Dengue is a mosquito-borne flavivirus that is spreading explosively in many parts of the world. Currently more than half of the world’s population is at risk of infection by one or more of the 4 serotypes of dengue virus. Clinically dengue can present as a serious febrile illness or a severe, life-threatening disease known as dengue hemorrhagic fever. The de Silva laboratory studies the basic virology, human immunology and pathogenesis of dengue. The follow projects are currently ongoing in the laboratory.
1. Human Antibodies in Protective and Pathogenic Immunity to Dengue
Antibodies are critical for protection from dengue infection. Antibodies can also enhance the ability of dengue virus to infect cells and potentially enhance disease in humans. Current studies focus on mapping viral epitopes recognized by human antibodies and defining the functional properties of different antibodies in cell culture and in vivo models.
2. The Cell Biology of Dengue Virus Entry into Cells
We study the receptors and pathways used by dengue to infect human cells. We are especially interested in how antibodies block or promote dengue viral entry.
3. The Human Antibody Response to Live Dengue Virus Vaccines
Vaccination remains one of the most promising tools for preventing dengue. We are currently extending our discoveries about the properties of antibodies induced after natural infection to evaluate the properties of antibodies induced by leading dengue vaccine candidates.
4. Nanoparticle Based Dengue Vaccines
We are currently working with a consortium of laboratories at UNC to use nanoparticles to design and deliver tetravalent dengue vaccines. We recently discovered that many human neutralizing antibodies bind to complex quaternary structure epitopes displayed on the viral surface. Studies are underway to recreate these epitopes on nanoparticles.
5. Viral Determinants of Dengue Emergence and Severe Disease
The clinical outcome of a dengue infection is dependent on both host and viral factors. The actual viral genetic elements, proteins and phenotypes responsible for severe disease have not been well-defined. Through long-term studies in South Asia, we have identified distinct genotypes of serotype 1 and 3 responsible for mild and severe disease epidemics. We are currently exploring several ideas about properties dengue viruses responsible for mild versus severe disease epidemics.
6. Dengue as a Vehicle for Promoting International Scientific Partnerships
We believe that access to scientific knowledge and the ability to conduct scientific research is integral to the independence and development of any country. Our research is guided by the principle that vibrant scientific institutions and communities need to be established in poor and middle income countries to solve problems like dengue. We have collaborated with colleagues in Sri Lanka for the past 20 years to understand changing epidemiology of dengue on the Island. We support the regular exchange of students and other researchers between UNC and Colombo to promote collaborative research and training activities.
Corbett KS, Katzelnick L, Tissera H, Amerasinghe A, de Silva AD, de Silva AM (2015) Preexisting Neutralizing Antibody Responses Distinguish Clinically Inapparent and Apparent Dengue Virus Infections in a Sri Lankan Pediatric Cohort. Journal of Infectious Diseases 211: 590-599.
Tissera H, Amarasinghe A, De Silva AD, Kariyawasam P, Corbett KS, Katzelnick L, Tam C, Letson GW, Margolis HS, de Silva AM (2014) Burden of dengue infection and disease in a pediatric cohort in urban Sri Lanka. The American Journal of Tropical Medicine and Hygiene 91: 132-137.
Smith SA, de Alwis AR, Kose N, Jadi RS, de Silva AM, Crowe JE (2014) Isolation of dengue virus-specific memory B cells with live virus antigen from human subjects following natural infection reveals the presence of diverse novel functional groups of antibody clones. Journal of Virology 88: 12233-12241.
Fibriansah G, Tan JL, Smith SA, de Alwis R, Ng T-S, Kostyuchenko VA, Jadi RS, Kukkaro P, de Silva AM, Crowe JE, Lok SM. 2015. A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. 2015 Nature Communications. 6:6341.
de Alwis R, Williams KL, Schmid MA, Lai C-Y, Patel B, Smith SA, Crowe JE, Wang W-K, Harris E, de Silva AM (2014) Dengue Viruses Are Enhanced by Distinct Populations of Serotype Cross-Reactive Antibodies in Human Immune Sera. PLoS Pathogens 10: e1004386.
Smith SA, de Alwis R, Kose N, Durbin AP, Whitehead SS, de Silva AM, Crowe JE (2013) Human monoclonal antibodies derived from memory B cells following live attenuated dengue virus vaccination or natural infection exhibit similar characteristics. Journal of Infectious Diseases 207: 1898-1908.
de Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM, White LJ, Diamond MS, Baric RS, Crowe JE, de Silva AM (2012) Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proceedings of the National Academy of Sciences 109: 7439-7444.
de Alwis R, Beltramello M, Messer WB, Sukupolvi-Petty S, Wahala WM, Kraus A, Olivarez NP, Pham Q, Brian J, Tsai WY, Wang WK, Halstead S, Kliks S, Diamond MS, Baric R, Lanzavecchia A, Sallusto F, de Silva AM (2011). Correction: in-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl Trop Dis. 5(8). doi: 10.1371/annotation/f585335f-ff77-40ae-a8b6-ad6019af31aa.
de Alwis R, Beltramello M, Messer WB, Sukupolvi-Petty S, Wahala WM, Kraus A, Olivarez NP, Pham Q, Brian J, Tsai WY, Wang WK, Halstead S, Kliks S, Diamond MS, Baric R, Lanzavecchia A, Sallusto F, de Silva AM (2011). In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl Trop Dis. 5(6):e1188.
Wahala WM, Donaldson EF, de Alwis R, Accavitti-Loper MA, Baric RS, de Silva AM (2010). Natural strain variation and antibody neutralization of dengue serotype 3 viruses. PLoS Pathog. 6(3):e1000821.
Wahala WM, Kraus AA, Haymore LB, Accavitti-Loper MA, de Silva AM (2009). Dengue virus neutralization by human immune sera: role of envelope protein domain III-reactive antibody. Virology. 392(1):103-13.
Srivastava SY, de Silva AM (2009). Characterization of Borrelia burgdorferi aggregates. Vector Borne Zoonotic Dis. 9(3):323-9.
Hacker K, White L, de Silva AM (2009). N-linked glycans on dengue viruses grown in mammalian and insect cells. J Gen Virol. 90(Pt 9):2097-106.
de Silva AM, Tyson KR, Pal U (2009). Molecular characterization of the tick-Borrelia interface. Front Biosci. 14:3051-63. Review.
Srivastava SY, de Silva AM (2008). Reciprocal expression of ospA and ospC in single cells of Borrelia burgdorferi. J Bacteriol. 190(10):3429-33.
Tyson KR, Elkins C, de Silva AM (2008). A novel mechanism of complement inhibition unmasked by a tick salivary protein that binds to properdin. J Immunol. 180(6):3964-8.
Kraus AA, Messer W, Haymore LB, de Silva AM (2007). Comparison of plaque- and flow cytometry-based methods for measuring dengue virus neutralization.
J Clin Microbiol.45(11):3777-80.
Strother KO, Hodzic E, Barthold SW, de Silva AM (2007). Infection of mice with lyme disease spirochetes constitutively producing outer surface proteins a and B. Infect Immun. 75(6):2786-94.
Nosbisch LK, de Silva AM (2007). Lack of detectable variation at Borrelia burgdorferi vlsE locus in ticks. J Med Entomol. 44(1):168-70.
Strother, K.O., Broadwater, A. and A. M. de Silva. (2005). Plasmid requirements for infection of ticks by Borrelia burgdorferi. Vector-borne and Zoonotic Dis. 5(3): 237-245.
Strother, K.O. and de Silva AM (2005) Role of Borrelia burgdorferi linear plasmid 25 in infection of Ixodes scapularis ticks. Journal of Bacteriology. 187(16) 5776-81.
Lambeth, C.R., White, L.J., Johnston, R.E., and de Silva A.M. (2005). Flow cytometry based assay for titrating dengue virus. Journal of Clinical Microbiology. 43 (7) 3267-72.
Gipson, C.L. and de Silva A.M. (2005) Interactions of OspA Monoclonal Antibody C3.78 with Borrelia burgdorferi within Ticks. Infection and Immunity 73 (3) 1644-7.