title: Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/β and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model.
abstract: Dengue is a mosquito-borne disease caused by four related but distinct dengue viruses, DENV-1 to DENV-4. Dengue is endemic in most tropical countries, and over a third of the world's population is at risk of being infected. Although the global burden is high, no vaccine or antiviral is licensed to combat this disease. An obstacle complicating dengue research is the lack of animal challenge models that mimic human disease. Advances in immunocompromised murine infection models resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice, which are deficient in both the IFN-α/β receptor (IFN-α/βR) and the IFN-γ receptor (IFN-γR). These models mimic features of dengue disease in humans. Here, we characterized lethal infection of AG129 mice by DENV-4 strain TVP-376 and found that AG129 mice developed clinical signs of illness and high viral loads in multiple tissues and succumbed 5 days after infection. Moreover, the splenic and hepatic histopathology of TVP-376-infected mice demonstrated the presence of cell activation and destruction of tissue architecture. Furthermore, infected mice had heightened levels of circulating cytokines. Comparison of the virulence phenotypes of DENV-4 strain TVP-376 and DENV-2 strain D2S10 revealed that TVP-376-induced mortality occurred in the absence of both IFN-α/βR and IFN-γR signalling, but not with intact signalling from the IFN-γR, whereas D2S10 required the absence of IFN-α/βR signalling only, indicating that it is more virulent than TVP-376. In conclusion, TVP-376 is lethal in AG129 mice, and this model provides a useful platform to investigate vaccine candidates and antivirals against DENV-4.
authors: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Vanessa V
authors: VV
authors: Sarathy
authors: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Ernesto
authors: E
authors: Infante
authors: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Li
authors: L
authors: Li
authors: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Gerald A
authors: GA
authors: Campbell
authors: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Tian
authors: T
authors: Wang
authors: Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.|Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.|Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Slobodan
authors: S
authors: Paessler
authors: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley, Berkeley, California, USA.
authors: P
authors: P
authors: Robert Beatty
authors: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
authors: Eva
authors: E
authors: Harris
authors: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Gregg N
authors: GN
authors: Milligan
authors: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Nigel
authors: N
authors: Bourne
authors: Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.|Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.|Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Alan D T
authors: ADT
authors: Barrett
mesh_terms: D000825:Animal Structures / Q000821:virology; D000818:Animals; D016207:Cytokines / Q000097:blood; D003715:Dengue / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D004195:Disease Models, Animal; D008099:Liver / Q000473:pathology; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency*; D017471:Receptors, Interferon / Q000172:deficiency*; D013154:Spleen / Q000473:pathology; D019562:Viral Load; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor