Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells.

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Human adenoviruses (HAdVs) cause diverse pathologies, and while immunity develops, the interaction between HAdVs, antibodies, and antigen-presenting cells (APCs) is not fully understood.
• Understanding these interactions is crucial for developing effective immune responses against HAdV infections.

Purpose of the Study:

• To investigate the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs).
• To elucidate the mechanisms by which IC-HAdV influences innate immune responses in APCs.

Main Methods:

• Utilized a multidisciplinary approach including microscopy, biochemical assays, and molecular/cell biology techniques.
• Compared the effects of IC-HAdV with control complexes (empty capsid, mutated HAdVs) on MoDCs.
• Assessed viral genome engagement with DNA pattern recognition receptors and downstream inflammasome activation.

Main Results:

• IC-HAdV formed stable ~200 nm complexes efficiently internalized by MoDCs.
• Protein VI-dependent endosomal escape was essential for HAdV genome to activate the AIM2 receptor.
• AIM2 activation led to ASC aggregation, inflammasome formation, caspase 1 activation, and pyroptotic MoDC death (IL-1β and GSDMD cleavage).

Conclusions:

• Humoral immunity, through IC-HAdV formation, initiates a potent innate immune response in human APCs.
• This pathway involves AIM2 inflammasome activation and pyroptotic cell death, providing a novel mechanism of HAdV control.
• The findings offer mechanistic insights into the interplay between adaptive and innate immunity against HAdV-C5.