Immunity to vaginal infection by herpes simplex virus type 2 in adult mice: characterization of the immunoglobulins in vaginal mucus

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 ؊/؊ ␥c ؊/؊ 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-␥). 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-␥. 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.

Section: Discussionmentioning

confidence: 99%

Mucosal Innate and Adaptive Immune Responses against Herpes Simplex Virus Type 2 in a Humanized Mouse Model

Kwant-Mitchell

Ashkar

Rosenthal

2009

“…Virus-specific antibody induced by parenteral vaccination could in theory affect a subsequent HSV infection via the genital tract at any point in its route from the mucosal epithelium to the CNS. The genital tract is unique among mucosal surfaces in that the quantity of antigen-specific IgG transcends that of IgA (18,25,35,44), although antigen-specific IgA may predominate after mucosal immunization (36) (unpublished data). IgA is produced primarily by plasma cells in the mucosa and is actively secreted, whereas IgG appears in genital secretions as a transudate from mucosal production sites and/or serum (3,31), in which IgG is the predominant Ig component.…”

Section: Discussionmentioning

confidence: 99%

“…Prophylactic immunization ideally would reduce infection of the genital epithelium and prevent latent infection of the ganglia, thereby eliminating the recurrent HSV-2 infections that provide opportunities for transmission to sex partners and newborns (60), as well as provide portals of entry for other pathogens such as human immunodeficiency virus (6,11,49). An understanding of how the response to immunization protects mucosally and systemically against subsequent HSV-2 genital infection would further the development of vaccines against sexually transmitted diseases, and HSV in particular.HSV-2 infection of the genital mucosa elicits HSV-specific immunoglobulin G (IgG) and IgA in the genital tracts of both humans (1) and mice (25,27,35,44). HSV-specific IgG, but not IgA, can also be detected in genital secretions after parenteral immunization of mice (36,56).…”

mentioning

confidence: 99%

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Vaccine-Induced Serum Immunoglobin Contributes to Protection from Herpes Simplex Virus Type 2 Genital Infection in the Presence of Immune T Cells

Morrison

Zhu

Thebeau

2001

Herpes simplex type virus 2 (HSV-2) is a sexually transmitted pathogen that causes genital lesions and spreads to the nervous system to establish acute and latent infections. Systemic but not mucosal cellular and humoral immune responses are elicited by immunization of mice with a replication-defective mutant of HSV-2, yet the mice are protected against disease caused by subsequent challenge of the genital mucosa with virulent HSV-2. In this study, we investigated the role of immune serum antibody generated by immunization with a replication-defective HSV-2 vaccine prototype strain in protection of the genital mucosa and the nervous system from HSV-2 infection. Passive transfer of replication-defective virus-immune serum at physiologic concentrations to SCID or B-cell-deficient mice had no effect on replication of challenge virus in the genital mucosa but did significantly reduce the incidence and severity of genital and neurologic disease. In contrast, B-cell-deficient mice immunized with replication-defective HSV-2 were able to control replication of challenge virus in the genital mucosa, but not until 3 days postchallenge, and were not completely protected against genital and neurologic disease. Passive transfer of physiologic amounts of immune serum to immunized, B-cell-deficient mice completely restored their capacity to limit replication of challenge virus in the genital mucosa and prevented signs of genital and systemic disease. In addition, the numbers of viral genomes in the lumbosacral dorsal root ganglia of immunized, B-cell-deficient mice were dramatically reduced by transfer of immune serum prior to challenge. These results suggest that there is an apparent synergism between immune serum antibody and immune T cells in achieving protection and that serum antibody induced by vaccination with replication-defective virus aids in reducing establishment of latent infection after genital infection with HSV-2.Mucosal surfaces are a favored entry site for numerous pathogenic microorganisms. Infections with some of these organisms remain localized to the mucosal epithelium, while others spread systemically. The mucosal entry points are thought to be guarded by local mucosal immune responses, but systemic immune protection also can extend into the mucosa. This is particularly true of humoral immunity; antibody bathes interstitial spaces and can pass through the mucosa as a transudate from serum. Herpes simplex virus type 2 (HSV-2) is a common human pathogen that enters the body primarily via the genital mucosa. HSV-2 replicates in the genital epithelium and spreads to lumbosacral sensory ganglia, where latent infection is maintained for the life of the individual. Periodic reactivation results in reinfection of the genital epithelium innervated by the infected dorsal root ganglia (DRG). Prophylactic immunization ideally would reduce infection of the genital epithelium and prevent latent infection of the ganglia, thereby eliminating the recurrent HSV-2 infections that provide opportunities for transmission to s...

“…This study did not determine what proportion of these antibodies were from local production as opposed to serum transudation. Numerous studies have indicated that the local production of IgG is an important component of the mucosal immune responses following traditional mucosal immunization or infection (1,36,37,44). A recent study showed that passive transfer of serum antibodies to mice did not lead to appreciable levels of IgG transudation in fecal extracts and vaginal wash fluids (14).…”

Section: Discussionmentioning

confidence: 99%

Serum and Mucosal Immune Responses to an Inactivated Influenza Virus Vaccine Induced by Epidermal Powder Immunization

Chen

Periwal

Larrivee

et al. 2001

Both circulating and mucosal antibodies are considered important for protection against infection by influenza virus in humans and animals. However, current inactivated vaccines administered by intramuscular injection using a syringe and needle elicit primarily circulating antibodies. In this study, we report that epidermal powder immunization (EPI) via a unique powder delivery system elicits both serum and mucosal antibodies to an inactivated influenza virus vaccine. Serum antibody responses to influenza vaccine following EPI were enhanced by codelivery of cholera toxin (CT), a synthetic oligodeoxynucleotide containing immunostimulatory CpG motifs (CpG DNA), or the combination of these two adjuvants. In addition, secretory immunoglobulin A (sIgA) antibodies were detected in the saliva and mucosal lavages of the small intestine, trachea, and vaginal tract, although the titers were much lower than the IgG titers. The local origin of the sIgA antibodies was further shown by measuring antibodies released from cultured tracheal and small intestinal fragments and by detecting antigen-specific IgA-secreting cells in the lamina propria using ELISPOT assays. EPI with a single dose of influenza vaccine containing CT or CT and CpG DNA conferred complete protection against lethal challenges with an influenza virus isolated 30 years ago, whereas a prime and boost immunizations were required for protection in the absence of an adjuvant. The ability to elicit augmented circulating antibody and mucosal antibody responses makes EPI a promising alternative to needle injection for administering vaccines against influenza and other diseases.