Inflammasome activation underlies central nervous system deterioration in HIV-associated tuberculosis

Abstract

Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis–immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.

Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome: Erratum

“…The gene transcripts that were most abundant in patients with IRIS versus non-IRIS controls, and clearly discriminatory on a PCA plot, were S100A9, IL-10, NLRP12, and COX-1. Increased expression of inflammasome and neutrophilassociated genes in TB-IRIS is consistent with previous results, 12,31 but the lower abundance of TCR-associated genes in patients with TB-IRIS was unexpected and deserves further analysis. This may reflect poor reconstitution of normal T-cell function in TB-IRIS and again supports the concept that the phenomenon is driven by innate inflammation without an orchestrated acquired immune response.…”

The pathogenesis of tuberculous meningitis

“…have also demonstrated that neutrophil abundant transcripts were significantly higher in those who develop IRIS from before ART initiation until the onset of TBM‐IRIS . After initiation of ART a significantly higher number of transcripts associated with canonic and noncanonic inflammasome activation were found in patients who went on to develop IRIS than in those who did not . These observations together with the finding that inflammasome activation can contribute to pyroptosis suggest that tissue injury observed in TBM may be partly induced by inflammasome‐mediated pyroptosis.…”

“…Using longitudinal microarray analysis of blood from patients with HIV and TBM Marais et al. have also demonstrated that neutrophil abundant transcripts were significantly higher in those who develop IRIS from before ART initiation until the onset of TBM‐IRIS . After initiation of ART a significantly higher number of transcripts associated with canonic and noncanonic inflammasome activation were found in patients who went on to develop IRIS than in those who did not .…”

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…It was concluded that MPO may be involved in the oxidative stress associated with BM, as well as potentially contributing to BBB disruption. Marais et al (2016) indicated a significant increase in neutrophil-dependent inflammatory response biomarkers, including MPO, in adult TBM and HIV co-infection patients with paradoxical immune reconstitution inflammatory syndrome. Lastly, Üllen et al (2013) indicated that BBB dysfunction associated with neuroinflammation caused by MPO can be partially reversed by using para-aminobenzoic acid (PABA) hydrazide, first shown by Forghani et al (2012) to effectively treat multiple sclerosis in mice.…”