Complement-driven inflammasome activation on circulating blood monocytes in immune reconstitution inflammatory syndrome in TB-HIV coinfected patients

Abstract

Abstract Inflammasome and complement pathways have been independently implicated in the pathogenesis of Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS), a clinical complication affecting individuals initiating antiretroviral therapy (ART). Here we sought to investigate whether dysregulated complement contributes to inflammasome activation during TB-IRIS. Caspase-1+ specks are cytosolic inflammasome aggregates responsible for IL-1β and IL-18 release. We detected higher numbers of monocytes with spontaneous caspase-1+ specks in IRIS patients (n=9, baseline median CD4 count= 46 cells/mL and VL= 606,754 copies/mL) in comparison with TB infected, non-IRIS controls (n=7, baseline median CD4 count= 47 cells/mL and VL= 85,831 copies/mL) at IRIS time-point (p<0.05). Patients experiencing IRIS also showed elevated C1q and C3 deposition on monocytes, followed by increased levels of the membrane attack complex (MAC) molecule, C9 (p<0.01). Levels of membrane-bound C9 (r= 0.69, p<0.05), and the cell-associated MAC inhibitor, CD59 (r = 0.6 p <0.05), correlated with IL-18 plasma levels and were associated with caspase-1 activation on patients-derived monocytes (r= 0.85, p<0.001 and r= 0.97, p<0.001, respectively to C9 and CD59), supporting a role for sublytic MAC-driven membrane pore formation in inflammasome activation on patient cells. Because the expression level of CD59 strongly correlated with caspase-1 activation within the CD14high monocyte subsets, our data suggest that those cells were able to prevent full MAC deposition, therefore undergoing sublytic MAC-driven inflammasome activation. This data may help identify new targets for prevention or treatment of TB-IRIS inflammatory syndrome.