Interaction Between Chikungunya and Dengue Viruses During Co-Infection in Aedes Mosquito Cells and in Aedes Aegypti Mosquito Margot Enguehard

Interaction between chikungunya and dengue viruses during co-infection in Aedes mosquito cells and in Aedes aegypti mosquito Margot Enguehard

To cite this version:

Margot Enguehard. Interaction between chikungunya and dengue viruses during co-infection in Aedes mosquito cells and in Aedes aegypti mosquito. Virology. Université de Lyon, 2017. English. NNT : 2017LYSE1161. tel-01767226

HAL Id: tel-01767226 https://tel.archives-ouvertes.fr/tel-01767226 Submitted on 16 Apr 2018

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N°d’ordre NNT : ;9:? ::>:

THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de l’Université Claude Bernard Lyon 1

Ecole Doctorale ED341 Evolution Ecosystème Microbiologie Modélisation

Spécialité de doctorat : Ecologie Microbienne Discipline : Virologie

Soutenue publiquement le 11/09/2017, par : Margot Enguehard

Interaction between chikungunya and dengue viruses during co-infection in Aedes mosquito cells and in Aedes aegypti mosquito

Devant le jury composé de :

PONTIER Dominique (Professeur, UCBL, Lyon) Présidente

ZHONG Jin (Professeur, Institut Pasteur Shanghai) Rapporteur VIGNUZZI Marco (Directeur de recherche, Institut Pasteur Paris) Rapporteur ROQUES Pierre (Directeur de Recherche, CEA) Rapporteur MISSE Dorothée (Chargée de recherche, IRD) Examinatrice

LAVILLETTE Dimitri (Professeur, Institut Pasteur Shanghai) Directeur de thèse LEGRAS-LACHUER Catherine (Maître de conférences, UCBL, Lyon) Co-directrice de thèse 9 @ ,5-$ (. &:($0 ,-$.5 8& ,)! -- /,,5 5,$

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Mes premiers remerciements vont à Dimitri, pour m’avoir donné l’opportunité tout d’abord de faire cette thèse, mais également d’avoir eu la chance de découvrir la Chine, l’Institut Pasteur de Shanghai et de pouvoir développer de magnifiques collaborations. Le parcours n’a pas été un long fleuve tranquil, mais on voit enfin le bout !! Merci à Catherine d’avoir accepté d’être ma co-directrice après le départ de Dimitri à Shanghai. Merci pour ta présence, tes nombreux conseils constructifs, nos réunions, ton soutien.

Merci aux membres de mon jury, d’avoir accepté de participer à ma soutenance, à Marco Vignuzzi, Pierre Roques et Jin Zhong d’avoir accepté d’être rapporteurs, et à Dorothée Missé, et Dominique Pontier d’avoir examiné mon travail.

Au cours de cette thèse, j’ai eu la chance d’être accueillie au sein de plusieurs laboratoires et équipes, ce qui a été riche en rencontres.

Je remercie tout d’abord Yvan Moenne Loccoz de m’avoir permis d’intégrer le laboratoire d’Ecologie Microbienne. Merci à Patrick et Claire pour l’accueil dans l’équipe 7. A Yoann, on a commencé notre thèse en même temps, Van, pour toutes les longues commandes, Stéphanie, pour nos fous rires pendant les captures de moustiques, Guillaume, pour m’avoir montré comment trouver des larves. Une pensée toute particulière pour Flo, partie trop tôt, tu restes dans ma mémoire comme une personne aimante, soucieuse du bien-être de chacun. Merci également à tous les membres de l’unité Eco Mic, qui m’ont toujours accueilli avec le sourire.

A l’unité de Gerland (Infections Virales et Pathologie Comparée), j’ai passé 5 ans mémorables, merci à tous pour votre soutien, nos nombreuses discussions et conseils. A Fabienne, pour diriger l’unité à merveille, depuis le départ (trop tôt) de Christophe. Aux membres des AlphaGirls, Carine, Marie, Céline et Catherine, merci pour votre bonne humeur, votre soutien, votre aide aussi, pour les qPCR et les titrations en grand nombre. Merci aussi à la team P3 : Maxime, Barbara G, Barbara V, Marie Pierre, merci d’avoir fait en sorte que je travaille en sécurité et dans de bonnes conditions dans ma deuxième maison : mon très cher et adoré P3, sans qui je n’aurai rien fait. Merci aux étudiants lyonnais pour nos discussions scientifiques ou pas : Marie, Wilhelm, Lucie, Marlène, Maryline et Margaux (Tea time), Nico et Nico de la Tour. Je n’oublie pas les anciens, Sarah, Franck, Claire et Najate. Pardon à ceux que j’oublie de mentionner.

A Pasteur Shanghai, grâce à la bourse du programme Avenir Lyon-Saint Etienne, j’ai pu passer 7 mois incroyables, découvrir une culture riche, des paysages magnifiques, apprendre le chinois, travailler sur Zika. Une pensée particulière à Mathilde, Matou, ma colloc et collègue, pour nos apéro WineAndCheese, nos soirées Mojitos, Bowen, voisin de bureau, Li, merci pour ton aide dans les tâches administratives parfois compliquées, Emilie, pour ta bonne humeur et ton aide précieuse, Lucie, pour m’avoir fait découvrir les meilleurs endroits de Shanghai. .

A Pasteur Paris, merci à Jean Claude Manuguerra de m’avoir accueilli dans l’unité. Grace à la bourse Calmette et Yersin et au réseau international Institut Pasteur, j’ai eu la merveilleuse occasion de découvrir “le monde des moustiques”. Merci à Valérie d’avoir accepté en tant que stagiaire, de m’avoir soutenue et tant appris, Michèle, pour la partie élevage des belles moustiques, Vincent, pour m’avoir supporté avec toutes mes questions, Emilie, pour m’avoir fait découvrir les spécificités des qPCR, Justine, Essia et Cécile, pour votre bonne humeur et nos discussions. Merci également à toute la Team CIBU, pour votre accueil et votre gentillesse.

Je remercie également les Collaborateurs du cytomètre: Sébastien et Thibault, pour toutes les heures passées au LSR, nos discussions, riches en conseils précieux.

Mes amis, qui ont été d’un grand soutien pendant toutes ces années. Charlotte, Apo, Virginie, Anna, Stephan, Val, Lucas, et tous les autres. Malgré les années qui passent et nos vies souvent prenantes, on arrive toujours à se retrouver.

Merci aussi à ma famille, Mes parents, mon frère qui m’a toujours soutenu, malgré cette thèse un peu envahissante. Mes grands-parents, j’espère vous rendre fiers. Ma cousine, une petite pensée pour toi, qui commence tout juste ta thèse, je te souhaite le meilleur pour toi, autant de joies et d’aventures, les bonnes comme les moins bonnes (ca fait aussi partie de la thèse). Ma belle-famille aussi, qui ont toujours eu une pensée pour moi, des petits mots d’encouragements réconfortants, Beatrice, Jacques, Emilie, Laurent, Mémie, Loen, Tom et tous les autres.

Le meilleur pour la fin… Mon plus grand soutien, Bastien, merci d’avoir été là pendant ces années, envers et contre moi. De n’avoir jamais râler de mes absences pendant les week ends de travail, les séjours à Shanghai, mon stage parisien, même si je sais que tu auras voulu me garder près de toi. Tu as été d’une patience incroyable. Merci pour ton soutien, ta présence, même dans les moments de doutes, tu sais qu’ils ont été assez nombreux. Cette thèse est pour toi, toi qui a toujours cru en moi et qui m’a poussé a donné le meilleur de moi-même.

My first acknowledgment is for Dimitri, for giving me the opportunity to do this PhD work. Thanks to you and your work in Pasteur Institute of Shanghai, we had many opportunities and collaborations. Catherine, I can never thank you to accept to be my co-director since the moving of Dimitri to Shanghai. For your presence, your advices, meetings and your support in any conditions, thank you.

To all members of the committee, I would like to thank Marco Vignuzzi, Pierre Roques and Jin Zhong for reviewing my manuscript, and Dorothée Missé and Dominique Pontier for examining my work.

During this PhD work I had the chance to be welcomed in few laboratories.

Firstly, I would like to thank Yvann Moenne Loccoz, for integrating me in the Microbial Ecology laboratory. Patrick and Claire, thank you for the welcome in the team. To Yoann, we started our PhD together, and we survived! To Van, for your help in the administration, to Stephanie for our laugh during the capture of mosquitoes and to Guillaume for showing me how to find larvae. Quite particular thought for my Flo, left too early, you stay in my memory as an affectionate person, worried about the well-being of each other. Thank you also to all the members of the Eco Mic unit, who always welcomed me with the smile.

In the unit of Gerland (Viral Infections and Compared Pathology), I spent 5 memorable years, thanks to all for your support, our numerous discussions and advices. To Fabienne, to manage the unit marvelously, since the departure too early of Christophe. To the members of the AlphaGirls, Carine, Marie, Céline and Catherine, thank you for your good mood, your support, your help also, for qPCR and titrations in large numbers. Thank you also in the team P3: Maxime, Barbara G, Barbara V, Marie Pierre, thank you for the advices, the work in safety and in good conditions in my second house: my dear BSL3, without I had nothing.

Thanks to the students of Lyon for our scientific discussions or not: Marie, Wilhelm, Lucie, Marlène, Maryline and Margot (Tea time), Nico and Nico de la Tour. I do not forget the former students, Sarah, Frank, Claire and Najate. Forgiveness to those I forget to mention.

To Pasteur Shanghai, thanks to the grant of the program Future Lyon - saint Etienne, I spent 7 incredible months, to discover a rich culture, magnificent landscapes, to speak Chinese. A particular thought for Mathilde, Ma Mathou, my roommate and colleague, for our apéro’ WineAndCheese, our lady’s nights Mojitos, Bowen, neighbor of office, Li, thank you for your help in the administrative tasks, sometimes complicated, Emilie, for your good mood and your precious help, and Lucie, for showing me the best places of Shanghai.

To Pasteur Paris, thanks to the Calmette and Yersin grant and the International Network Pasteur Institute to give the chance to work in the unit of Jean Claude Manuguerra. Valérie, thank you for welcoming me in your team, and for your kindness, Michèle, for showing me how to give birth mosquitoes, and for your help every day, Vincent, for supporting me with all my questions, Emilie, for your explanations in the specificities of qPCR, Justine, Essia and Cecile, for your good mood and our discussions. Thank you also in all Team CIBU, for your welcome and your kindness.

I also thank the Collaborators of the cytometry: Sébastien and Thibault, for every hour spent in the LSR, our discussions, and rich in precious advices.

My friends, who were of a big support during all these years. Charlotte, Apo, Virginie, Anna, Stephan, Val, Lucas, and the others. In spite of the years which pass and our often-fascinating lives, we are always be there for each other.

Thank you also to my family, My parents, my brother who always supported me, in spite of this “intrusive” thesis. My grandparents, I hope to make you proud. My cousin, a small thought for you, who just begins your thesis, I wish you the best for you, so many enjoyments and adventures, the good ones as the least good (it is also a part of the thesis). My family in-law also, which always had a thought for me, for your encouragements, Beatrice, Jacques, Emilie, Laurent, Mémie, Loen, Tom and the others.

The best for the end … My biggest support, Bastien, thank you for having been there during these years, to and against me. For your patience during my long weeks spent in Shanghai, or my Parisian internship, even if I know that you prefer keeping me at home. You have an incredible patience. Thank you for your support, your presence; even during the moments of doubts. This thesis is for you, who always believed in me and who pushed me to give the best.

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6 : GE S!66E `^^fTH +3!2!.E 0$! (0!/0 (.#!J/ (! +10.!' %/ 1..!*0(5 + 1..%*# "+. 0$! "%./00%)!%*0$!)!.% * +*0%*!*0"+((+3%*#%*0.+ 1 0%+*+" /%*#!*+05,!E .!(0! 0+/0.%*/% !*0%"%! %*/%S%* * +*!/%%*`^êE%*$%*%*`^_È* %*0$! $%(%,,%*!/ %* `^_aT S).&!! !0 (HE `^_bTH %0$ *+ ,,.+2! 2 %*! +. *0%2%.( 0.!0)!*0E)%((%+*/+",!+,(!.%/'0+!%*"! 0! H %//,.! 50$!%0!+"0$!$%#$(5*0$.+,+,$%(% '-%( )+/-1%0+E* 0+ (!//!.!40!*0E5/!$% ()'H'/,,H)+/-1%0+!/(/+0.*/)%0 H(0$+1#$/ -%( +*/0%010! 0$!)%*2! 0+./,! %!/"+. %* !*5 1.%*#0$!)&+.`^^b +10.!'E / !$% ()' 3/ 0$! ,.%* %,( 2! 0+. %* /1 !! %*# !,% !)% / %* +*E #/ .E !1*%+** ,.+(5.%!*S .%1'%&!*#!0(HE`^^fF !.+5!0 (HE `^^gF ).&!! !0 (HE `^_bF *# !0 (HE `^^fTH / 0$! /)! ' /,,H )+/-1%0+!/ 0.*/)%0 +0$ ,0$+#!*/E 0$!.! %/ .!/+*(! !4,! 00%+* 0$0 0$! !,% !)%+(+#5 +" * %*"! 0%+*/%/0!),+.((5* /,0%((5.!(0! H$!/!+2!.(,,%*#(! / 0+$%#$!. !0! 0%+*+" +J %. 1(0%+** +J%*"! 0%+*%*$1)*/* )+/-1%0+!/H+J %*"! 0%+*/.!%* .!/%*#(5!%*#.! +#*%6! E%*0.2!(!./ +)%*#".+)+10$!.*/%+. ".% S$*#!0(HE`^_^F5.!0(HE`^êF,,!!0(HE`^_^TE3!((/%*%*$%0*0/%* * %+.".% S$$.!0(HE`^^gF !.+5!0(HE`^^gF..!%.!0(HE`^_bT* )+.! .! !*0(5%*+10$)!.% E +*"%.)%*#,.!2%+1/ 0S5!./* .!5E_gdeTH 0%/*+0 (!. %" +J%*"! 0%+* (! / 0+ *+2!( (%*% ( !*0%05 3%0$ /,! %"% +. /!2!.! /5),0+)/ S).&!!!0(HE`^_bTH +3!2!.E$!)+..$#% +),(% 0%+*/%* +J%*"! 0! ,0%!*0$ !!*.!,+.0! S,,!!0(HE`^_^TH/! +*0$!(0!/0!,% !)% /E0$!,!. !*0#!+" +J %*"! 0%+* 3$!* 2%.1/!/ +J %. 1(0! %/ !03!!* `Ja^h * (( /!.+05,!/ 3!.! %*2+(2! S1.15J *)+.% !0 (HE `^_dF (30 !0 (HE `^__F ).&!! !0 (HE `^_bF .,$ . !0 (HE `^_`TH 1.0$!.)+.!E 0$! )+/-1%0+ ' !$% ()' +1( ..5 /%)1(0*!+1/(5 * %* 0$! "%!( S.+* !0 (HE `^_`TH .( +J%*"! 0%+* +" '!$% ()'$/!!*/$+3*0+!,+//%(!!4,!.%)!*0((51/%*#/0.%*/+"J_ * ,.+2% ! %* 0$! /)! (++ J)!( S6!%((! !0 (HE `^_^TH $!/! +J%*"! 0! )+/-1%0+!/,.!/!*0+0$2%.1/!/%*0$!%./(%2* *,+0!*0%((50.*/)%0+0$2%.1/!/ 0+#!0$!.H +.! .! !*0(5E /1 !//"1( 1(J%*"! 0%+*/ 3%0$ E +. $2! +*"%.)! ,.!2%+1/3+.'%*'-%( )+/-1%0+S>!.06!0(HE`^_eF1 '!.0!0(HE `^_eTH

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`* 1.%*#0$!/!-1!*0%( +J%*"! 0%+*+" %""!.!*0)+/-1%0+ !((/H$%/!4,!.%)!*0( /0.0!#5 ((+3! 1/ 0+ /01 5 * +J%*"! 0%+* )%)% '%*# 0$! /1,!. %*"! 0%+* +" ,.!2%+1/(5 %*"! 0! )+/-1%0+ 1.%*# /! +* (++ )!( 1.%*# /%)1(0*!+1/ +10.!'/H 5 1/%*# ' !$% ()'* ' -%( !(( (%*!/E 3! /$+3! 0$0,.!J%*"! 0%+*5 *,.+)+0!%*"! 0%+*5J`2%.1/H!/$+3! 0$00$%/,$!*+)!*+*%/.!(0%2!(5.+ / ,.+)+0!%*"! 0%+*+"J_EJ a* JbE/3!((/%*"! 0%+*5!((+3!2!.%.1/* %'%.1/H%*((5E3!(/+ /$+3! 0$0*+0$!.!%* &)'E0$!!)(%'%+.!/02%.1/E *(/+%* .!/!%*"! 0%+*5 J`H (0+#!0$!.E +1. 0 !)+*/0.0! 0$0 ,.!J%*"! 0%+* +" )+/-1%0+ 5 !%* &)'' *%* .!/!%*"! 0%+*5!* * &)''H

6 : GG

4 ,*!$+7%, '+

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MOI 0,1 MOI 0,1 MOI 1 *** ** ** *** *** *** *** MOI 1 9 *** ** 100 100 ** * * *** 10 109 80 8 8 10 80 60 10 107 40 107 20 6 60 106 10 10 5 105 10 40 8 104 104 6 103 103 20 4 2 10 102 DENV-2 positive cells (%) 2 DENV-2 Viral (ffu/ml) Titer DENV-2 Viral (ffu/ml) Titer 0 DENV-2 positive cells (%) 101 0 101 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i.

MOI 1 MOI 0,1 MOI 0,1 MOI 1 800 80 20 8 600 60

!" 400 15 6 40 200 20 10 4 100 10 4 2.0 80 3 1.5 60 5 2 1.0 40

1 0.5 20 DENV-2 (RNA copie/GAPDH) (RNA DENV-2 DENV-2 (RNA copie/RpL27) (RNA DENV-2 0 copie/GAPDH) (RNA DENV-2 0 0 copie/RpL27) (RNA DENV-2 0.0 0,1D1D2D3D6 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - CHIKV + CHIKV - CHIKV + CHIKV - CHIKV + CHIKV

ns ns 100 25 107 100000

106 90 20 80000 105 80 15 60000 104 70 10 40000 103

60 5 102 20000 CHIKV positive cells (%) cells positive CHIKV CHIKV Viral (pfu/ml) Titer CHIKV (RNA copie/RpL27) (RNA CHIKV 50 0 101 copie/GAPDH) (RNA CHIKV 0 D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. + DENV-2 + DENV-2 - DENV-2 + DENV-2 + DENV-2 + DENV-2 + DENV-2 + DENV-2 + DENV-2 MOI 0,1 MOI 1 - DENV-2 - DENV-2 - DENV-2 MOI 0,1 MOI 1 MOI 0,1 MOI 1 MOI 0,1 MOI 1

$"/, AG8 (. ,.$)(- /,$(")9$(! .$)()! #,)($&&3$(! . E;BE &&-8 $!,!.)%//%2!*!//+"J`%* $.+*% %*"! 0! dPad !((/.!*(56! 51/%*#03+ %""!.!*0 _ST * Ê_STHdPad*<2! !((/S.! T* $.+*% %*"! 0! dPad !((/S#.!!*T3!.!$.2!/0! E,!.)!%(%6! * /0%*! +"J`,.+0!%*!4,.!//%+*0 5Ê_EÈa* d,+/0%*"! 0%+*H!. !*0#!/+"J`,+/%0%2! !((/ 0! $0%)!,+%*03!.! !0!.)%*! 5"(+3 50+)!0.5H0.!,.!/!*0 )! %1) 2(1!/ +" 0$.!! %* !,!* !*0 !4,!.%)!*0/H%.(/".+)%*"! 0! !((/3%0$ _ST* Ê_ST3!.!-1*0%"%! * *+.)(%6! 3%0$, è $+1/!'!!,%*##!*!H$.+*% %05+" %* !((/%/(/++/!.2! 5 0$! /0%*%*# +" ,/% ,.+0!%* !4,.!//%+*H !. !*0#!/+" ,+/%0%2! !((/0! $0%)!,+%*03!.! !0!.)%*! 5"(+3 50+)!0.5STE* 2%.(3!.! -1*0%"%! * *+.)(%6! 3%0$, è$+1/!'!!,%*##!*!STH!/1(0/.!.!,+.0! / +,%!/ +),.!0+, è #!*!H1,!.*0*0/3!.!0.*/"!..! +*0+!.+d !((/%*+. !.0+-1*0%"50$!2%.(,.+ 1 0%+*+"J`0 _ ST* Ê_S TE".+) $.+*% %*"! 0! dPad !((/H ,.+ 1 0%+*%* $.+*% %*"! 0! dPad !((/3/(/+ 0%0.0! S TH %.( 0%0!./ 3!.! !0!.)%*! bf$ ,+/0 %*"! 0%+* * .!/1(0/.!.!,+.0! /"+ %"+.)%*#1*%0/,!.)( S""1P)(TH%.(/3!.!-1*0%"%! * *+.)(%6! 3%0$ $+1/!'!!,%*##!*!H!/1(0/.!.!,+.0! / +,%!/ +),.!0+ #!*!S E * TH

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MOI 0,01 MOI 0,1 MOI 0,01 100 100 12 MOI 0,1 10 1012

10 80 80 10 1010

8 60 60 10 108

6 6 40 40 10 10

104 104 20 20 CHIKV positive cells (%) CHIKV positive cells (%) cells positive CHIKV 2 2

CHIKV Viral (pfu/ml) Titer 10 CHIKV Viral (pfu/ml) Titer 10 0 0 D0 H12 D1 D2 D0 H12 D1 D2 Inoc D0 H12 D1 D2 Inoc D0 H12 D1 D2 Time p.i. Time p.i. Time p.i. Time p.i.

MOI 0,01 MOI 0,1 MOI 0,01 MOI 0,1 100 100 2000 4000

80 80 1500 3000

60 60 1000 2000 40 40 500 1000 20 20 CHIKV (RNA copie/GAPDH) (RNA CHIKV CHIKV (RNA copie/RpL27) (RNA CHIKV

CHIKV (RNA copie/RpL27) (RNA CHIKV 0 0 0 copie/GAPDH) (RNA CHIKV 0 Inoc D0 H12 D1 D2 D0 H12 D1 D2 D0 H12 D1 D2 Inoc D0 H12 D1 D2 Time p.i. Time p.i. Time p.i. Time p.i. - DENV-2 + DENV-2 - DENV-2 + DENV-2 - DENV-2 + DENV-2 - DENV-2 + DENV-2

15 100 107 4000 ** ** 90 106 3000 10 5 80 10 104 2000 70 5 103 1000 60 2

!" 10 DENV-2 positive cells (%) DENV-2 Viral (ffu/ml) Titer DENV-2 (RNA copie/RpL27) (RNA DENV-2 50 0 101 copie/GAPDH) (RNA DENV-2 0 D0 H12 D1 D2 D0 H12 D1 D2 D0 H12 D1 D2 D0 H12 D1 D2 Time p.i. Time p.i. Time p.i. Time p.i. + CHIKV + CHIKV - CHIKV + CHIKV + CHIKV + CHIKV + CHIKV + CHIKV + CHIKV - CHIKV - CHIKV - CHIKV MOI 0,01 MOI 0,01 MOI 0,1 MOI 0,01 MOI 0,1 MOI 0,01 MOI 0,1 MOI 0,1 $"/, AH8 (. ,.$)(- /,$(")9$(! .$)()!9A#,)($&&3$(! . E;BE &&-8 *"! 0%+*/3%0$03+ %""!.!*0 +" %*J` $.+*% %*"! 0! dPad !((/.!%*2!/0%#0! S* THdPad *<2! !((/S.! T* J` $.+*% %*"! 0! dPad !((/S#.!!*T3!.!$.2!/0! E,!.)!%(%6! * /0%*! 3%0$ ,/% ,.+0!%*!4,.!//%+*0Ê_`$+1./E_E* ` 5/,+/0%*"! 0%+*H!. !*0#!/+" ,+/%0%2! !((/0! $0%)! ,+%*03!.! !0!.)%*! 5"(+3 50+)!0.5H0.!,.!/!*0)! %1)2(1!/+"0$.!!%* !,!* !*0!4,!.%)!*0/H%.( ".+)%*"! 0! !((/3%0$ 0 Ê_ST* Ê^_ST3!.!-1*0%"%! * 3!.!.!,+.0! / +,%!/ +),.! 0+ , è $+1/!'!!,%*# #!*!H 0 .!,.!/!*0 )! %1) 2(1!/ +" 03+ %* !,!* !*0 !4,!.%)!*0/H J` $.+*% %*"! 0%+*+"dPad !((/3/ !0!.)%*! 5"(+3 50+)!0.5"0!./0%*%*#1/%*#0$!,.+0!%*STE* 2%.( 3/ -1*0%"%! 5 J- STH !/1(0/ .! .!,+.0! / ,!. !*0#!/+" ,+/%0%2! !((/* +,%!/ +),.! 0+ , è $+1/!'!!,%*# #!*!H 1*0%"% 0%+* +" 2%.( ,.+ 1 0%+* "0!. /1,!.J%*"! 0%+* 3%0$ +*0+ J` $.+*% %*"! 0! !((/%/*(56! 50%0.0%+*+"/1,!.*0*0/%*!.+d !((/H0 Ê^_ST* Ê_S TE 2%.(0%0!./3!.! !0!.)%*! bf$,+/0%*"! 0%+*HJ`,.+ 1 0%+*%* $.+*% %*"! 0! dPad !((/3/(/+0%0.0! S TH!/1(0/.!.!,+.0! /,(-1!"+.)%*#1*%0/,!.)(S,"1P)(TH%.(/%*/1,!.*0*03!.!-1*0%"%! 5J -* .!/1(0/.!.!,+.0! / +,%!/ +),.!0+ $+1/!'!!,%*##!*!S E * TH* 5J-"0!. !40. 0%+*S TH

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6 : ??? MOI 1 ** ** *** MOI 1 *** 50 100 107 107

40 90 106 106

105 105 30 80 104 104 20 70 103 103 10 60 102 102 DENV-2 positive cells (%) cells positive DENV-2 CHIKV Viral (pfu/ml) Titer 0 DENV-2 Viral (ffu/ml) Titer 50 101 101

D0 D1 D2 D3 D6 CHIKV-mcherry positive cells (%) D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - DENV-2 + DENV-2 1 - DENV-2 + DENV-2 1 - CHIKV + CHIKV MOI 1 *** 100 100 MOI 1 ** 7 107 10 80 6 80 106 10

5 60 60 105 10

104 104 40 40 103 103 20 20 102 102 CHIKV positive cells (%) cells positive CHIKV DENV-2 positive cells (%) cells positive DENV-2 CHIKV Viral (pfu/ml) Titer 0 0 DENV-2 Viral (ffu/ml) Titer 1 1 D0 D1 D2 D3 D6 10 10 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - DENV-2 + DENV-2 1 - CHIKV + CHIKV - DENV-2 + DENV-2 1 $"/, B?8 (. ,.$)(- /,$(" )9$(! .$)( )! #,)($&&3 $(! . "A =) '!$> ( C8C =) !$%#> &&-8

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6 : ??A " ! MOI 1 *** MOI 1 * * *** *** 8 100 10 7 100 10 107 80 106 90 106 5 5 10 60 80 10 4 104 10 40 70 103 103 2 $% 20 10 60 102 DENV-1 Viral (ffu/ml) Titer

DENV-1 positive cells (%) cells positive DENV-1 1 10 CHIKV Viral (pfu/ml) Titer 1 0 50 Inoc D0 D1 D2 D3 D6 10

D0 D1 D2 D3 D6 CHIKV-mcherry positive cells (%) D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - CHIKV + CHIKV - DENV-1 +1 DENV-1 - DENV-1 + DENV-1 1 MOI 1 MOI 1 7 *** *** *** 9 * ** ** *** 10 100 100 10 108 106 80 90 107 105 6 60 80 10 4 105 10 40 70 4 10 103 3

$& 10 20 60 2 2 10

DENV-3 positive cells (%) 10 CHIKV Viral (pfu/ml) Titer 0 (ffu/ml) VIralTiter DENV-3 50 101 101

D0 D1 D2 D3 D6 CHIKV-mcherry positive cells (%) D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - DENV-3 + DENV-3 + CHIKV - CHIKV - CHIKV + CHIKV - DENV-3 + DENV-3 1 MOI 1 * *** ** MOI 1 ** *** ** 7 100 100 109 10 8 10 106 80 90 107 5 6 10 60 80 10 105 104 40 70 4 10 103 103 20 60 2 $' 10 102 DENV-4 positive cells (%) CHIKV Viral (pfu/ml) Titer DENV-4 Viral (ffu/ml) Titer 0 50 101 101 D0 D1 D2 D3 D6 CHIKV-mcherry positive cells (%) D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - DENV-4 +1 DENV-4 - CHIKV + CHIKV - DENV-4 + DENV-4 1 MOI 1 * * MOI 1 ** 100 100 1010 106 109 80 90 5 108 10 107 60 80 104 106 105 40 70 103 4

10 3 20 60 10 102 YFV positive cells (%) cells positive YFV YFV Viral Titer (ffu/ml) 102 0 50 101 101 D0 D1 D2 D3 D6 CHIKV mcherry positive cells (%) D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 CHIKV-mcherry Viral (pfu/ml) Titer D0 D1 D2 D3 D6 Time p.i. Time p.i. Time p.i. Time p.i. - CHIKV + CHIKV - YFV + YFV 1 - CHIKV + CHIKV - YFV + YFV $"/, B@(#( ' (.)!&&"%##' ' ,-$(*, - ( )! $(E;BE &&-8 %2! S.! T +. $.+*% %*"! 0! S#.!!*T dPad !((/ 3!.! %*"! 0! 3%0$/!.+05,!/* 0 _H !.)%//%2!*!//%*0$!/! !((/3!.!"%./0(5*(56! "+.J_STE Ja STE Jb ST * ST "0!. /0%*%*#1/%*#,.+0!%*0 5^E_E`Ea* d,+/0%*"! 0%+*H *,.((!(E0$! J) $!..5 $.+*% %053/*(56! "0!.%*"! 0%+*/SJJJ TH!. !*0#!/+"J`* ,+/%0%2! !((/0! $0%)!,+%*03!.! !0!.)%*! 5 "(+3 50+)!0.5 1/%*# 0$! ) $!..5 ,.+0!%* !4,.!//%+*H .*/"!..! +*0+ !.+dE /1,!.*0*0/ .! 0%0.0! 0+ !0!.)%*! 0$! 2%.( ,.+ 1 0%+* "+((+3%*# 0$! %*"! 0%+*H $! /0%*%*# 3/ ,!."+.)! bf$ ,+/0 %*"! 0%+* * %*"! 0%+1/0%0!./3!.!.!,+.0! /"+ %"+.)%*#1*%0/,!.)(S""1P)(TH$! $.+*% ,.+ 1 0%+*3/(/+*(56! %*/)!/1,!.*0*0/E* 3/.!,+.0! /,(-1!"+.)%*#1*%0S,"1P)(TH4,!.%)!*0/3!.!,!."+.)! "+.J_S * TEJaS * TEJbS* T* S* T"+.* !0! 0%+*E.!/,! 0%2!(5H0 .!,.!/!*0)! %1)2(1!/+"0$.!!%* !,!* !*0!4,!.%)!*0/H

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MOI 1** ** MOI 1 ** * 100 109 108 80 107 60 106 105 40 104 3 20 10 102 DENV-2 positive cells (%) cells positive DENV-2 DENV-2 Viral (ffu/ml) Titer 0 101 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 Time p.i. Time p.i. - SFV + SFV - SFV + SFV $"/, BA8# #,)($ '&$%$), -.$,/-$(! .$)($(E;BE &&- (#( -.# 9A$(! .$)(8 %2!S.! T+. $.+*% %*"! 0! S#.!!*TdPad !((/3!.!%*"! 0! 3%0$J`0 _H!.)%//%2!*!//ST+" J`%* !((/%/ !0!.)%*! 5"(+3 50+)!0.5.!,+.0! /,!. !*0#!+",+/%0%2! !((/H$!2%.(,.+ 1 0%+*ST+" J`%*/1,!.*0*03!.! !0!.)%*! 50%0.0%+** /0%*%*#+*0+!.+d"0!.bf$,+/0%*"! 0%+*H *"! 0%+1/ 0%0!./ .! .!,+.0! / "+ % "+.)%*# 1*%0/ ,!. )( S""1P)(TH 0 .!,.!/!*0 )! %1) 2(1!/ +" 0$.!! %* !,!* !*0 !4,!.%)!*0/H

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100 100 80

ells (%) ells 80 60 60

40 40

20 20 VSV GFP infectedVSV GFP c 0 0

0,1 1 CHIKV-mcherry positive cells (%) Infectious doses - + 0,1 + 1 VSV GFP VSV GFP + CHIKV MOI 0,1 *** *** 100 100

80 80

60 60

40 40

20 20

CHIKV- GFP positiveCHIKV- GFP cells (%) 0 0

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MOI 0,001 MOI 0,01 MOI 0,01 MOI 0,01 100 100 1011 1011 1010 1010 80 80 109 109 108 108 60 60 107 107 106 106 40 40 105 105 104 104 20 20 103 103 2 2 CHIKV Viral (ffu/ml) Titer CHIKV Viral (ffu/ml) Titer CHIKV positive cells (%) cells positive CHIKV CHIKV positive cells (%) cells positive CHIKV 10 10 0 0 101 101 D0 D1 D2 D0 D1 D2 Inoc d0 h12 d1 d2 Inoc d0 h12 d1 d2 Time p.i. Time p.i. Time p.i. Time p.i. - DENV-2 + DENV-2 - DENV-2 + DENV-2 - DENV-2 + DENV-2 - DENV-2 + DENV-2

MOI 0,1 MOI 0,1 10 7 100 100 10 10 9 10 6 90 10 80 108 105 107 60 80 106 104 40 70 105 103 104 20 60 102 103 CHIKV Viral (ffu/ml) Titer CHIKV positive cells (%) DENV-2 Viral (ffu/ml) Titer DENV-2 positive cells (%) cells positive DENV-2 0 50 102 101 D0 D1 D2 d0 h12 d1 d2 Inoc d0 h12 d1 d2 d0 h12 d1 d2 Time p.i. Time p.i. Time p.i. Time p.i. - DENV-2 + DENV-2 + CHIKV - DENV-2 + DENV-2 + CHIKV - CHIKV - CHIKV MOI 0,01 MOI 0,01 + CHIKV + CHIKV + CHIKV + CHIKV MOI 0,001 MOI 0,1 MOI 0,001 MOI 0,1 /**@8 (. ,.$)(- /,$(")9$(! .$)()!#,)($&&3$(! . C8C &&-8 <2!S.! T* J` $.+*% S#.!!*T%*/! 0 !((/3!.!%*"! 0! 3%0$ 0 Ê^^_ST* Ê^_STE* Ê_ST +. %*#0+0$!!4,!.%)!*0(/0.0!#5 !/ .%! %*%#H`H %*"! 0%+*$ !!* !0!.)%*! 5"(+3 50+)!0.5E * .!,+.0! / ,!. !*0#! +" ,+/%0%2! !((/H $! $.+*% %05 +" J` %* !((/ %/ *(56! "0!. %*"! 0%+*STH1,!.*0*0/3!.!0.*/"!..! +*0+!.+d !((/%*+. !.0+-1*0%"50$!2%.(,.+ 1 0%+*"+((+3%*#0$! %*"! 0%+*H *"! 0%+1/ 0%0!./ $2! !!* !0!.)%*! 5 +1*0%*# "+ % 1* !. )% .+/ +,5 "0!. /0%*%*# 1/%*# .!2!(0%+*E* .!,+.0! /"+ %"+.)%*#1*%0/,!.)(S""1P)(TH$.!!%*"! 0%+1/ +/!/+" 3!.!1/! E0 Ê^^_E Ê^_* Ê_SJTH$! $.+*% ,.+ 1 0%+*+"J`3/(/+0%0.0! S TH

MOI 1 *** MOI 1 100 108 107 80 106 60 105 4 40 10 103 20 102 DENV-2 positive cells (%) DENV-2 Viral (ffu/ml) Titer 0 101 D0 D1 D2 D3 D6 Inoc D0 D1 D2 D3 D6 Time p.i. Time p.i. - CHIKV St Martin + CHIKV St Martin - CHIKV St Martin + CHIKV St Martin /**A8(#( ' (.)!9A0$,/-$(! .$)(( *,) /.$)(3 #,)($$(! . "A &&-/-$(" $(.,.$(-.,$(8

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_bb^"!)(!/.!!4,+/! 3%0$0$!"%./0(++ )!("+.+0$0.%(/H+.0$!/! +* (++ )!(Ef^* _f^)+/-1%0+!/ .!!4,+/! 0+J`S!*#+.#! "!)(!/TH$!,!. !*0#!+"!*#+.#! "!)(!/$/!!*%* .!/! %*0$!/! +* 0.%(E ".+) _dEdh 0+ aeEch S T * ".+) `dEdh 0+ c^h SJ`TH $! ,!. !*0#! +" /! +* .5 !*#+.#! )+/-1%0+!/,.!J!4,+/! 3%0$ %//0%(((+3E (+/!0+_eh"+.+0$0.%(/H * %0%+*E"+.+0$(++ )!(/E0$.!!!*#+.#! "!)(!/$2!!!* +((! 0! * 0$! 2%.( (+ / $2! !!* *(56! 0+ +*0.+( 0$! ,.!/!* ! +" 2%.1/ %* )+/-1%0+!/ "0!. %*#!/0%+*H+. E+0$0.%(/1/! (++ )!(00%0!.+"aHa4_^fP)(H!.! (!0+ !0! 0cHe4_^b* cHd4_^b +,%!/P)+/-1%0+H((+"0$!0$.!!)+/-1%0+!/ 3!.!,+/%0%2!"+. !0! 0%+*S(!FTH * +*0./0E"+.J`E+*(5+*!)+/-1%0+ ,.!/!*0 J` ,+/%0%2! !0! 0%+* "+. 0$! "%./0 0.%(E 3%0$ 0%0!. +" `Ha 4 _^b +,%!/ P)+/-1%0+H$!0%0!.+"0$!(++ )!(3/aHa4_^eP)(H+.0$!/! +* 0.%(E 0$!%* .!/!+"0$!2%.((+ %*(++ )!(S_He4_^fP)(T((+3/0+%* .!/!0$! ,!. !*0#!+"%*"! 0! )+/-1%0+* 0$!2%.((+ !0! 0! %* +)!*"0!.%*#!/0%+* S`H_4_^c +,%!/P)+/-1%0+TH

6 ; ?A@ 9A +,%!/P)+/-1%0+ * h +,%!/P)+/-1%0+ * h ,$&@ cHe4_^b aJ_^^ `Ha4_^b aRaaEa ,$&A cHd4_^b aJ_^^ `H_4_^c aJ_^^ & F8 (! .$)/-*,.$& -$( )' ()! (")," ! '& -!. ,&)) ' &-8

+.+0$0.%(/E0$! 0%0!.3/0aHa4_^fP)(E3$!.!/0$!0%0!.+"J`3/0aHa4_^eP)("+.0$!"%./0 0.%(* 0_He4_^fP)(H+. * J`(++ )!(Ea"!)(!/$ !!* +((! 0! * *(56! "0!.(++ )!(H.!"!./0+0$!0+0(*1)!.+""!)(!/0!/0! H

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6 ; ?AA Midgut Salivary glands 8 10 108 7 10 107 106 106 105 105 104 104 103 103 102 102

CHIKV (RNA copie/midgut) (RNA CHIKV 101 101

G2 d3 d7 d10 d14 CHIKV (RNA copie/salivary gland) G2 d3 d7 d10 d14 Time p.i. Time p.i. - DENV-2 + DENV-2 - DENV-2 + DENV-2 $"/, BE8 (! .$)($(#'!$'$ "/.( -&$0,3"&( -$()9$(! .$)(),().1$.#9A8 1.%*#0$!/! +* (++ )!(E* !2!.50$.!! 5/Ec)+/-1%0+!/"+.! $ +* %0%+*.! +((! 0! E0+ %//! 0)% #10 * /(%2.5 #(* /H 0 5 _bE +*(5 ` /1.2%2%*# )+/-1%0+!/ 3!.! *(56! H +((! 0! %*0+ 1""!.E 2%.( / 3!.! !40. 0! * J-3/,!."+.)! 0+ !0! 0 %*)% #10ST* %*(%2.5#(* /STH!/1(0/.! .!,+.0! / +,%!/,!.+.#*E* +..!/,+* +"03+%* !,!* !*00.%(/H

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6 ; ?AB

Midgut Salivary glands 106 106

105 105

104 104

103 103

102 102

1 1 DENV-2 (RNA copie/midgut) 10 10 d3 d7 d10 d14 d3 d7 d10 d14 DENV-2 (RNA copie/salivary gland) Time p.i. Time p.i. - CHIKV + CHIKV - CHIKV + CHIKV $"/, BF89A$(! .$)($(#'!$')-+/$.)'$ "/.( -&$0,3"&( -!)&&)1$("*, 9$(! .$)( 1$.# 8 *0$!/)!/),(!/+" %//! 0! +.#*/0$*1/! "+.0$! !0! 0%+*+" EJ`3/ !0! 0! %*)% #10 ST* %*(%2.5#(* /ST"0!.0$!,.!J%*"! 0%+*3%0$ H!/1(0/ +..!/,+* +"03+%* !,!* !*00.%(/* .!.!,+.0! / +,%!/,!.+.#*H

3* %'(! -1 #!""" 0 _^ ,%E _^ )+/-1%0+!/ %* ! $ +* %0%+* 3!.! 1/! "+. /(%2 !40. 0%+*H $!*E ,+/%0%2!/(%2/),(!/$2!!!**(56! 0+ !0! 02%.((+ "+.J`* H 1.,.%/%*#(5E*+*!+"/(%23/,+/%0%2!"+.J`%*)+*+* +J%*"! 0%+* +* %0%+*/ S 0 *+0 /$+3*TH (0$+1#$ J` 3/ *+0 ,.!/!*0 %* /(%2E 2%.1/ 3/ %* /(%2.5 #(* ///$+3*,.!2%+1/(5S%#1.!BETH+. Ef+"_^/(%2,+//!//! ,.0% (!/HJ`,.!/!* ! +!/*+0%), 00$!2%.((+ +" %*/(%2S%#1.!BFTH +3!2!.E%0K/%),+.0*00+*+0% !0$!3!'2%.((+ E.+1* _^^ +,%!/P/(%2H

Saliva 103

102

101

CHIKV (RNA copie/saliva) (RNA CHIKV 100 CHIKV CHIKV + DENV -2

d10 $"/, BG8 . .$)()! $(-&$0)!#'!$')-+/$.)!. ,@? 3-*)-.$(! .$)(8 _^ 5/,+/0%*"! 0%+*E_^)+/-1%0+!/,!. +* %0%+*.! %/,+/! +*#(///(% !* 0$!%.,.++/ %/.!%*0.+ 1 ! %*0+ 0%, +*0%*%*# _^ X( +" )! % J_cH "0!. 0!/0%*# +" /(%2%*01!5+0(+0E+",+/%0%2!/(%23!.! !40. 0! * 2%.( 3!.! !0! 0! 5 J- 1/%*# /!0 +" ,.%)!. /,! %"% "+. +0$ 2%.1/H J` 3/ *+0 !0! 0! %*)+*+* +J%*"! 0%+* +* %0%+*/H %/ !0! 0! %*+0$ +* %0%+*/E%*!2!.5,+/%0%2!/(%2/),(!/H

6 ; ?AC 4!+-++!'&

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6 < ?BA

Chikungunya virus genome Dengue virus genome 5’ 3’ CAP Génomic polyprotein An C Non structural polyprotein Structural polyprotein An

C M E NS1NS1N NS2AA NS2BN B NS3N 3 NS4AN A NNS4BB NS5N P123 nsP4

Structural Proteins Non structural Proteins SPs NSPs 5’ 3’ nsP1 nsP2 nsP3 C E3 E2 6K E1

nsP2 protease Capsid furin Signal Peptidase p5 SP CHIKV 3’ UTR p5 BlastiR CMV SPs DENV-2 3’ UTR SV40polyA BlastiR

Transfection Transfection Lipofectamine 2000 Lipofectamine 2000 Mammalian cells SPs CHIKV Mammalian cells SPs DENV-2 VeroE6 VeroE6 BHK-21 BHK-21

T2A

CMV NSPs DENV-2 3’ UTR SV40polyA SP6 nsPs CHIKV GFP NeoR 3’ UTR

Transfection Transfection Lipofectamine 2000 Lipofectamine 2000 Mammalian cells Mammalian cells RNAsin nsPs CHIKV NSPs DENV-2 VeroE6 VeroE6 BHK-21 BHK-21 Insect cells C6/36

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?6?68@,*-,-*$(*',"&+ "0!.0$!0.*/"! 0%+** /!(! 0%+*+"#!*!/!* + %*#/0.1 01.(,.+0!%*/%*!.+d* J`_ !((/E,.+0!%*/.! !0! 0! 53!/0!.*(+0H *+0$ !(((%*!/E,.+0!%*Scc'T %/2%/1(%6! 00$!!4,! 0! /%6!S%#1.!C?TH $! !*0.5 ,.+ !// 3/ "%./0(5 %*2!/0%#0! %* ,.!/!* ! +. *+0 +" J` /0.1 01.( ,.+0!%*/ S/ J`TH /!1 +J,.0% (!/ .! +),+/! +" !%* &)'' #(5 +,.+0!%*E * $+.! +*0+.!0.+2%.( +.!* 0$!50.*/ 1 !.!,+.0!.#!*!0$0((+3/,.! %/! -1*0%"% 0%+*+"0$!!*0.5/0!,H//$+3*%*%#1.!C?* C?E0$!,.!/!* !+"J `/0.1 01.(,.+0!%*/ +*+0%), 00$!!%* &)'',/!1 +J,.0% (!/ !*0.5 %* !.+d * J`_ !((/ S%#1.! C?* C?TH * +. !. 0+ 0!/0 %" J` / )5 $2! * %), 0+"+0$!./0!,/+"0$!!%* &)'.!,(% 0%+* 5 (!E !((//0(5!4,.!//%*#J` / 3!.! %*"! 0! 5 .!,(% 0%*# H 1,!.*0*0/ 3!.! $.2!/0! 1*0%(a 5/ "+((+3%*#0$!%*"! 0%+*H$!!4,.!//%+*+"/J`%*!.+d !((//!!)/0+(%)%00$! .!,(% 0%+*0 _%* +),.%/+*0+.!,(% 0%+*%**<2!!.+d !((/S%#1.! C?TH0 ^E_E0$!%*$%%0%+*%/(!///%#*%"% *0S%#1.!C?TH +3!2!.E0$%/"%./0.!/1(0 3/*+0/%)%(.%* J`_ !((/S%#1.!C?* C?TH+ %""!.!* !/%* %*"! 0%+* 3!.!+/!.2! %*,.!/!* !+.*+0+"/J`%*0$%/ !((05,!/H$%/ %/ .!,* 5)5 ! 1!0+)+.!.,% !(()+.0(%05%*!.+d0$*%* `_H+.!!4,!.%)!*0/3%((! *!! ! 0+ +*"%.)0$!,.!(%)%*.5.!/1(0/H $!!4,.!//%+*/%*)))(%** %*%*/! 0 !((/.!2!.5 %""!.!*0H*50!/0/3!.! ,!."+.)! %*+. !.0+"%* 0$!)+/0!""% %!*0!4,.!//%+*%*%*/! 0 !((/E* 0$!,.+)+0!. ,c ".+) ,.2+2%.1/ 3/ /!(! 0! H $%/ ,.+)+0!. %/ !""% %!*0 * %0 %/ /)((!. 0$* 0$! 0%* c ,.+)+0!. ".+) .+/+,$%( ((+3%*# (+*%*# +" %##!. ".#)!*0/H $! ,.+)+0!.3//1/0%010! 5c,.+)+0!.* 0$!(/0% % %*.!/%/0* !#!*!((+3! 0$!/!(! 0%+*+"0.*/"! 0! !((/S%#1.!C? TH4,.!//%+*+"J`0.1 01.(,.+0!%*/

6 < ?BD %*dPad !((/(%*!/$ !!**(56! "0!.0.*/"! 0%+** /!(! 0%+* S%#1.! C? TH +3!2!.E1*"+.01*0!(5E1,0+*+3E*+!4,.!//%+*3/ !0! 0! 53!/0!.*(+0H

BHK-21 6 VeroE6 6 VeroE6 BHK-21 10 10 105 105

104 104

103 103

102 102

101 101 DENV-2 DENV-2 SPs DENV-2 DENV-2 SPs DENV-2 100 100 Infectious particles units (UI/ml) Infectious particles units (UI/ml) E – 55kDa VSV-G CHIKV SINV VEEV WEEV SFV VSV-G CHIKV SINV VEEV WEEV SFV Alphaviruses pseudotypes Alphaviruses pseudotypes Tub – 60 kDa - SPs DENV-2 + SPs DENV-2 - SPs DENV-2 + SPs DENV-2

VeroE6 CHIKV MOI - 0,1 VeroE6 CHIKV MOI - 1 BHK-21 CHIKV MOI - 0,1 BHK-21 CHIKV MOI - 1 10 10 10 10

8 8 8 8 /ml /ml /ml /ml 50 50 50 50 6 6 6 6 TCID TCID TCID TCID 10 10 4

10 4 10 4 4 Log Log Log Log 2 2 2 2

0 0 0 0 Inoc H6 J1 J2 J3 Inoc H6 J1 J2 J3 Inoc H6 J1 J2 J3 Inoc H6 J1 J2 J3 Time p.i. Time p.i. Time p.i. Time p.i. - SPs DENV-2 + SPs DENV-2 - SPs DENV-2 + SPs DENV-2 - SPs DENV-2 + SPs DENV-2 - SPs DENV-2 + SPs DENV-2 C6/36

p5 SP DENV2 3’ UTR p5 BlastiR SPs DENV-2 SPs DENV-2 DENV-2 DENV-2 E – 55kDa Actin - 42 kDa $"/, C?8 .,/./,& *,). $(- )! 9A 2*, --$)( $( '''&$( &&-( $'*.)( (.,3( , *&$.$)(8 "0!.0.*/"! 0%+*%*0+)))(%* !((/S!.+d* J`_TE0$! !0! 0%+*+"2%.(,.+0!%*/S,.+0!%*Ecc'T3!.! ,!."+.)! 53!/0!.*(+0STHJ`%*"! 0%+1/ !(((5/0!3/1/! /,+/%0%2! +*0.+(H!((/(%*!/!4,.!//%*#J J`.!.!,.!/!*0! %*(%#$0!.(1! +(+.E%* +),.!+"3%( 05,! !(((%*!/%* .'!.(1! +(+.H!%* &)'' ,/!1 +,.0% (!/ ,.+ 1 ! %*0+ `ga / ,.!2%+1/(5 !/ .%! =,.)-# .&87A??B> 3!.! 1/! 0+ %*2!/0%#0! 0$! %), 0 +" !4,.!//%+* +" J` +* 0$! !*0.5 ,.+ !// %* !.+d ST * J`_ !((/ STH .+30$ 1.2! !4,!.%)!*0/%*!.+d !((/* %*J`!.+d !((/S* T* %* J`_ !((/* %*J` J`_ S* T3%0$ 00$!%* % 0! H *+ 1(1)* /1,!.*0*0/3!.!$.2!/0! ".+)d 0+ 5a,H%HE* 0$! 2%.( 0%0!./ 3!.! +0%*! 5 (%)%0%*# %(10%+* //5/ %* !.+dH!/1(0/.!.!,+.0! /_Ec(+#_^S P)(TH+ %""!.!* !/3!.!+/!.2! "+.0$!!*0.5+"0$!.!,(% 0%+*+" %*0+ !((/!4,.!//%*#J`%* +),.%/+*+" 3%( 05,! !(( 05,!/H * +. !. 0+ !4,.!// 2%.( ,.+0!%*/ %* %*/! 0 !((/E 0$! ,.+)+0!. $2! 0+ ! .!,( ! 5 ,.2+2%.1/,c,.+)+0!.S TH$!(/0% % %*.!/%/0* !#!*!1* !.0$!/)!,.+)+0!.(! 0+0$!/!(! 0%+*+" !((/ !4,.!//%*#2%.(,.+0!%*/H"0!.0.*/"! 0%+*%*0+%*/! 0 !((/SdPadTE0$!3!/0!.*(+0 +!/*+0((+30$! !0! 0%+*+" 0$!J`,.+0!%*S TE%* +*0./0+"J`%*"! 0%+1/ !(((5/0!1/! /,+/%0%2! +*0.+(H

?6@68@'&,*-,-*$(*',"&+ +((+3%*# /%)%(. ,.+0+ +(/ 0$* "+. J` /E *+*J/0.1 01.( ,.+0!%*/ 3!.! !4,.!//! %*!.+d* J`_ !((/H"0!./!(! 0%+*E0$!2%.(,.+0!%*/!4,.!//%+*3/ *(56! 5 3!/0!.* (+0 / /$+3* %* %#1.! C@H $! /0(! !4,.!//%+* +" J` / %/ /0.+*#(5 /1##!/0! 5 0$! ,+/%0%2! !0! 0%+* +" _ S$+)+ %)!. .+1* f^ 'TH *+. !.0+0!/0%"0$!/0(!!4,.!//%+*+"J`/)5%*"(1!* !!%* &)'

6 < ?BE !*0.5E !((/3!.!%*"! 0! 3%0$ %""!.!*0!%* &)',/!1 +05,!/H$%(!0$!,.!/!* !+" J`/%*!.+d$ *+%), 0+*!%* &)''!*0.5S%#1.!C@TE0$!!*0.5+" E E E * ,/!1 +J,.0% (!/ %/ ! .!/! %* J`_ !((/ S%#1.!C@TH$!!""! 0+"J`/+*0$!3$+(! !(( 5 (!+"!%* &)'3/0$!* 0!/0! 3%0$3%( 05,!2%.1/!/H$!.!,(% 0%2! 2%.1/%/(/+ ./0% ((5 ! .!/! 3%0$03+ %""!.!*0 ^E_* _S%#1.!C@* C@T%*,.!/!* !+"/J`%* J`_ !((/E 10 *+0 %* !.+d !((/ S%#1.! C@* C@TH $!/! .!/1(0/E 0+ ! +*"%.)! E /1##!/0 0$0 / J` )5 $2! !(( 05,! /,! %"% !""! 0 * 0$!5 %*$%%0!.(5/0!,+"0$! !*0.5P.!,(% 0%+*+*(5%* J`_ !((/H +!4,.!///J`%*%*/! 0 !((/E,.+)+0!.$ 0+!.!,( ! 5,.2+2%.1/ ,c ,.+)+0!.E !""% %!*0 %* %*/! 0 !((/E / /$+3* %* %#1.! C@ H $! /%6! +" ,(/)% %/ +*/%/0!*0* 0$! +*/0.1 0%+*%//0%((+*#+%*#H/! +*.!/1(0/%*)))(%* !((/E0$! ,.!/!* !+"/J`%*%*/! 0 !((/)5%*"(1!* !0$! .!,(% 0%+*/0!,/H

VeroE6 BHK-21 106 106

105 105

104 104

103 103 VeroE6 BHK-21 102 102

101 101 Infectious particles units (UI/ml) Infectious particles units (UI/ml) VSV-G CHIKV SINV VEEV WEEV SFV VSV-G CHIKV SINV VEEV WEEV SFV Alphaviruses pseudotypes Alphaviruses pseudotypes - NSPs DENV-2 + NSPs DENV-2 - NSPs DENV-2 + NSPs DENV-2 DENV-2 DENV-2 DENV-2 DENV-2 NSPs DENV-2 NSPs DENV-2 NSPs DENV-2 NSPs DENV-2

VeroE6 CHIKV - MOI 0,1 BHK-21 CHIKV MOI - 0,1 100 kDa 10 10

70 kDa 8 8 /ml /ml 50 50 6 6 TCID TCID 10 10 4 4 Actin - 42 kDa Log Log 2 2

0 0 Inoc H6 J1 J2 J3 Inoc H6 J1 J2 J3 Time p.i. Time p.i. - NSPs DENV-2 + NSPs DENV-2 - NSPs DENV-2 + NSPs DENV-2 T2A p5 NSPs DENV-2 3’ UTR SV40polyA VeroE6 CHIKV - MOI 1 BHK-21 CHIKV MOI - 1 10 10

8 8 /ml /ml 50 50 6 6 TCID TCID 10 10 4 4 Log Log 2 2

0 0 Inoc H6 J1 J2 J3 Inoc H6 J1 J2 J3 Time p.i. Time p.i. - NSPs DENV-2 + NSPs DENV-2 - NSPs DENV-2 + NSPs DENV-2 $"/, C@8)(.,/./,&*,). $(-)!9A 2*, --$)($('''&$( &&-( $'*.)( (.,3( , *&$.$)(8 .*/"! 0! %*0+!.+d* J`_E#!*!/!* + !"+.*+*J/0.1 01.(,.+0!%*/(! 0+0$!%.!4,.!//%+*/.!2!(0$! /0%*%*#+"_,.+0!%*53!/0!.*(+0STHJ`%*"! 0%+1/ !(( (5/0! 3/ 1/! / ,+/%0%2! +*0.+(H !((/ (%*!/ !4,.!//%*#JJ`.!.!,.!/!*0! %*(1! +(+.E%* +),.!+"3%( 05,! !(((%*!/%*#.!!* +(+.H/ !/ .%! ,.!2%+1/(5"+.0$! !((/!4,.!//%*#J`E!%* &)'',/!1 +,.0% (!/3!.!1/! 0+*(56!0$!%), 0+*0$! !*0.5 ,.+ !// +" J` 3%0$ !.+d ST * J`_ STE * #.+30$ 1.2! !4,!.%)!*0/ 3%0$ 0 0$! %* % 0! %* !.+d * J`_ !((/ !4,.!//%*# J` SJJJTH *+ 1( * /1,!.*0*0/ 3!.!

6 < ?BF $.2!/0! ".+)d 0+ 5a,H%HE* 0$!2%.(0%0!./3!.!+0%*! 5(%)%0%*# %(10%+*//5/%*!.+dH!/1(0/.! .!,+.0! /_Ec(+#_^S P)(TH+ %""!.!* !/3!.!+/!.2! "+.0$!!*0.5+"0$!.!,(% 0%+*+" %*0+!.+d !((/ !4,.!//%*# J` %* +),.%/+* +" 3%( 05,! !(( 05,!/S* TH * J`_ !((/E!4,.!//%+*+" J`(! /0+.! 1 0%+*+" .!,(% 0%+*E3%0$03+ S* TH4,!.%)!*03/,!."+.)! +*(5+* !* *!! 0+!.!,.+ 1 ! 0+ +*"%.).!/1(0/H *+. !.0+!4,.!//2%.(,.+0!%*/%*%*/! 0 !((/E0$!,.+)+0!.$2!0+ !.!,( ! 5,.2+2%.1/,c,.+)+0!.%*0$!,(/)% S TH

1* !#"& !""

@6?6 ,*-,-*$(*',"&+ 0.1 01.( ,.+0!%*/ +" S/ T 3!.! "%./0(5 !4,.!//! %* !.+d !((/H .+0!%*/ 3!.! 1* !. +*0.+( +" ,.+)+0!. ,c ".+) ,.2+2%.1/E !""% %!*0 %* +0$ )))(%* * %*/! 0 !((/H +3!2!.E *+ !0! 0%+* +" 2%.( ,.+0!%* 3/ +/!.2! 5 3!/0!.*(+0E//$+3*%*%#1.!CAH

VeroE6 CHIKV SPs CHIKV

Capsid – 37kDa

Actin - 42 kDa $"/, CA8.,/./,&*,). $(-)! 2*, --$)($('''&$( &&-8 (/)% +*0%*%*# 1* !.0$! +*0.+(+",.2+2%.1/,c,.+)+0!.3/0.*/"! 0! %*0+)))(%* !((/ S!.+dTE* !((/3!.!(5/! 0+ !0! 02%.(,.+0!%*/53!/0!.*(+0H/%*#**0%+ 5#%*/0,/% ,.+0!%*Sae 'TE*+*!,.+0!%*%/ !0! 0! E%* +),.!+" %*"! 0%+1/ !(((5/0!1/! /,+/%0%2! +*0.+(H

@6@6 '&8+,*-,-*$(*',"&+ * +. !. 0+ !4,.!// *+*J/0.1 01.( ,.+0!%*/ S /T 3! #!*!.0! .!,(% +* 3%0$ d 0.*/ .%,0%+* ,.+)+0!.H $/ !!* 0.*/ .%! # * (&$* 0.*/"! 0%*)))(%*S!.+dT* %*/! 0SdPadT !((/H$!2%/1(%60%+*+".!,+.0!. #!*! 5 )% .+/ +,5 +*"%.)! 0$! #++ !4,.!//%+* +" 0$! ,.+0!%*/ * %* %.! 0(5 +" 0$! 2%.( ,.+0!%*/ S%#1.! CBTH $! /!(! 0%+* +" 0.*/"! 0! )))(%* !((/3/*+0,+//%(!H 03/*+0/1.,.%/%*#E/E%*)))(%* !((/E*/`#!*!%/'*+3* 0+%* 1 ! 50+,0$% !""! 0E%),! ! 0$!/0(!!4,.!//%+*+"2%.(,.+0!%*/H$!/1,!.J %*"! 0%+*3%0$J`+*0$!/! !((/3/*+0,+//%(!E +*/% !.%*#0$!/00!+" !((/H

6 < ?BG +*0..5 0+ )))(%* !((/E 50+,0$% !""! 0 3/ *+0 +/!.2! %* %*/! 0 !((/H "0!. "!33!!'/E0$!/!(! 0%+*+"0.*/"! 0! dPad !((/((+3/0+ !0! 0c^h+" !((/3$% $ !4,.!// ,.+0!%* / /$+3* 5 )% .+/ +,5 S%#1.! CBT * 5 "(+3 50+)!0.5 S%#1.!CBTH 0%/,+//%(!0$0"0!."!3 5 (!/E0$!.!,(% +*!4 (1 !/0$!,.+0!%*E 3$% $ ,.!2!*0 0+ .! $ _^^h +" !((/ !4,.!//%*# /H !/0!.* (+0 3%(( ! ,!."+.)! %* 0$! "101.! 0+ !0! 0 *+*J/0.1 01.( ,.+0!%*/ 3$!* *0%+ 5 3%(( ! 2%((! %* 0$! (+.0+.5H 1,!.J%*"! 0%+* 3%0$ J` 3/ ,!."+.)! * %*"! 0! !((/3!.!/0%*! a ,%H//$+3*%*%#1.!CB70$!,.!/!* !+"*// %*%*/! 0 !((/(! 0+0$!%* .!/!+"J`%*"! 0%+*HJ`%*"! 0/ch+"dPad !((/* 0$! ,.!/!* !+"*// %*dPad !((/!*$* !/0$!%*"! 0%2%050+`^hH$%/,.!(%)%*.5 .!/1(0/1##!/0/0$0*// .!%),(%! %*0$!,.!2%+1/(5+/!.2! !""! 0 1.%*# +J %*"! 0%+*%*%*/! 0 !((/H+#+"1.0$!.E%* !,!* !*0,.+0!%*//$+1( !!4,.!//! %* !((/ %*+. !.0+%*2!/0%#0!0$!%), 0+"! $,.+0!%*H

VeroE6 VeroE6 nsP CHIKV

C6/36 C6/36 nsPs ChikV

DENV-2 MOI 1 50

40 *

10 DENV-2 positive cells (%) cells positive DENV-2 0 DENV-2 J3

- nsP CHIKV + nsP CHIKV $"/, CB8)(9-.,/./,&*,). $(-)! $('''&$(( $(- . &&-( -/* ,9$(! .$)(1$.#9A8 !* + %*# +*J/0.1 01.(,.+0!%*/3!.!0.*/"! 0! %*0+!.+d* dPad !((/S* TH! 1/!+"0$! %* 1 0%+*+" 50+,0$% !""! 0+"*/`,.+0!%*%*)))(%* !((/STE0$!/!(! 0%+*+"0.*/"! 0! !((/(! /0+0$! !0$H$!!""% %!* 5+"0.*/"! 0%+*%*!.+d3/+/!.2! bf$,+/00.*/"! 0%+*H$!0.*/"! 0! %*/! 0 !((/3!.! +/!.2! 5)% .+/ +,5ST* 5"(+3 50+)!0!.STH"0!./!(! 0%+*3%0$!+)5 %* .1#EdPad !((/!4,.!//%*# *// 3!.! %*"! 0! 3%0$ J`H a ,%E !((/ 3!.! $.2!/0! .!/0%*! 3%0$J`*0%+ 5H$! ,!. !*0#!+"%*"! 0! !((/3/ !0!.)%*! 5"(+3 50+)!0.5E* .!,+.0! /,!. !*0#!+",+/%0%2! !((/STH

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