An Fc receptor and IgA functional signature identifies TB disease in children living with HIV

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Background Tuberculosis (TB) is a leading cause of morbidity and mortality among children living with HIV (CLHIV). Poor diagnostic performance is a significant contributor. Serological assays that determine levels of Mycobacterium tuberculosis reactive antibodies inconsistently detect TB. However, antigen-specific antibody Fc receptor engagement and effector functions are promising biomarkers of TB disease. Methods This study evaluated serum from a well-characterized cohort of Kenyan CLHIV via two orthogonal approaches: 1) longitudinally following over the course of TB treatment and 2) assessing a cross-section with and without clinical TB disease. For each individual sample, 13 antibody functional properties against 8 Mtb and 4 non- Mtb microbial antigens were measured and analyzed via univariate and multivariate machine-learning approaches. Findings FcαR/CD89 immune complex formation with antibodies reactive to four Mtb antigens including ESAT-6 & CFP-10, FcψRI/CD64 associated with one Mtb antigen, and HIV gp120 IgA1 levels decreased during the intensive and continuation/consolidation phases of TB therapy. This antibody signature also highlighted treatment non-responsiveness and distinguished children with from those without TB disease with predictive capacity similar to Xpert. Interpretation An Mtb and HIV reactive peripheral blood antibody functional signature of FcαR/CD89, FcψRI/CD64, and IgA1 has the potential to complement current clinical tools and those in development to diagnose pulmonary TB disease in CLHIV. Funding This work is supported by UT Southwestern Disease Oriented Scholars Award (LLL), NIAID 5R01AI158858 (LLL), Burroughs-Wellcome Fund UTSW Training Resident Doctors as Innovators in Science (YJK), NICHD K12HD000850, NIAID K23AI143479 and R21AI192086 (LMC), NICHD R01 HD023412 (GJS), NIAID 75N93019C00071 (CW).