Cholesterol Oxidase Binds TLR2 and Modulates Functional Responses of Human Macrophages

Abstract

Cholesterol oxidase (ChoD) is considered to be an important virulence factor for Mycobacterium tuberculosis (Mtb), but its influence on macrophage activity is unknown. Here we used Nocardia erythropolis ChoD, which is very similar to the Mtb enzyme (70% identity at the amino-acid level), to evaluate the impact of bacterial ChoD on the activity of THP-1-derived macrophages in vitro. We found that ChoD decreased the surface expression of Toll-like receptor type 2 (TLR2) and complement receptor 3 (CR3) on these macrophages. Flow cytometry and confocal microscopy showed that ChoD competed with lipoteichoic acid for ligand binding sites on TLR2 but not on CR3, suggesting that ChoD signaling is mediated via TLR2. Binding of ChoD to the membrane of macrophages had diverse effects on the activity of macrophages, activating p38 mitogen activated kinase and stimulating production of a large amount of interleukin-10. Moreover, ChoD primed macrophages to enhance the production of reactive oxygen species in response to the phorbol myristate acetate, which was reduced by “switching off” TLR-derived signaling through interleukin-1 receptor-associated kinases 1 and 4 inhibition. Our study revealed that ChoD interacts directly with macrophages via TLR2 and influences the biological activity of macrophages during the development of the initial response to infection.

Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities

“…30 The guaB3 gene resides in a three-gene operon Rv3409c - guaB3 - guaB2 , and Rv3409c is required for bacterial survival and growth in macrophages. 31 We also identified frameshift deletions in Rv0678 , Rv2552c , and Rv3267 from ASR1. These genes are involved in the regulation of a cell efflux system, aromatic amino acid synthesis, and cell-wall synthesis, respectively.…”

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“…Cholesterol oxidase (ChoD) is another virulent factor of Mtb which effects macrophage, but its role is still unclear. To investigate its impact on macrophage another bacterial ChoD from Nocardia erythropolis is used, which is 70% similar to Mtb enzyme [10]. ChoD is known to function in both pathogenic and non-pathogenic forms of bacteria but in a different way, as in non-pathogenic bacteria it is used to degrade cholesterol and in pathogenic bacteria it is used to alter the membranous structure and infect the host [11].…”

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“…ChoD, a cholesterol oxidase, also binds TLR2 and participates in immune responses. ChoD activates the MAPK pathway and stimulates the production of IL-10 [115]. Rv0577 can drive DC maturation and pro-inflammatory cytokine expression by activating MAPK and NF-κB pathways in a TLR2-dependent manner.…”