MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival

Poh, X. Y.; Loh, F. K.; Bai, C.; Chong, H. T.; Teo, W. K.; Hong, J. M.; Miow, Q. H.; Thong, P. M.; Vilaysane, B.; Hu, T. H.; Chhabra, S.; Wang, Y.; Tiong, S. C.; Fong, S. M.; Kamihigashi, M.; Rajarethinam, R.; Looi, W. D.; Cheow, E. S. H.; Bonney, G. K.; Pakkiri, L. S.; Drum, C. L.; Peng, Y. F.; Lee, M.; Tan, C. L.; Ding, C. S. L.; Lim, T. C. C.; Yeo, T. W.; Tay, J. K.; Vallejo, A. F.; Ong, C. W. M.

doi:10.1101/2023.10.05.561002

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bioRxiv · 10.1101/2023.10.05.561002

MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival

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Abstract

Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still cause permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of tuberculous meningitis (TBM) and non-TBM patients. We determined significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) are up-regulated in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we created a CNS-TB murine model which show neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, resembling human CNS-TB. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.

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Poh, X. Y., Loh, F. K., Bai, C., Chong, H. T., Teo, W. K., Hong, J. M., Miow, Q. H., Thong, P. M., Vilaysane, B., Hu, T. H., Chhabra, S., Wang, Y., Tiong, S. C., Fong, S. M., Kamihigashi, M., Rajarethinam, R., Looi, W. D., Cheow, E. S. H., Bonney, G. K., Pakkiri, L. S., Drum, C. L., Peng, Y. F., Lee, M., Tan, C. L., Ding, C. S. L., Lim, T. C. C., Yeo, T. W., Tay, J. K., Vallejo, A. F., Ong, C. W. M.. 2023-10-07. MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival. https://doi.org/10.1101/2023.10.05.561002

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