Exploring the Molecular Intersection of Posterior Ocular Tuberculosis: Mycobacterium tuberculosis Proteins, Ocular Autoimmunity, and Immune Receptor Interactions

Abstract

Purpose

The presentation of posterior ocular tuberculosis (TB) varies greatly along with the need for immunomodulatory therapy to control inflammation. In this study, we explore the potential mechanisms and pathways for autoimmune-related inflammation in ocular TB using molecular mimicry-based mathematical modeling.

Design

Computational protein analysis.

Methods

Twenty-three TB-related proteins, including ESAT-6 subgroup proteins, and 23 retinal ganglion cells, photoreceptor, and retinal pigment epithelium (RPE) cellular proteins were included in this study. The 3-dimensional structure and sequence of the TB AG proteins were compared to the above-mentioned retinal, photoreceptor, and RPE cellular proteins. All retinal proteins were obtained from the UniProt database. The sequence and 3-dimensional structure of TB-related proteins and retinal proteins were compared with the TM-align server. The interactions of proteins showing significant similarity (template modeling score above 0.5, root mean square deviation [RMSD] value below 5A°) with cytokines (interleukin [IL]6, IL10, IL12A, IL12B, TLR2, TLR3, and TLR4) were analyzed. Autoimmune and autoinflammation-related protein–receptor interaction of similar proteins was assessed using the CABS-dock web server.

Main Outcome Measures

Template modeling score, structural alignment accuracy using RMSD value, protein–cytokine interaction.

Results

We detected a high level of structural similarity between ESAT-6 (EsxA, EsxB) proteins and rhodopsin, HSPA1A, RPE-related BEST-1, ABCC-1, ABCC-4, ABCC-5, SLC47A1, SLC1A5, SLC38A7, SLC6A6, SLC5A6, LAT-1, and SLC16A1 proteins. When we evaluated the likelihood/potential to stimulate an immune response via a cytokine release, TLR-2 (most common), TLR-3, and TLR-4, which are highly susceptible to Mycobacterium tuberculosis ESAT-6 (ESXA and ESXB) proteins, showed a potential receptor–protein interaction with retinal proteins. Moreover, some eye-related proteins had the capacity to trigger the T-cell response by binding to cytokines such as IL-12, IL-10, and IL-6, which are all highly overexpressed in TB infections.

Conclusions

Our study demonstrates that TB proteins may have significant structural similarities with many eye-related proteins. These eye-related proteins are therefore immunological target sites and may be secondarily affected by any immune response toward TB.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.