Abstract
Human adenoviruses (HAdVs) are nonenveloped proteinaceous particles containing a linear double-stranded DNA genome. HAdVs cause a spectrum of pathologies in all populations regardless of health standards. Following repeat exposure to multiple HAdV types, we develop robust and long-lived humoral and cellular immune responses that provide life-long protection from de novo infections and persistent HAdV. How HAdVs, anti-HAdV antibodies and antigen presenting cells (APCs) interact to influence infection is still incompletely understood. In our study, we used physical, pharmacological, biochemical, fluorescence and electron microscopy, molecular and cell biology approaches to dissect the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs). We show that IC-HAdV generate stabilized complexes of ~200 nm that are efficiently internalized by, and aggregate in, MoDCs. By comparing IC-HAdV, IC-empty capsid, IC-Ad2ts1 (a HAdV-C2 impaired in endosomal escape due to a mutation that impacts protease encapsidation) and IC-AdL40Q (a HAdV-C5 impaired in endosomal escape due to a mutation in protein VI), we demonstrate that protein VI-dependent endosomal escape is required for the HAdV genome to engage the DNA pattern recognition receptor AIM2 (absent in melanoma 2). AIM2 engagement induces pyroptotic MoDC death via ASC (apoptosis-associated speck protein containing a caspase activation/recruitment domain) aggregation, inflammasome formation, caspase 1 activation, and IL-1β and gasdermin D (GSDMD) cleavage. Our study provides mechanistic insight into how humoral immunity initiates an innate immune response to HAdV-C5 in human professional APCs.
Highlights
Adenoviruses (AdVs) have a 28–42 kilobase pair double-stranded DNA genome encapsidated in a nonenveloped proteinaceous icosahedral shell
In addition to the impact of human AdVs (HAdVs) infections on healthy and immune suppressed hosts, humoral immunity hampers the use of human adenovirus vectors during gene transfer
Our study shows that anti-adenovirus humoral immunity engages an innate immune response to cause pyroptosis of antigen-presenting cells
Summary
Adenoviruses (AdVs) have a 28–42 kilobase pair double-stranded DNA genome encapsidated in a nonenveloped proteinaceous icosahedral shell. In immune-competent individuals, human AdVs (HAdVs) (of which there are approximately 70 types) cause self-limiting respiratory, ocular and gastro-intestinal tract infections. We typically develop multifaceted long-lived memory immune responses [1,2,3] that efficiently blunt HAdV-induced disease. In spite of the robust cross-reacting cellular and humoral immune responses, HAdVs can establish subclinical persistent infections that last for years, if not decades [4,5]. HAdV type-specific humoral immunity before hematopoietic stem cell transplantation is predictive of escape of the same type during immune suppression [6]. In B-cell competent/T-cell compromised patients, the loss of control of persistent HAdV infection might trigger, or exacerbate, graft-versus host disease [10,11,12]. How IC-HAdVs are processed and affect DC function are unknown
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