Title | Unabated adenovirus replication following activation of the cGAS/STING-dependent antiviral response in human cells. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Lam E, Falck-Pedersen E |
Journal | J Virol |
Volume | 88 |
Issue | 24 |
Pagination | 14426-39 |
Date Published | 2014 Dec |
ISSN | 1098-5514 |
Keywords | Adenoviruses, Human, Cell Line, Host-Pathogen Interactions, Humans, Interferon Regulatory Factor-3, Membrane Proteins, Nucleotidyltransferases, Protein-Serine-Threonine Kinases, Virus Replication |
Abstract | UNLABELLED: The cGAS/STING DNA sensing complex has recently been established as a predominant pathogen recognition receptor (PRR) for DNA-directed type I interferon (IFN) innate immune activation. Using replication-defective adenovirus vectors and replication-competent wild-type adenovirus, we have modeled the influence of the cGAS/STING cascade in permissive human cell lines (A549, HeLa, ARPE19, and THP1). Wild-type adenovirus induced efficient early activation of the cGAS/STING cascade in a cell-specific manner. In all responsive cell lines, cGAS/STING short hairpin RNA (shRNA) knockdown resulted in a loss of TBK1 and interferon response factor 3 (IRF3) activation, a lack of beta interferon transcript induction, loss of interferon-dependent STAT1 activation, and diminished induction of interferon-stimulated genes (ISGs). Adenoviruses that infect through the coxsackievirus-adenovirus receptor (CAR) (Ad2 and Ad5) and the CD46 (Ad35) and desmoglein-2 (Ad7) viral receptors all induce the cGAS/STING/TBK1/IRF3 cascade. The magnitude of the IRF3/IFN/ISG antiviral response was strongly influenced by serotype, with Ad35>Ad7>Ad2. For each serotype, no enhancement of viral DNA replication or virus production occurred in cGAS or STING shRNA-targeted cell line pools. We found no replication advantage in permissive cell lines that do not trigger the cGAS/STING cascade following infection. The cGAS/STING/TBK1/IRF3 cascade was not a direct target of viral antihost strategies, and we found no evidence that Ad stimulation of the cGAS/STING DNA response had an impact on viral replication efficiency. IMPORTANCE: This study shows for the first time that the cGAS DNA sensor directs a dominant IRF3/IFN/ISG antiviral response to adenovirus in human cell lines. Activation of cGAS occurs with viruses that infect through different high-affinity receptors (CAR, CD46, and desmoglein-2), and the magnitude of the cGAS/STING DNA response cascade is influenced by serotype-specific functions. Furthermore, activation of the cGAS cascade occurred in a cell-specific manner. Activation of the cGAS/STING response did not impact viral replication, and viral immune evasion strategies did not target the cGAS/STING/TBK1/IRF3 cascade. These studies provide novel insight into the early innate recognition response to adenovirus. |
DOI | 10.1128/JVI.02608-14 |
Alternate Journal | J Virol |
PubMed ID | 25297994 |
PubMed Central ID | PMC4249147 |
Grant List | R01 AI094050 / AI / NIAID NIH HHS / United States CCSG CA020374 / CA / NCI NIH HHS / United States |
Submitted by wcm_microbiolog... on October 14, 2020 - 4:54pm