Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor

Stichling, Nicole; Suomalainen, Maarit; Flatt, Justin W.; Schmid, Markus; Pačesa, Martin; Hemmi, Silvio; Jungraithmayr, Wolfgang; Maler, Mareike D.; Freudenberg, Marina A.; Plückthun, Andreas; May, Tobias; Köster, Mario; Fejér, György; Greber, Urs F.

doi:10.1371/journal.ppat.1006914

Cited by 63 publications

(68 citation statements)

References 99 publications

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“…Analysis of mouse spleen sections at 30 min after intravenous administration of HAdv-C5 and staining with antibodies specific for the virus and defined macrophage markers revealed that shortly after intravenous delivery, HAdv particles predominantly accumulate in two distinct populations of macrophages in the splenic marginal zone, with one population expressing CD169 (MOMA-2) and the other macrophage scavenger receptor MARCO (SR-A6 [38]). It has also been shown that deletion of the hexon HVR1 loop in HAdv-C5 was sufficient to abrogate virus binding and transduction of alveolar macrophages and that MARCO can mediate entry into macrophages for Ad of species B and D (HAdv-B35 and HAdv-D26, respectively) [53]. However, it appears that when HAdv interaction with hepatic cells is reduced via pharmacological conditioning or through ablation of interactions with blood factors by introducing mutations to the virus capsid [12,51], the accumulation of HAdv in the spleen is significantly increased [51].…”

Section: Mechanisms Of Hadv Sequestration In Tissue Macrophagesmentioning

confidence: 99%

“…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 has also been shown that deletion of the hexon HVR1 loop in HAdv-C5 was sufficient to abrogate virus binding and transduction of alveolar macrophages and that MARCO can mediate entry into macrophages for Ad of species B and D (HAdv-B35 and HAdv-D26, respectively) [53]. Therefore, in the context of intravenous administration of high doses of coagulation FX-binding-ablated viruses, upon passing through the splenic marginal zone, the virus particles can directly bind to scavenger receptor MARCO on the surface of macrophages.…”

Section: Mechanisms Of Hadv Sequestration In Tissue Macrophagesmentioning

confidence: 99%

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Innate immunity to adenovirus: lessons from mice

2019

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Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.Human adenovirus (HAdv) is remarkably efficient at infecting and replicating in human cells. These properties made HAdv-based vectors an attractive platform for developing novel therapeutics to combat genetic diseases and cancer. Unfortunately, early studies revealed that HAdv is a potent activator of the innate and adaptive arms of the immune system, and administration to animals or patients of high doses of HAdv-based vectors, especially via an intravascular route, leads to severe immunopathology, manifested by cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which may lead to morbidity and even mortality. To harness the full potential of HAdv as a gene delivery or oncolytic virus platform, a complete understanding of the molecular and cellular components of innate Abbreviations is a founder, shareholder, and chief scientific officer of AdCure Bio, LLC, which develops Ad-based therapies for clinical use.

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Section: Mechanisms Of Hadv Sequestration In Tissue Macrophagesmentioning

confidence: 99%

Section: Mechanisms Of Hadv Sequestration In Tissue Macrophagesmentioning

confidence: 99%

Innate immunity to adenovirus: lessons from mice

2019

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“…In the same study, the combination of an anti-CD46 antibody and cyclic-RGD peptides on patient myeloma cells mediated complete protection against killing by HAdV26, suggesting that both receptors, CD46 and ␣v integrins, are utilized by the virus to infect these target cells (27). Finally, very recently, the scavenger receptor SR-A6 has been implicated in facilitating HAdV26 entry into murine alveolar-macrophage-like MPI cells (28). HAdV26 receptor usage has also been investigated for peripheral blood mononuclear cells (25) or malignant B cells (27), while HAdV26 receptor usage in epithelial cells is less well defined.…”

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confidence: 91%

αvβ3 Integrin Is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26

Nestić

Uil

et al. 2019

J Virol

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Human adenoviruses (HAdVs) are being explored as vectors for gene transfer and vaccination. Human adenovirus type 26 (HAdV26), which belongs to the largest subgroup of adenoviruses, species D, has a short fiber and a so-far-unknown natural tropism. Due to its low seroprevalence, HAdV26 has been considered a promising vector for the development of vaccines. Despite the fact that thein vivosafety and immunogenicity of HAdV26 have been extensively studied, the basic biology of the virus with regard to receptor use, cell attachment, internalization, and intracellular trafficking is poorly understood. In this work, we investigated the roles of the coxsackievirus and adenovirus receptor (CAR), CD46, and αv integrins in HAdV26 infection of human epithelial cell lines. By performing different gain- and loss-of-function studies, we found that αvβ3 integrin is required for efficient infection of epithelial cells by HAdV26, while CAR and CD46 did not increase the transduction efficiency of HAdV26. By studying intracellular trafficking of fluorescently labeled HAdV26 in A549 cells and A549-derived cell clones with stably increased expression of αvβ3 integrin, we observed that HAdV26 colocalizes with αvβ3 integrin and that increased αvβ3 integrin enhances internalization of HAdV26. Thus, we conclude that HAdV26 uses αvβ3 integrin as a receptor for infecting epithelial cells. These results give us new insight into the HAdV26 infection pathway and will be helpful in further defining HAdV-based vector manufacturing and vaccination strategies.IMPORTANCEAdenovirus-based vectors are used today for gene transfer and vaccination. HAdV26 has emerged as a promising candidate vector for development of vaccines due to its relatively low seroprevalence and its ability to induce potent immune responses against inserted transgenes. However, data regarding the basic biology of the virus, like receptor usage or intracellular trafficking, are limited. In this work, we found that efficient infection of human epithelial cell lines by HAdV26 requires the expression of the αvβ3 integrin. By studying intracellular trafficking of fluorescently labeled HAdV26 in a cell clone with stably increased expression of αvβ3 integrin, we observed that HAdV26 colocalizes with αvβ3 integrin and confirmed that αvβ3 integrin expression facilitates efficient HAdV26 internalization. These results will allow further improvement of HAdV26-based vectors for gene transfer and vaccination.

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“…Studies with AdV show further cell-to-cell heterogeneity, namely in virion binding to the cells [20], endosomal and cytoplasmic trafficking [21,22], and virion uncoating [23 -28]. Single-cell, single-particle analyses show that different steps of entry occur 5 with different efficiencies in individual infected cells and thus the number of vDNAs delivered into the nucleus varies between cells [21,25,27].…”

Section: Introductionmentioning

confidence: 99%

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

Suomalainen

Prasad

Kannan

et al. 2020

Preprint

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These authors contributed equally to this work. Abstract In clonal cultures, not all cells are equally susceptible to virus infection. Underlying mechanisms of infection variability are poorly understood. Here, we developed imagebased single cell measurements to scrutinize the heterogeneity of adenovirus (AdV) infection. AdV delivers, transcribes and replicates a linear double-stranded DNA genome in the nucleus. We measured the abundance of viral transcripts by singlemolecule RNA fluorescence in situ hybridization (FISH), and the incoming ethynyldeoxy-cytidine (EdC)-tagged viral genome by copper(I)-catalyzed azide-alkyne cycloaddition (click) reaction. The early transcripts increased from 2-12 hours, the late ones from 12-23 hours post infection (pi), indicating distinct accumulation kinetics. Surprisingly, the expression of the immediate early transactivator gene E1A only moderately correlated with the number of viral genomes in the cell nucleus, although the incoming viral DNA remained largely intact until 7 hours pi. Genome-to-genome heterogeneity was found at the level of viral transcription, as indicated by colocalization with the large intron containing early region E4 transcripts, uncorrelated to the multiplicity of incoming genomes in the nucleus. In accordance, individual genomes exhibited heterogeneous replication activity, as shown by single-strand DNA-FISH and immunocytochemistry. These results indicate that the variability in viral gene expression and replication are not due to defective genomes but due to host cell heterogeneity. By analyzing the cell cycle state, we found that G1 cells exhibited the highest E1A expression, and significantly increased the correlation between E1A expression and viral genome copy numbers. This combined imagebased single molecule procedure is ideally suited to explore the cell-to-cell variability in viral infection, including transcriptional activators and repressors, RNA splicing mechanisms, and the impact of the 3-dimensional nuclear topology on gene regulation. 3 Author SummaryAdenoviruses (AdV) are ubiquitous pathogens in vertebrates. They persist in infected people, and cause unpredictable outbreaks, morbidity and mortality across the globe.Here we report that the common human AdV type C5 (AdV-C5) gives rise to considerable infection variability at the level of single cells in culture, and that a major underlying reason is the cell-to-cell heterogeneity. By combining sensitive single molecule in situ technology for detecting the incoming viral DNA and newly synthesized viral transcripts we show that viral gene expression is heterogeneous between infected human cells, as well as individual genomes. We report a moderate correlation between the number of viral genomes in the nucleus and immediate early E1A transcripts. This correlation is increased in the G1 phase of the cell cycle, where the E1A transcripts were found to be more abundant than in any other cell cycle phase. Our results demonstrate the importance of cell-to-cell variability measurements for understand...

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Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor

Cited by 63 publications

References 99 publications

Innate immunity to adenovirus: lessons from mice

Innate immunity to adenovirus: lessons from mice

αvβ3 Integrin Is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26

Cell-to-cell and genome-to-genome variability of Adenovirus transcription tuned by the cell cycle

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