bishai, 2006; Mehta, Karls, White, Ades, & Quinn, 2006).…”

Host-directed therapies for bacterial and viral infections

“…The outcome of vasculogenesis-focused HDT for TB is likely to depend on the stage of disease and the treatment objective, namely, interference with either angiogenesis or vascular permeability. In patients with active TB, factors that induce neovascularization, notably vascular endothelial growth factor (VEGF) and its receptor VEGFR, are abundant in the circulation [238][239][240] and have been proposed as biomarkers of disease severity 241 . Bevacizumab, a mAb against VEGF, is approved for the treatment of certain cancers, and several other antibodies that target VEGF or VEGFR are in clinical trials.…”

“…In animal models of TB, VEGF and VEGFR inhibitors have revealed beneficial effects when given in combination with conventional drugs, by limiting bacterial dissemination and boosting the activity of drugs that target hypoxic Mtb 242,243 . Conversely, there is a risk that the administration of such biologics without concurrent chemotherapy may promote TB reactivation 244,245 and bacillary dissemination 240 .…”