Mucosal innate and adaptive immune responses against herpes simplex virus type 2 in a humanized mouse model.
Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is one of the most prevalent sexually transmitted diseases worldwide and a risk factor for acquiring human immunodeficiency virus. Although many vaccine candidates have shown promising results in animal models, they have failed to be effective in human trials. In this study, a humanized mouse strain was evaluated as a potential preclinical model for studying human immune responses to HSV-2 infection and vaccination. Immunodeficient mouse strains were examined for their abilities to develop human innate and adaptive immune cells after transplantation of human umbilical cord stem cells. A RAG2(-/-) gammac(-/-) mouse strain with a BALB/c background was chosen as the most appropriate model and was then examined for its ability to mount innate and adaptive immune responses to intravaginal HSV-2 infection and immunization. After primary infection, human cells in the lymph nodes were able to generate a protective innate immune response and produce gamma interferon (IFN-gamma). After intravaginal immunization and infection, human T cells and NK cells were found in the genital tract and iliac lymph nodes. In addition, human T cells in the spleen, lymph nodes, and vaginal tract were able to respond to stimulation with HSV-2 antigens by replicating and producing IFN-gamma. Human B cells were also able to produce HSV-2-specific immunoglobulin G. These adaptive responses were also shown to be protective and reduce local viral replication in the genital tract. This approach provides a means for studying human immune responses in vivo using a small-animal model and may become an important preclinical tool.
Kwant-Mitchell
Amanda
A
Michael G. DeGroote Institute for Infectious Disease Research, Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Ashkar
Ali A
AA
Rosenthal
Kenneth L
KL
D000282:Administration, Intravaginal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004195:Disease Models, Animal; D006558:Herpes Genitalis / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007114:Immunization; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology; D014470:Umbilical Cord
D000914:Antibodies, Viral; D022301:Herpes Simplex Virus Vaccines