Key Role of the Scavenger Receptor MARCO in Mediating Adenovirus Infection and Subsequent Innate Responses of Macrophages

Abstract

The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses in vivo. Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.

Innate immunity to adenovirus: lessons from mice

“…This is somewhat surprising, as several unique populations of macrophages and DCs reside in the splenic marginal zone, and virus interaction with these cells plays a key role in activating deleterious systemic inflammatory responses that limit the clinical utility of HAdv-based vectors (discussed below). Recent studies by Maler et al [52] demonstrated that mouse alveolar macrophages are readily transduced in vitro by HAdv-C5 via interaction with MARCO. It is unclear whether HAdv-C5 is sequestered in these cells through the mechanism of a direct virus binding to macrophage cell-surface receptors or via an indirect 'bridging' by the blood factors.…”

Impact of Historic Migrations and Evolutionary Processes on Human Immunity

“…The trend towards lower inflammatory responses in European populations is strengthened by the fixation of a TLR1 gene variant that results in lower proinflammatory gene expression in populations with a European ancestry compared with those with an African one [33]. The largest population differences in gene expression between Africans and Europeans have been found in the macrophage receptor with collagenous structure (MARCO), a protein implicated in responses against viral infections and TLR-induced dendritic cell activation [34], the chemokine receptor CX3CR1, which mediates effector lymphocyte functions, and also several IFN-stimulated genes [35]. West Eurasian populations present a high frequency of TIRAP Ser180Leu SNPs [36].…”

Glycomics and Proteomics Approaches to Investigate Early Adenovirus–Host Cell Interactions

“…In addition, Piccolo et al [99,100] demonstrated that helper-dependent adenoviral vectors interact with SR-A and SR expressed on endothelial cells in vitro and in vivo. Moreover, the SR MARCO was shown to facilitate AdV infection of murine alveolar macrophages [101].…”