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Frängsmyr, Lars
Publications (10 of 31) Show all publications
Becker, M., Conca, D. V., Dorma, N., Mistry, N., Hahlin, E., Frängsmyr, L., . . . Gerold, G. (2023). Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells. Journal of Virology, 97(10)
Open this publication in new window or tab >>Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells
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2023 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 97, no 10Article in journal (Refereed) Published
Abstract [en]

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. EAdVs have a unique capsid architecture and exhibit — unlike other human adenoviruses — a relatively strict tropism for gastrointestinal tissues with, to date, understudied infection mechanism and unknown target cells. In this study, we turn to potentially limiting host factors by comparing EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking, and transmission electron microscopy. Our analyses highlight kinetic advantages for EAdVs in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake, and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understanding pathogenesis and developing new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a cell line originating from a relevant tissue. IMPORTANCE Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.

Keywords
clathrin-mediated endocytosis, electron microscopy, enteric adenovirus, single particle tracking, virus entry
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-216662 (URN)10.1128/jvi.00770-23 (DOI)37823645 (PubMedID)2-s2.0-85175844402 (Scopus ID)
Funder
Swedish Research Council, 2020-06242Swedish Research Council, 2019-01472Knut and Alice Wallenberg FoundationKnut and Alice Wallenberg Foundation
Available from: 2023-11-27 Created: 2023-11-27 Last updated: 2023-11-28Bibliographically approved
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
Rosendal, E., Mihai, I. S., Becker, M., Das, D., Frängsmyr, L., Persson, B. D., . . . Lenman, A. (2022). Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections. mBio, 13(3), Article ID e00892-22.
Open this publication in new window or tab >>Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections
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2022 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed) Published
Abstract [en]

The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

Place, publisher, year, edition, pages
American Society for Microbiology, 2022
Keywords
A1AT, alpha-1-antitrypsin, antithrombin III, ATIII, COVID-19, PAI1, plasminogen activator inhibitor 1, SARS-CoV-2, serpin, TMPRSS2
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-203186 (URN)10.1128/mbio.00892-22 (DOI)000797888900001 ()35532162 (PubMedID)2-s2.0-85133144334 (Scopus ID)
Funder
Science for Life Laboratory, SciLifeLabSwedish National Infrastructure for Computing (SNIC), SNIC 2020/6-251Swedish Heart Lung Foundation, 2020038Knut and Alice Wallenberg Foundation, 2020.0182Knut and Alice Wallenberg Foundation, C19R:028Swedish Society for Medical Research (SSMF)The Kempe Foundations, JCK-1827Swedish Research Council, 2016-06598
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-07-03Bibliographically approved
Rajan, A., Palm, E., Trulsson, F., Mundigl, S., Becker, M., Persson, D., . . . Lenman, A. (2021). Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses. Viruses, 13(2), Article ID 298.
Open this publication in new window or tab >>Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses
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2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 2, article id 298Article in journal (Refereed) Published
Abstract [en]

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins-a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
capsid proteins, enteric adenovirus, fiber knobs, heparan sulfate, short fibers
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-181795 (URN)10.3390/v13020298 (DOI)000623302300001 ()2-s2.0-85102606288 (Scopus ID)
Available from: 2021-04-01 Created: 2021-04-01 Last updated: 2024-01-17Bibliographically approved
Ballmann, M. Z., Raus, S., Engelhart, R., Kaján, G. L., Beqqali, A., Hadoke, P. W. .., . . . Baker, A. H. (2021). Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development. Journal of Virology, 95(22), Article ID e00387-21.
Open this publication in new window or tab >>Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development
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2021 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 95, no 22, article id e00387-21Article in journal (Refereed) Published
Abstract [en]

Preexisting immune responses toward adenoviral vectors limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest in vectorizing novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full-genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton base, which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor-binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver, and spleen and triggered robust inflammatory immune responses. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination.

Place, publisher, year, edition, pages
American Society for Microbiology, 2021
Keywords
Cell and tissue transduction, Expression vector, Low seroprevalence, Novel adenovirus serotype, Potent T-cell responses
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-189474 (URN)10.1128/JVI.00387-21 (DOI)000718339200005 ()34469243 (PubMedID)2-s2.0-85118238152 (Scopus ID)
Funder
EU, Horizon 2020, 825670EU, FP7, Seventh Framework Programme, 324325
Available from: 2021-11-16 Created: 2021-11-16 Last updated: 2023-09-05Bibliographically approved
Persson, B. D., Lijo, J., Rafie, K., Strebl, M., Frängsmyr, L., Ballmann, M. Z., . . . Arnberg, N. (2021). Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46. Proceedings of the National Academy of Sciences of the United States of America, 118(3), Article ID e2020732118.
Open this publication in new window or tab >>Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 3, article id e2020732118Article in journal (Refereed) Published
Abstract [en]

Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.

Place, publisher, year, edition, pages
National Academy of Sciences, 2021
Keywords
adenovirus, hexon, CD46, receptor, vaccine
National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-180646 (URN)10.1073/pnas.2020732118 (DOI)000609633900068 ()33384338 (PubMedID)2-s2.0-85099119953 (Scopus ID)
Available from: 2021-02-24 Created: 2021-02-24 Last updated: 2021-02-24Bibliographically approved
Persson, D., Lenman, A., Frängsmyr, L., Schmid, M., Ahlm, C., Plückthun, A., . . . Arnberg, N. (2020). Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells. Journal of Virology, 94(14), Article ID e00542-20.
Open this publication in new window or tab >>Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells
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2020 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 94, no 14, article id e00542-20Article in journal (Refereed) Published
Abstract [en]

Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses—and other viruses that engage cell adhesion molecules—enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin—a common innate immune component secreted to respiratory mucosa—for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.

IMPORTANCE: Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell—apical or lateral/basolateral—is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.

Place, publisher, year, edition, pages
American Society for Microbiology, 2020
Keywords
adenovirus, CAR, cellular receptor, lactoferrin, tropism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-173890 (URN)10.1128/JVI.00542-20 (DOI)000550190300011 ()32376620 (PubMedID)2-s2.0-85087533884 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2020-08-06 Created: 2020-08-06 Last updated: 2023-03-24Bibliographically approved
Johansson, E., Caraballo, R., Mistry, N., Zocher, G., Qian, W., Andersson, C. D., . . . Elofsson, M. (2020). Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections. ACS Chemical Biology, 15(10), 2683-2691
Open this publication in new window or tab >>Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections
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2020 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 15, no 10, p. 2683-2691Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-176796 (URN)10.1021/acschembio.0c00446 (DOI)000582580100008 ()32845119 (PubMedID)2-s2.0-85093538705 (Scopus ID)
Available from: 2020-11-24 Created: 2020-11-24 Last updated: 2023-03-24Bibliographically approved
Chandra, N., Frängsmyr, L. & Arnberg, N. (2019). Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus. Viruses, 11(3), Article ID E242.
Open this publication in new window or tab >>Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus
2019 (English)In: Viruses, E-ISSN 1999-4915, Vol. 11, no 3, article id E242Article in journal (Refereed) Published
Abstract [en]

Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
GAG-mimetic, adenovirus, cellular receptor, decoy receptor, epidemic keratoconjunctivitis, glycosaminoglycans
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-158516 (URN)10.3390/v11030242 (DOI)000464389700002 ()30870979 (PubMedID)2-s2.0-85062983171 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2013.0019
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2024-01-17Bibliographically approved
Chandra, N., Frängsmyr, L., Imhof, S., Caraballo, R., Elofsson, M. & Arnberg, N. (2019). Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment. Viruses, 11(5), Article ID 395.
Open this publication in new window or tab >>Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment
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2019 (English)In: Viruses, E-ISSN 1999-4915, Vol. 11, no 5, article id 395Article in journal (Refereed) Published
Abstract [en]

Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
adenovirus, cellular receptor, epidemic keratoconjunctivitis, pharyngoconjunctival fever, sialic acid, tropism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-159268 (URN)10.3390/v11050395 (DOI)000472676600006 ()31035532 (PubMedID)2-s2.0-85065483937 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2019-05-23 Created: 2019-05-23 Last updated: 2024-01-17Bibliographically approved
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