Inflammasome-associated immune dysregulation in TB-HIV coinfection

Tuberculosis (TB) and HIV co-infection are characterized by dysregulated inflammation and increased risk of immune reconstitution inflammatory syndrome (IRIS) following antiretroviral therapy (ART) initiation. Inflammasomes are key regulators of innate immune responses, but their role in TB-HIV co-infection and IRIS remains incompletely understood. We investigated inflammasome-related gene expression and cytokine profiles in TB, HIV-1, and TB-HIV individuals, and their association with IRIS development.

Fifty-nine participants were stratified into four groups: TB-HIV (n = 20; 4 with IRIS), HIV-1 (n = 12), TB (n = 17), and healthy controls (n = 10). These individuals were followed up at HGNI and INI-Fiocruz (Rio de Janeiro/Brazil) from 2014 to 2016. Whole-blood PAXgene expression of inflammasome-related genes (AIM2, CASP1, GSDMD, IL1β, IL18, and NLRP3) was quantified using TaqMan RT-qPCR. Plasma levels of IL-1β, IL-18, IL-33, and IL-6 were measured by ELISA. Associations were evaluated using multivariable linearregression and partial Pearson correlation analyses.

TB-HIV co-infected individuals showed significantly higher expression of AIM2, CASP1, GSDMD, IL1β, and IL18 compared to all other groups (all P < 0.01), while NLRP3 expression remained unchanged. Elevated plasma levels of IL-6, IL-18, and IL-33 further supported a systemic inflammatory profile in the TB-HIV co-infection group. Strong positive correlations were observed among AIM2, CASP1, GSDMD, IL1β, and IL18 gene expressions at baseline (r= 0.853-0.965), and, to a lesser extent, among them and IL-6 and IL-18 cytokines (r= 0.440-0.645), indicating a coordinated inflammasome-related transcriptional profile, whereas NLRP3 showed no or weak associations. Longitudinal analysis revealed significant reductions in AIM2, CASP1, GSDMD, IL18, and IL1B expression from baseline to week 2, after two weeks of anti-TB therapy and before ART initiation, and from baseline to week 6, after six weeks of anti-TB therapy and four weeks of ART (all P < 0.05).

TB-HIV coinfection was characterized by distinct inflammasome-related transcriptional and inflammatory profiles, highlighting AIM2 as a potential pathway for further investigation. Our findings indicate that TB-HIV coinfection is associated with a coordinated inflammasome-related transcriptional and cytokine profile, characterized by increased expression of AIM2 and downstream effector genes, without detectable changes in NLRP3 transcript abundance.