PROJECT SUMMARY/ABSTRACT
Brain tuberculosis (TB), the most severe form of tuberculosis, is associated with a complex inflammatory
response, tissue damage and cerebral edema. Typically, management of fluid, waste, and immune-
surveillance in the periphery is performed by tissue infiltrating lymphoid vessels. While the brain parenchyma
does not have lymphoid vessels, recent research has identified that brain fluids (cerebrospinal fluid and
interstitial fluid) are collected by meningeal and cribriform lymphoid vessels surrounding the brain, which are
crucial for waste clearance and tissue homeostasis in the CNS. It has been shown that inhibition of lymphatic
transport accelerates disease pathology and cognitive decline in Alzheimer’s disease, traumatic brain injury,
and Parkinson’s disease, but little is known about the potential modulatory role of lymphoid vessels in CNS
tuberculosis. Recently we reported that autoimmune inflammation induces lymphangiogenesis at the cribriform
plate through the production of VEGFC from inflammatory dendritic cells. Functionally, the induction of new
lymphoid vessels upregulates immunoregulatory molecules, and blocking new lymphoid vessel formation has
consequences in regulating the severity of the autoimmune disease. In this proposal, we will test how CNS
tuberculosis affects meningeal and cribriform lymphoid vessels formation and consequently, their fluid and cell
draining function (Aim 1) To understand the impacts on immune-surveillance, we will study how
CNS mycobacterial tuberculosis (Mtb) infection alters the expression of immune regulatory molecules on
draining lymphoid vessels and how these lymphoid vessels modify brain-derived dendritic cells and their ability
to influence downstream T cell priming in the lymph node (Aim 2). Lastly, we will use agents that block or
promote lymphangiogenesis to test how brain inflammation, bacterial load, dissemination, and anti-bacterial
immunity are affected by alterations of brain drainage with the hope of decreasing CNSTB associated
pathologies (Aim 3). CNS tuberculosis is one of the most common bacterial infections of the brain with high
mortality with a pressing need for new therapies, and these studies will lead to novel therapeutic strategies in
CNSTB.
The objectives of this proposal are (1) to test whether infiltrating or resident immune cells produce VEGFC
that contributes to cribriform plate-associated, dorsal meningeal, or basal meningeal lymphangiogenesis during
central nervous system tuberculosis (CNSTB) (Aim 1); to define cellular and bacterial interaction between Mtb-
infected dendritic cells, Mtb, and lymphoid endothelial cells (LECs) (Aim 2); and to understand the translational
value of lymphangiogenesis regulators on CNSTB pathogenesis, bacterial control, anti-bacterial responses,
and bacterial dissemination (Aim 3).
These studies will lead to a new aspect of brain TB pathology and reveal novel information comparing
lymphatic vessel responses and brain drainage in different brain inflammations. These studies' long-
term objective is to define how the lymphatic system represents a novel target in combating CNSTB.