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S41467 019 10192 2.Pdf ARTICLE https://doi.org/10.1038/s41467-019-10192-2 OPEN The viral protein corona directs viral pathogenesis and amyloid aggregation Kariem Ezzat 1,2, Maria Pernemalm 3, Sandra Pålsson1, Thomas C. Roberts4,5, Peter Järver1, Aleksandra Dondalska1, Burcu Bestas2,18, Michal J. Sobkowiak6, Bettina Levänen7, Magnus Sköld8,9, Elizabeth A. Thompson10, Osama Saher2,11, Otto K. Kari12, Tatu Lajunen 12, Eva Sverremark Ekström 1, Caroline Nilsson13, Yevheniia Ishchenko14, Tarja Malm14, Matthew J.A. Wood4, Ultan F. Power 15, Sergej Masich16, Anders Lindén7,9, Johan K. Sandberg 6, Janne Lehtiö 3, Anna-Lena Spetz 1,19 & Samir EL Andaloussi2,4,17,19 1234567890():,; Artificial nanoparticles accumulate a protein corona layer in biological fluids, which sig- nificantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid β-peptide (Aβ42), a major constituent of amyloid plaques in Alzheimer’s disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral–host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies. 1 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm 10691, Sweden. 2 Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm 14152, Sweden. 3 Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory and Karolinska Institutet, Stockholm 17176, Sweden. 4 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX13PT, UK. 5 Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA. 6 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 14186, Sweden. 7 Unit for Lung and Airway disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17165, Sweden. 8 Respiratory Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden. 9 Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm 17176, Sweden. 10 Immunology and Allergy Unit, and Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden. 11 Faculty of Pharmacy, Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo 11562, Egypt. 12 Drug Research Program, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki 00014, Finland. 13 Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet and Sachs’ Children and Youth Hospital, Stockholm 11883, Sweden. 14 A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland. 15 Centre of Experimental Medicine, Queens’ University Belfast, Belfast BT97BL, UK. 16 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 17177, Sweden. 17 Evox Therapeutics Limited, Oxford Science Park, Oxford OX44HG, UK. 18Present address: Discovery Sciences, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Sweden. 19These authors contributed equally: Anna-Lena Spetz, Samir EL Andaloussi. Correspondence and requests for materials should be addressed to K.E. (email: [email protected]) or to A.-L.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:2331 | https://doi.org/10.1038/s41467-019-10192-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-10192-2 he term “protein corona” refers to the layer of proteins that latency19. Latent HSV-1 is occasionally reactivated causing adhere to the surfaces of nanostructures when they peripheral pathology and under certain circumstances it can T fl encounter biological uids. Nanoparticles adsorb biomo- migrate into the central nervous system causing herpes simplex lecules in biological fluids due to the high free energy of their encephalitis, the most common cause of sporadic fatal viral surfaces1. The importance of the corona layer stems from the fact encephalitis19. In the context of the current work, we focused that it constitutes the actual surface of interaction with biological on the presumptive role of HSV-1 in the pathology of AD. A membranes or “what the cell sees” in the in-vivo context2. number of risk factors have been associated with AD, including Hundreds of proteins have been identified to confer a distinct the E4 allele of the apolipoprotein E (Apo-E), diabetes, vascular biological identity of nanoparticles in different microenviron- pathology, neuroinflammation, and infections20. Several recent ments depending on their size, chemistry, and surface modifica- studies have supported the theory of a significant role of HSV-1 tion (recently reviewed in ref. 3). These factors were found to be in the disease21. HSV-1 DNA was found to be localized within critical determinants of the biodistribution and pharmacody- amyloid plaques in AD patients and HSV-1 infection has been namics of nanoparticles. On the other hand, the ability of the shown to promote neurotoxic Aβ accumulationinhuman surfaces of nanoparticles to partially denature certain corona neural cells and to the formation of Aβ deposits in the brains of proteins exposing “cryptic epitopes” highlights the role of the infected mice22,23. Moreover, the presence of anti-HSV IgM protein corona in the toxicology of nanoparticles4–6. The for- antibodies, which indicate HSV reactivation, is correlated with mation of a protein corona is particularly important in the con- a high risk of AD and antiherpetic treatment is correlated with text of nanoparticle interaction with amyloidogenic peptides such a reduced risk of developing dementia24,25. Despite these cor- β β as amyloid- (A 42) and islet amyloid polypeptide (IAPP), which relations, the mechanism by which viruses induce amyloid are associated with Alzheimer’s disease (AD) and diabetes mel- aggregation, the major pathological hallmark of AD, is litus type 2 disease, respectively. Nanoparticles have been shown not known. to catalyze amyloid formation via binding of amyloidogenic In the present study, we demonstrated that upon encountering peptides in their corona, thereby increasing local peptide con- different biological fluids, RSV accumulated extensive and dis- centration and inducing conformational changes that facilitate tinct protein coronae compared with HSV-1 and synthetic lipo- fibril growth via a heterogenous nucleation mechanism7,8. This somes. The various coronae were dependent on the biological surface-assisted (heterogenous) nucleation has been demon- fluid and exerted markedly different effects on RSV infectivity strated for several nanoparticles with different amyloidogenic and capacity to activate monocyte-derived dendritic cells β 9,10 peptides including IAPP and A 42 . (moDCs). Moreover, upon interaction with an amyloidogenic Here we studied viruses in terms of their biophysical equiva- peptide derived from IAPP, RSV accelerated the process of lence to synthetic nanoparticles in extracellular environments. As amyloid aggregation via surface-assisted heterogenous nucleation. nanosized obligate intracellular parasites, viruses lack any meta- This amyloid catalysis was also demonstrated for HSV-1 and the β fi bolic activity outside the cell and can thus be expected to interact A 42 peptide in vitro and in an AD animal model. Our ndings with host factors in the microenvironment similar to artificial highlight the importance of viral protein corona interactions for nanoparticles. In the current work, we used well-established viral pathogenesis and provide a direct mechanistic link between techniques of nanotechnology to study the protein corona of viral and amyloid pathologies. respiratory syncytial virus (RSV) in comparison with herpes simplex virus type 1 (HSV-1) and synthetic liposomes. In addi- tion, we studied the interaction of both RSV and HSV-1 with Results amyloidogenic peptides. Rich and unique protein coronae for RSV and HSV-1. Based on RSV is an enveloped Orthopneumovirus with a diameter the extensive literature describing the significant role of corona between 100 and 300 nm, and a single-stranded negative-sense factors in synthetic nanoparticle functionality, we used estab- RNA genome with 10 genes encoding 11 proteins11. It is a leading lished techniques to answer questions regarding RSV patho- cause of acute lower respiratory tract infections in young children genicity26. Using proteomics, we assessed the RSV protein corona worldwide, causing up to an annual estimate of 34 million cases12. profiles in adult human plasma (HP), juvenile (6-month-old By the second year of life, nearly 90% of children get infected with infants tested RSV negative at the time of sample collection) HP RSV causing up to 196,000 yearly fatalities13. Reinfection
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