Defining mechanisms of tissue destruction in tuberculosis-HIV co-infection and tuberculosis immune reconstitution inflammatory syndrome

Abstract

Tuberculosis (TB) is the leading cause of death in HIV-infected patients. The paradoxical TB-immune reconstitution inflammatory syndrome (TB-IRIS) complicates antiretroviral therapy (ART). Matrix metalloproteinases (MMPs) are implicated in TB immunopathology, causing pulmonary matrix degradation. I explored the hypothesis that MMPs drive immunopathology in TB-HIV co- infection. I also investigated invariant Natural Killer T (iNKT) cells, cytotoxic T cells with innate immune functions. In a cross-sectional study in Cape Town, South Africa, HIV-infected and uninfected TB patients were compared to respiratory symptomatic and healthy controls. In a longitudinal study of HIV-infected ART naïve TB patients from TB diagnosis, for the first 3 months of ART, patients who developed TB-IRIS were compared with those who did not. Clinical features of disease severity were recorded, induced sputum and plasma collected for MMP and cytokine quantification by multiplex, and plasma for procollagen III N-terminal propeptide (PIIINP) quantification. Peripheral blood iNKT cells were enumerated by flow cytometry, using CD1d tetramers. In the cross-sectional study, 227 patients were enrolled. TB and TB-HIV co- infection were associated with elevated sputum MMP-1, -3, and -8. MMP-1 was 33-fold higher in HIV-uninfected and 4-fold higher in HIV-infected TB patients, than corresponding controls. MMP-1 correlated with radiographic inflammation. Plasma PIIINP was increased in TB and TB-HIV co-infection and correlated with sputum MMPs and radiographic inflammation.

In the longitudinal study, 49 HIV-infected TB patients were enrolled and followed up. 29 (59%) developed TB-IRIS. In TB-IRIS, sputum MMP-7 and MMP- 10 were elevated, prior to and during ART, in addition to plasma MMP-1, -3, and -8 and PIIINP. TB and HIV infection were associated with reduced iNKT cell frequencies. In TB-IRIS iNKT cell frequencies were elevated compared to non- IRIS controls. Elevated MMP activity in TB-HIV co-infection is a novel target for host-directed therapy. INKT cells may have a pathological or protective role in TB immunopathology. Further study is required.