bioRxiv preprint doi: https://doi.org/10.1101/2020.06.10.144089; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.

1 The low-density receptor-related -1 is essential for

2 Dengue virus infection

3 Vivian Huerta1*, Alejandro M. Martin1, Mónica Sarría1, Osmany Guirola1, Alexis Yero1#a,

4 Yassel Ramos1, Dianne Pupo1#b, Dayron Martin1#c, Alessandro Marcello2 and Glay

5 Chinea1

6 1Department of System Biology, Direction of Biomedical Research, Center for Genetic

7 Engineering and Biotechnology, Havana, Cuba.

8 2Laboratory of Molecular Virology, International Centre for Genetic Engineering and

9 Biotechnology, Trieste, Italy.

10 *Corresponding author

11 Email: [email protected] (VH)

12 #aCurrent Address: Department of Biological Sciences, Université du Québec á

13 Montreal, Montréal, QC, Canada. Email: [email protected]

14 #bCurrent Address: Department of Immunology and Cell Biology. Université de

15 Sherbrooke, Québec, Canada. Email: [email protected].

16 #cCurrent Address: Grupo de Sericultura, Estación Experimental de Pastos y Forrajes

17 Indio Hatuey. Email: [email protected]

1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.10.144089; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.

18 Abstract

19 Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral

20 disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous

21 cell surface have been proposed as DENV entry factors. Among these, the

22 phosphatidylserine receptor TIM-1 is the only one known to mediate virus

23 internalization. However, several cellular models lacking TIM-1 are permissive to DENV

24 infection, suggesting that other receptors exist. Here we show that the Low-density

25 lipoprotein receptor-related protein-1 (LRP1) binds DENV virions by interacting with the

26 DIII of the viral envelope glycoprotein. DENV infection is effectively inhibited by the

27 purified receptor at 5x10-8 mol/L and the interaction of the envelope protein with LRP1 is

28 also blocked by a natural ligand of LRP1. Depletion of LRP1 causes 100-fold lower

29 production of infectious virus than controls. Our results indicate that LRP1 is another

30 DENV receptor thus, becoming an attractive target to evaluate for the development of

31 effective antiviral drugs against DENV.

32 Author summary

33 Dengue virus (DENV) is a complex of four related viruses, recognized as serotypes,

34 designated as DENV1-4. Any of the four DENV serotypes can cause a self-limited

35 disease of mild flu-like symptoms known as dengue or its life threatening form, severe

36 dengue, with hemorrhagic manifestations, organ impairment and shock. This disease is

2 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.10.144089; this version posted June 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.

37 widely spread in tropical and sub-tropical areas worldwide, where the incidence of

38 severe dengue has been increasing steadily. So far, efforts that target components of