Rebecca Rico-Hesse, Ph.D., M.P.H.
Department of Molecular Virology and Microbiology and Pediatrics
Dengue virus is a single-stranded RNA Flavivirus that causes dengue fever (DF), the most prevalent arthropod-borne viral illness in humans. Dengue viruses cause an estimated 50 million new cases of DF and 500,000 cases of dengue hemorrhagic fever (DHF) per year in tropical and subtropical areas of the world, with >100 countries with endemic transmission. Currently, no specific treatment or licensed vaccine is available for either DF or DHF. Given its global burden, increased travel and military activity in dengue-endemic areas, there is an urgent need for: (a) animal models of disease, to understand the basics of dengue pathogenesis, especially the mechanisms that lead to the more severe DHF, and whether vaccination might actually enhance disease, and (b) to develop therapeutics for treatment after infection, or for persons at high risk of developing severe disease. The humanized mouse model of dengue developed by the Rico-Hesse laboratory is the only one that shows consistent signs of disease as in humans, after infection with low-passage, or “clinical” isolates of the virus, via mosquito bite. We have streamlined the production of these mice, using NOD/SCID/IL2gnull mice and human hematopoietic stem cells from normal birth cord blood and we also infect these mice by mosquito bite, to mimic natural transmission. We currently pursue two lines of research:
The effect of mosquito saliva on dengue virus pathogenesis. Our preliminary data point to a major enhancement of dengue virus replication and pathogenesis in humanized mice, due to mosquito saliva components; the mice develop the typical “saddleback”, prolonged viremia and rash that occurs in humans, before going on to develop more severe disease. These mice also develop human antibodies to dengue after mosquito bite, in contrast with no antibodies after virus injection by syringe, providing evidence that these mice can mount an adaptive immune response. These results have led us to propose studies to define the specific mechanisms of infection and pathogenesis in this unique laboratory system that mimics the natural cycle of dengue transmission. The specific aims are: (a) Definition of determinants of dengue pathogenesis in humanized mice, including pinpointing specific genome regions involved in viral replication and tropism, measurement of human antibodies and cellular immunity after mosquito infection, and the possibility of inducing typical DHF, with hemorrhagic signs of disease, after serial infection; and (b) Evaluation of the individual and combined effects of mosquito saliva components on rates of infection and dengue pathogenesis in humanized mice, including using injection of recombinant saliva proteins and deletion or knockdown of some of these saliva proteins, in engineered mosquitoes.
Testing genetically-modified, neutralizing monoclonal antibodies, for efficacy in treating the clinical signs of DF or DHF in humanized mice, caused by all DV serotypes. We expect to validate that these mAbs, which are modified in their Fc regions to eliminate the possibility of antibody-dependent enhancement of infection (ADE), are safe and effective therapeutic agents for infection by the 4 serotypes of dengue virus. We will test independently and together, in humanized mice, a strongly neutralizing anti-envelope protein antibody that recognizes the highly cross-reactive fusion loop on domain II and a second antibody that binds the conserved A-strand of domain III and is serocomplex-specific (i.e., all dengue serotypes). Humanized and modified forms of these mAbs will be tested as a post-infection therapeutic in the humanized mouse model (days 3 and 7 post-infection). We also propose to test for ADE in vivo, after serial infection of mice, to compare parent and modified mAbs, and whether they cause severe dengue clinical signs in humanized mice. The production, testing, and validation of these modified humanized antibodies in a unique and more relevant animal model of disease is critical in developing novel immunotherapeutics against this NIAID category A pathogen.
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77007
M.P.H., University of Minnesota
Ph.D., Cornell University
Postdoctoral, Centers for Disease Control
Awards, Appointments and Honors
1977- National Hispanic Student Award, Los Angeles, CA
1983 - W.F. Scherer Memorial Award, American Society of Tropical Medicine & Hygiene
1985 - National Research Council Postdoctoral Fellowship, National Academy of Science
1988 - Charles C. Shepard Science Award, Centers for Disease Control, Atlanta, GA
1989 - Public Health Service Special Recognition Award, National Institutes of Health, Bethesda, MD
1990- Councilor, American Society of Tropical Medicine and Hygiene
1992- Chair, American Committee on Arthropod-borne Viruses
1993 - Research Career Development Award, National Institutes of Health
2001- Chair, Gorgas Memorial Research Award Committee
2007- Chair, Virology Program Committee, American Society of Tropical Medicine and Hygiene
2010- Outstanding Cultural and Scientific Achievements Award, Instituto Cultural de Mexico, San Antonio, TX
Cologna, R., and Rico-Hesse, R. (2003). American genotype structures decrease dengue virus output from human monocyte and dendritic cells. J. Virol. 77:3929-3938.
Armstrong, P.M., and Rico-Hesse, R. (2003). Efficiency of dengue serotype 2 virus strains to infect and disseminate in Aedes aegypti. Am. J. Trop. Med. Hyg. 68:539-544.
Cologna, R., Armstrong, P.M., and Rico-Hesse, R. (2005). Selection for virulent dengue viruses occurs in humans and mosquitoes. J. Virol. 79:853-859.
Bente, D.A., Melkus, M.W., Garcia, J.V., and Rico-Hesse, R. (2005). Dengue fever in humanized NOD/SCID mice. J. Virol. 79:13797-13799.
Anderson, J.A., and Rico-Hesse, R. (2006). Aedes aegypti vectorial capacity is determined by the infecting genotype of dengue virus. Am. J. Trop. Med. Hyg. 75:886-892.
Rico-Hesse, R. (2007). Dengue virus evolution and virulence models. Clin. Inf. Dis. 44:1462-1466.
Mota, J., and Rico-Hesse, R. (2009). Humanized mice show clinical signs of dengue fever according to infecting virus genotype. J. Virol. 83: 8638-8645.
Sukupolvi-Petty, S, Austin, SK, Engle, M, Brien, JD, Dowd, KA, Williams, KL, Johnson, S, Rico-Hesse, R, Harris, E, Pierson, TC, Fremont, DH, Diamond, MS. (2010). Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. J Virol 84:9227-9239.
Mota, J, Rico-Hesse, R. (2011). Dengue virus tropism in humanized mice recapitulates human dengue fever. PLoS One 6:e20762-20771.
Cox, J, Brown, HE, Rico-Hesse, R. (2011). Variation in vector competence for dengue viruses does not depend on mosquito midgut binding affinity. PLoS Neglected Trop. Dis. 5:e1172-1178.
Cox, J, Mota, J, Sukupolvi-Petty, S, Diamond, MS, Rico-Hesse, R. (2012). Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice. J. Virol. 86:7637-7649.
Janine Dailey Garnes
Mary Richter Haac