A Dengue Virus Type 4 Model of Disseminated Lethal Infection in AG129 Mice.
Dengue is a mosquito-borne disease of global public health significance that is caused by four serologically and genetically related viruses (DENV-1 to DENV-4). Most human DENV infections are asymptomatic, but clinical cases can range in severity from a relatively mild self-limiting illness to a severe life-threatening disease. Infection with one serotype of DENV results in life-long homotypic immunity but only short term heterotypic protection. There are no licensed vaccines or antivirals for dengue due in part to difficulty in developing small animal models that mimic the systemic disease seen in humans. Consequently, an important advance was the description of models of DENV-2 infection in AG129 mice (deficient in interferon alpha/beta and gamma receptor signaling) that resemble human disease. However, the need for well characterized models of disease due to DENV-1, -3, and -4 still remains. Here we describe a new AG129 mouse model utilizing a non-mouse-adapted Thai human DENV-4 strain 703-4. Following intraperitoneal challenge, animals experience a rapidly progressive lethal infection without developing neurologic clinical signs of disease. High virus titers are seen in multiple visceral tissues including the liver, spleen and large intestine, and the infected animals develop vascular leakage and thrombocytopenia, hallmarks of human dengue. Taken together, our studies demonstrate that this model is an important addition to the field of dengue research particularly in understanding similarities and differences in the pathologic basis of the disease caused by different DENV serotypes and in determining comparative efficacy of putative vaccines and antivirals.
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America; Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Gregg N
GN
Milligan
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Vanessa V
VV
Sarathy
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America.
Ernesto
E
Infante
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Li
L
Li
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Gerald A
GA
Campbell
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, United States of America.
P Robert
PR
Beatty
Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
Eva
E
Harris
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Alan D T
AD
Barrett
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America; Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Nigel
N
Bourne
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002452:Cell Count; D018925:Chemokines / Q000097:blood; D002522:Chlorocebus aethiops; D003715:Dengue / Q000097:blood / Q000150:complications / Q000821:virology*; D003716:Dengue Virus / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D007422:Intestines / Q000098:blood supply / Q000473:pathology; D007970:Leukopenia / Q000097:blood / Q000209:etiology; D008099:Liver / Q000098:blood supply / Q000473:pathology; D051379:Mice; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology; D014709:Vero Cells; D014766:Viremia / Q000097:blood / Q000821:virology
D000914:Antibodies, Viral; D018925:Chemokines