Arboviruses are transmitted by biting arthropods (e.g. mosquitoes, ticks and midges) to mammals (including humans) and can cause severe disease. Important arboviruses affecting humans and life stocks are the mosquito-borne chikungunya virus, dengue virus, Zika virus, Rift valley fever virus; the midge-borne Schmallenberg virus, Bluetongue virus and the tick-borne Crimean Congo haemorrhagic fever virus and tick borne encephalitis virus.
Arboviral infections in vertebrate cells result in strong cytophatic effects. In sharp contrast, in arthropod cells persistent, non-cytopathic infections are usually observed, most likely due to an effective innate immune response.
The focus of my work is the study of virus-host/vector interactions, especially for arthropod-borne viruses (arboviruses) and their interactions with innate immune pathways especially in arthropod vectors. My aim is to understand the factors determining the outcome of virus infection in arthropods (persistence, clearance or pathogenesis) especially in mosquitoes and thereby contribute to understanding vector competence. Understanding the factors that influence arbovirus replication and transmission is also thus key to determining the likelihood of arbovirus emergence and
subsequently their impact on human and animal health. To answer this question, my group uses several approaches. On the one hand we intend to characterize the interplay of the mosquito RNAi response and arboviruses in more detail to understand how antiviral responses are initiated, regulated or executed and how this influences the outcome of infection.
It is known for several arthropods that they have different innate immune responses against viruses, some working globally antiviral and others been specific for a certain virus. The RNA interference (RNAi) pathway is able to restrict virus infection in a wide range of arthropods including mosquitoes and ticks. RNAi can be divided in several pathway depended on the small RNAs produced: small interfering RNA (siRNA) either exogenous (known as antiviral response) or endogenous, microRNA (miRNA) and PIWI-interacting RNA (piRNA). These molecules have divergent roles in different cellular processes and virus-vector interactions.
Recently, it has been shown that antiviral responses implicating RNAi pathways are also present in mosquito cells, which lack the well-known antiviral RNAi response.
The piRNA-mediated response has been recently suggested as an additional antiviral pathway in mosquitoes following the discovery of arboviral specific piRNA-like molecules in infected aedine mosquitoes and their derived cell lines. However, little is known about the induction, mechanism and importance of the piRNA pathway on arboviral and mosquito-specific viral infection in aedine mosquitoes.
Presently, research in my group focuses mainly on mosquito-borne (arbo)viruses (such as Zika virus, chikungunya virus and dengue virus) and the role of poorly characterized small RNA pathways (such as the piRNA pathway) in the antiviral response in mosquitoes. The aim is to determine the influence of these pathways on successful arbovirus transmission from the mosquito vector to a mammalian host (vector competence).
In addition to arboviruses that infect and replicate in both arthropods and vertebrates, there is a class of arthropod-specific viruses that replicate only in arthropods. In recent years, the list of these ‘mosquito specific viruses’ (MSVs) has been growing, encompassing viruses from different families (Flaviviridae, Bunyaviridae, Togaviridae) as well as some that are unclassified. Studies show that many mosquitoes are naturally infected with at least one MSV, but it is not known if some MSVs are an ancestral form of arboviruses. Moreover, recent evidence suggests that co- or sequential- infections of MSVs and arboviruses in mosquitoes can change the infection outcome of arboviruses and the vector competence of mosquitoes, possibly through their interaction with the mosquito innate immune response.
Assessing the possibility of MSVs to become arboviruses, and effects of MSV infection on arbovirus transmission, present an additional research interest.
Induction and suppression of tick cell antiviral RNAi response by tick-borne flaviviruses
Schnettler E*, Tykalová H, Watson M, Sharma M, Sterken MG, Obbard DJ, Lewis SH, McFarlane M, Bell-Sakyi L, Barry G, Weisheit S, Best SM, Kuhn RJ, Pijlman GP, Chase-Topping ME, Gould EA, Grubhoffer L, Fazakerley JK, Kohl A*.
(* first shared author)
Nucleic Acids Res. 2014 Aug;42(14):9436-46. doi: 10.1093/nar/gku657. Epub 2014 Jul 22
Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host
Varela M, Schnettler E, Caporale M, Murgia C, Barry G, McFarlane M, McGregor E, Piras IM, Shaw A, Lamm C, Janowicz A, Beer M, Glass M, Herder V, Hahn K, Baumgärtner W, Kohl A, Palmarini M.
PLoS Pathog. 2013 Jan;9(1):e1003133. doi: 10.1371/journal.ppat.1003133. Epub 2013 Jan 10.
RNA interference targets arbovirus replication in Culicoides cells
Schnettler E*, Ratinier M*, Watson M, Shaw AE, McFarlane M, Varela M, Elliott RM, Palmarini M, Kohl A.
(* first shared author)
J Virol. 2013 Mar;87(5):2441-54. doi: 10.1128/JVI.02848-12. Epub 2012 Dec 26.
Knockdown of piRNA pathway proteins results in enhanced Semliki Forest virus production in mosquito cells
Schnettler E#, Donald CL, Human S, Watson M, Siu RW, McFarlane M, Fazakerley JK, Kohl A, Fragkoudis R#.
(#shared corresponding author)
J Gen Virol. 2013 Jul;94(Pt 7):1680-9. doi: 10.1099/vir.0.053850-0. Epub 2013 Apr 4.
Non-coding flavivirus RNA displays RNAi suppressor activity in insect and mammalian cells
Schnettler E, Sterken MG, Leung JY, Metz SW, Geertsema C, Goldbach RW, Vlak JM, Kohl A, Khromykh AA, Pijlman GP.
J Virol. 2012 Dec;86(24):13486-500. doi: 10.1128/JVI.01104-12. Epub 2012 Oct 3.
Advancing vector biology research: a community survey for future directions, research applications and infrastructure requirements.
Kohl, A; Pondeville, E; Schnettler, E; Crisanti, A; Supparo, C; Christophides, GK; Kersey, PJ; Maslen, GL; Takken, W; Koensraadt, CJM; Oliva Nuria Busquets, CF; Abad, FX; Failloux, AB; Levashina, EA; Wilson, AJ; Veronesi, E; Pichard, M; Arnaud Marsh, S; Simard, F and Vernick, KD.
Pathogens and Global Health. 2016. Vol 0, Issue 0, 1-9.
Host inflammatory response to mosquito bites defines severity of arbovirus infection.
Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl A, Merits A, Fazakerley JK, Graham GJ, McKimmie CS.
Immunity. 2016 Jun 21;44(6):1455-69. doi: 10.1016/j.immuni.2016.06.002
Wolbachia blocks viral genome replication early in infection without a transcriptional response by the endosymbiont or host small RNA pathways.
Rainey SM, Martinez J, McFarlane M, Juneja P, Sarkies P, Lulla A, Schnettler E, Varjak M, Merits A, Miska EA, Jiggins FM, Kohl A.
PLoS Pathog. 2016 Apr 18;12(4):e1005536. doi: 10.1371/journal.ppat.1005536. eCollection 2016 Apr.
Dengue in Java, Indonesia: relevance of mosquito indices as risk predictors.
Wijayanti, APM; Sunaryo, S; Suprihatin, S; McFarlane, M; Rainey, SM; Dietrich, I; Schnettler, E; Biek, R and Kohl, A.
PLOS Neglected Tropical Diseases 2016 Mar 11;10(3):e0004500. doi: 10.1371/journal.pntd.0004500. eCollection 2016.
Modulation of potassium channels inhibits bunyavirus infection.
Hover, S.; King, B.; hall, B.; Loundras, EA; Taqi, H; Daly, J; dallas, M; Peers, C; Schnettler, E; McKimmie, C; Kohl, A; Barr, JN and Mankouri, J.
J Biol Chem 2016 Feb 12;291(7):3411-22.
Newly identified RNAs of Raspberry leaf blotch virus encoding a related group of proteins.
Yuwen Lu, Wendy McGavin, Peter J.A. Cock, Esther Schnettler, Fei Yan, Jianping Chen and Stuart MacFarlane.
Journal of General Virology 2015 Nov;96(11):3432-9.
A novel insect-specific flavivirus replicates only in Aedes-derived cells and persists at high prevalence in wild Aedes vigilax populations in Sydney, Australia.
Breeanna McLean; Jody Hobson-Peters; Cameron E Webb; Daniel Watterson;
Natalie A Prow; Hong Duyen Nguyen ; Sonja Hall-Mendelin; David Warrilow; Cheryl A Johansen; Cassie Jansen; Andrew van den Hurk; Nigel W Beebe; Esther Schnettler; Ross T Barnard; Roy Hall
Virology 2015 Dec;486:272-83. doi: 10.1016/j.virol.2015.07.021.
Transcriptome analysis reveals the host response to Schmallenberg virus in bovine cells and antagonistic effects of the NSs protein.
Blomström A.-L., Q. Gu, G. Barry, G. Wilkie, J. K. Skelton, M. Baird, M. McFarlane, E. Schnettler, R. M. Elliott, M. Palmarini, and A. Kohl.
BMC Genomics 2015 Apr 19;16:324. doi: 10.1186/s12864-015-1538-9.
Fighting arbovirus transmission: nutural and engineerd control of vector competence in Aedes mosquitoes.
Kean, J., Rainey, S.M., McFarlane, M., Donald, C.L., Schnettler, E., Kohl, A. And Pondeville, E. (2015)
Insects. 6(1): 236-278
Induction and suppression of tick cell antiviral RNAi response by tick-borne flaviviruses.
Schnettler, E.#; Tykalova, H.; Watson, M.; Sharma, M.; Sterken, M.G.; Obbard, D.J.; Lewis, S.H.; McFarlane, M.; Bell-Sakyi, L.; Barry, G.; Weisheit, S.; Best, S.; Kuhn, R.; Pijlman, G.; Chase-Topping, M.E.; Gould, E.A.; Grubhoffer, L.; Fazakerley, J. and Kohl, A.# (2014)
Nucleic Acid Research 42(14): 9436-46
Characterization of Aedes aegypti innate-immune pathways that limit Chikungunya virus replication.
McFarlane, M.; Arias-Goeta, C.; Martin, E.; O`Hara, Z.; Lulla, A.; Mousson, L.; Graham, S.M.; Misbah, S.; Schnettler, E.; Donald, C.L.; Merits, A.; Kohl, A. and Failloux, A-B. (2014)
PLOS neglected tropical diseases 8(7): e2994. Doi: 10.1371/journal.pntd.0002994
NSs protein of Schmallenberg virus counteracts the antiviral response of the cell by inhibiting its transcriptional machinery.
Barry, G., M. Varela, M. Ratinier, A. L. Blomstrom, M. Caporale, F. Seehusen, K. Hahn, E. Schnettler, W. Baumgartner, A. Kohl and M. Palmarini (2014).
J Gen Virol. 95(8): 1640-1646
Non-structural proteins of arthropod-borne bunyaviruses: roles and functions.
Eifan, S.*; Schnettler, E.*; Dietrich, I.; Kohl, A. And Blomstrom, A. (2013)
Viruses, 5(10): 2447-2468
viRome: an R package for the visualization and analysis of viral small RNA sequence datasets.
Watson, M.; Schnettler, E. and Kohl, A. (2013).
Bioinformatics, 29(15): 1902-1903
Knockdown of piRNA pathway proteins results in enhanced Semliki Forest virus production in mosquito cells.
Schnettler, E.#; Donald, C.L.; Human, S.; Watson, M.; Siu, R.W.C.; McFarlane, M.; Fazakerley, J.K.; Kohl, A. & Fragkoudis, R.# (2013)
J Gen Virol. 94 (7): 1680-1689
Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host.
Varela, M.; Schnettler, E.; Caporale, M.; Murgia, C.; Barry, G.; McFarlane, M.; McGregor, E.; Piras, I.M.; Shaw, A.; Lamm, C.; Beer, M.; Glass, M.; Herder, V.; Hanh, K.; Baumgärtner, W.; Kohl, A. & Palmarini, M. (2013)
PLoS Pathog. 9(1): e1003133
RNA interference targets arbovirus replication in Culicoides cells.
Schnettler, E.*; Ratinier, M.*; Watson, M.; Shaw, A.; McFarlane, M.; Varela, M.; Elliott, R.M.; Palmarini, M. & Kohl, A. (2013)
J Virol., 87(5): 2441-54
Gene silencing in tick cell lines using small interfering or long double-stranded RNA.
Barry, G.; Alberdi, P.; Schnettler, E.; Weisheit, S.; Kohl, A.; Fazakerley, J.K. and Bell-Sakyi, L. (2013).
Experimental and Applied Acarology, 59(3): 319-338
Prophenol oxidase activity acts as a mosquito innate immune response against infection with Semliki Forest virus.
Julio Rodriguez-Andres, J.; Rani, S.; Varjak, M.; Chase-Topping, M. E.; Ferguson, M. C.; Schnettler, E.; Fragkoudis, R.; Beck, M. H.; Barry, G.; Nash, A. A.; Merits, A.; Fazakerley, J. K.; Strand M. R. and Kohl, A.
PLoS Pathog. 8(11): e1002977
Non-coding flavivirus RNA displays RNAi suppressor activity in insect and mammalian cells.
Schnettler, E.; Sterken, M.G.; Leung, J.Y.; Metz, S.W.; Geertsema, C.; Goldbach, R.W.; Vlak, J.M.; Kohl, A.; Khromykh, A.A.; Pijlman, G.P. (2012)
J Virol. 86(24): 13486-13500
New insights into control of arbovirus replication and spread by insect RNA interference pathways.
Donald, C.; Kohl, A. and Schnettler, E. (2012)
Insects. 3(2): 511-531
West Nile virus encodes a microRNA-like small RNA in the 3’ untranslated region which upregulates GATA4 mRNA and facilitates virus replication in mosquito cells.
Hussain, M.; Torres, S.; Schnettler, E.; Funk, A.; Grundhoff, A.; Pijlman, G.; Khromykh, A.; Asgari, S. (2012)
Nucleic Acids Res. 40(5): 2210-2223
Diverging affinity of tospovirus RNA silencing suppressor proteins, NSs, for various RNA duplex molecules.
Schnettler, E.*, Hemmes, H.*, Huismann, R., Goldbach, R.; Prins, M & Kormelink, R. (2010).
J Virol. Nov;84(21):11542-54
Chikungunya virus nonstructural protein 2 inhibits type I/II interferon2 stimulated JAK-STAT signaling.
Fros, J., Liu, W. J., Prow, N. A., Geertsema, C., Ligtenberg, M., Vanlandingham, D. L., Schnettler, E., Vlak, J. M., Khromykh, A. A., Pijlman, G. P. (2010)
J Virol. Oct;84(20):10877-87
Binding of siRNA molecules is crucial for RNAi suppressor activity of Rice hoja blanca virus NS3 in plants.
Hemmes, H., Kaaij, L., Lohuis, D., Prins, M., Goldbach, R. & Schnettler, E. (2009)
J Gen Virol. 90: 1762-1766.
The NS3 protein of rice hoja blanca virus complements the RNAi suppressor function of HIV-1 Tat.
Schnettler, E.*, de Vries, W.*, Hemmes, H., Haasnoot, J., Kormelink, R., Goldbach, R. & Berkhout, B. (2009)
EMBO Rep 10: 258-63).
Binding of siRNA molecules is crucial for RNAi suppressor activity of Rice hoja blanca virus NS3 in plants.
Hemmes, H., Kaaij, L., Lohuis, D., Prins, M., Goldbach, R. & Schnettler, E. (2009)
J Gen Virol. 90: 1762-1766.
The NS3 protein of rice hoja blanca virus complements the RNAi suppressor function of HIV-1 Tat.
Schnettler, E.*, de Vries, W.*, Hemmes, H., Haasnoot, J., Kormelink, R., Goldbach, R. & Berkhout, B. (2009)
EMBO Rep 10: 258-63).
The NS3 protein of rice hoja blanca virus suppresses RNA silencing in mammalian cells.
Schnettler, E., Hemmes, H., Goldbach, R. and Prins, M. (2008)
J Gen Virol, 89, 336-340
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