Berberine governs NOTCH3/AKT signaling to enrich lung-resident memory T cells during tuberculosis

Abstract

Stimulation of naïve T cells during primary infection or vaccination drives the differentiation and expansion of effector and memory T cells that mediate immediate and long-term protection. Despite self-reliant rescue from infection, BCG vaccination, and treatment, long-term memory is rarely established against Mycobacterium tuberculosis (M.tb) resulting in recurrent tuberculosis (TB). Here, we show that berberine (BBR) enhances innate defense mechanisms against M.tb and stimulates the differentiation of Th1/Th17 specific effector memory (TEM), central memory (TCM), and tissue-resident memory (TRM) responses leading to enhanced host protection against drug-sensitive and drug-resistant TB. Through whole proteome analysis of human PBMCs derived from PPD+ healthy individuals, we identify BBR modulated NOTCH3/PTEN/AKT/FOXO1 pathway as the central mechanism of elevated TEM and TRM responses in the human CD4+ T cells. Moreover, BBR-induced glycolysis resulted in enhanced effector functions leading to superior Th1/Th17 responses in human and murine T cells. This regulation of T cell memory by BBR remarkably enhanced the BCG-induced anti-tubercular immunity and lowered the rate of TB recurrence due to relapse and re-infection. These results thus suggest tuning immunological memory as a feasible approach to augment host resistance against TB and unveil BBR as a potential adjunct immunotherapeutic and immunoprophylactic against TB.

Berberine as a new neuraminidase inhibitor drug: A systematic review

“…The antioxidant properties and anti-inflammatory effects of berberine cause a decrease in the negative symptoms in neuropathic patients (36,37). Studies have shown that berberine has also a potent effect on lung damage and other pulmonary inflammations (38)(39)(40). Furthermore, berberine has been shown to have antiviral effects against viruses such as herpes simplex, human cytomegalovirus, and influenza A (41)(42)(43).…”

Biapenem, a Carbapenem Antibiotic, Elicits Mycobacteria Specific Immune Responses and Reduces the Recurrence of Tuberculosis

“…Therefore, we evaluated the potential of BPM in modulating T cell memory responses to mediate long-term memory against M.tb . Recently we and others have shown how antimycobacterial compounds elicit M.tb specific long-term immunity ( 50 – 52 ). Here, again, we observed that BPM boosted the memory responses in both the lung and the spleen of infected animals.…”

The uncharted territory of host-pathogen interaction in tuberculosis

“…This is further complemented by adjunct therapy with BCG as well as DOTS therapy, that results in higher T scm responses that further give rise to different memory pools and effector T cells (77, 78). Similarly, whole proteomics analysis of Purified protein derivative (PPD +) healthy individuals when treated with an immunomodulator, Berberine, showed upregulation of glycolytic pathway along with NOTCH3, that may possibly play role in prompting protective T cell effector function against TB (79).…”