Cade Janke

Introduction: Activation of the innate immune response is key in fighting off Mycobacterium tuberculosis (Mtb).^[1][2] However, Mtb alters the PAMP-TLR2 relationship to evade this response. Alterations include modified bacterial wall components that are recognized by TLR2.^[2] This results in decreased production of proinflammatory cytokines which are necessary to effectively fight Mtb infections.^[1] Understanding the interaction of Mtb and TLR2 helps understand Mtb pathophysiology and assess potential therapeutics for the future. Methods: To determine if recombinant leucine responsive regulatory protein’s (rLRP) blocks TLR signaling, cells were pretreated with varying concentration of rLRP then stimulated with lipopolysaccharide (LPS). TNF-a, IL-6 and IL-12 levels were measured using ELISA.^[3] To determine the effects of Lipoprotein E (LprE) on cytokine production, cells infected with Mtb, Mtb with altered LrpE, and Mtb with LprE bound to complement strands, were harvested to isolate total RNA and proteins.^[4] Transcriptional levels of CYP27B1 and VDR were determined using qRT-PCR. Results: Studies show the direct inhibitory interaction between rLRP and TLR2 and how TLR inhibition affects the immune response.^[3][5] “rLRP binding to TLR2-activated PI3K-protein kinase b (Akt) dependent signaling and inhibited LPS-induced cytokine production and NF-kB activation by blocking IRAK1, TRAF6, and TAK1 signalosome formation.”^[3] Deletion of LprE decreased the virulence of Mtb in macrophages due to an increase in vitamin D3 responsive cathelicidin expression through a TLR2 dependent signaling pathway.^[4  Furthermore, infection with LprE Mtb mutants allows for macrophages to accumulate autophagy related proteins, as well as increase recruitment of phagosomal and lysosomal proteins.^[4] It was also determined that Guttiferone K demonstrates an anti-inflammatory effect on macrophages infected with Mtb by interfering with the TLR/IRAK-1 mediated Akt and NF-kB pathway.^[6] This is potentially therapeutic.^[6] Discussion: Evidence supporting anti-inflammatory or immunomodulatory agents as treatments to improve Mtb infection outcomes is growing.^[6] As multidrug resistant Mtb rises, host directed therapy is becoming increasingly important.^[6] Guttiferone K and other potential treatments suppress inflammation and have many overlaps with the mechanism used by Mtb to avoid the immune system.^[6] This indicates that further exploration of the mechanisms behind Mtb pathogenicity and immune evasion will lead to improved treatments and prevention strategies.

[1] Hunter RL. The Pathogenesis of Tuberculosis: The Early Infiltrate of Post-primary (Adult Pulmonary) Tuberculosis: A Distinct Disease Entity. Front Immunol. 2018;9:2108. Published 2018 Sep 19. doi:10.3389/fimmu.2018.02108

[2] Liu Y, Li JY, Chen ST, Huang HR, Cai H. The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism. Cell Mol Immunol. 2016;13(6):729-746. doi:10.1038/cmi.2015.58

[3] Liu Y, Cai H. The Lrp of Mycobacterium tuberculosis regulates the innate immune response of macrophages. Cell Mol Immunol. 2018;15(10):934-936. doi:10.1038/cmi.2018.6

[4] Padhi A, Pattnaik K, Biswas M, Jagadeb M, Behera A, Sonawane A. Mycobacterium tuberculosis LprE Suppresses TLR2-Dependent Cathelicidin and Autophagy Expression to Enhance Bacterial Survival in Macrophages. J Immunol. 2019;203(10):2665-2678. doi:10.4049/jimmunol.1801301

[5] Liu CH, Liu H, Ge B. Innate immunity in tuberculosis: host defense vs pathogen evasion. Cell Mol Immunol. 2017;14(12):963-975. doi:10.1038/cmi.2017.88

[6] Zhang Q, Sun J, Fu Y, et al. Guttiferone K Exerts the Anti-inflammatory Effect on Mycobacterium Tuberculosis- (H37Ra-) Infected Macrophages by Targeting the TLR/IRAK-1 Mediated Akt and NF-κB Pathway. Mediators Inflamm. 2020;2020:8528901. Published 2020 Oct 10. doi:10.1155/2020/8528901