Modulating sonic hedgehog (SHH) pathway to create a rapid CNS-TB model: Facilitating drug discovery

Area of Science:

• Neuroscience
• Immunology
• Infectious Diseases

Background:

• Tuberculous meningitis (CNS-TB) is a severe complication of Mycobacterium tuberculosis (M. tb) infection, characterized by bacilli dissemination in the brain.
• The integrity of the blood-brain barrier (BBB) is crucial in preventing CNS infections, and its disruption facilitates M. tb entry and disease progression.
• The Sonic Hedgehog (SHH) signaling pathway is implicated in various physiological processes, but its role in CNS-TB pathogenesis remains largely unexplored.

Purpose of the Study:

• To investigate the role of the SHH signaling pathway in regulating BBB integrity during M. tb infection.
• To determine the effect of SHH pathway modulation on M. tb invasion into the central nervous system (CNS).
• To evaluate the impact of SHH signaling on disease progression and immunopathology in a murine model of CNS-TB.

Main Methods:

• A Balb/c mouse model of CNS-TB was established.
• The SHH pathway was modulated using the agonist Purmorphamine (PUR) and the antagonist Cyclopamine (CYC).
• Bacterial load, BBB integrity, inflammation, immune cell infiltration, and Matrix Metalloproteinase-9 (MMP-9) levels were assessed via quantitative bacterial counts, histopathology, and immunohistochemistry.

Main Results:

• Cyclopamine (CYC) treatment led to a 99% increase in M. tb brain invasion and exacerbated BBB breakdown, reactive gliosis, and inflammation.
• Purmorphamine (PUR) treatment reduced M. tb loads by 50%, delayed disease progression, and partially attenuated BBB disruption and inflammatory responses.
• CYC upregulated MMP-9 secretion, a key factor in BBB disruption, while PUR showed a mitigating effect.

Conclusions:

• The SHH signaling pathway plays a critical role in maintaining BBB integrity and modulating the immunopathological response during CNS-TB.
• Inhibition of SHH signaling accelerates M. tb invasion and CNS damage, whereas activation offers neuroprotection.
• Targeting the SHH pathway presents a potential therapeutic strategy for managing CNS-TB and warrants further investigation for drug discovery.