Evidence that deficient IFN-γ production is a biological basis of herpes simplex virus type-2 neurovirulence

1998 ◽  
Vol 81 (1-2) ◽  
pp. 66-75 ◽  
Author(s):  
Gail Lewandowski ◽  
Monte Hobbs ◽  
Alfred Geller
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Biological Basis ◽  
Ifn Γ ◽  
Simplex Virus

scholarly journals Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

2001 ◽  
Vol 82 (4) ◽  
pp. 845-853 ◽  
Author(s):  
Ali M. Harandi ◽  
Bo Svennerholm ◽  
Jan Holmgren ◽  
Kristina Eriksson
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
B Cells ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Ifn Γ ◽  
Simplex Virus

The role of B, CD4+ T and CD8+ T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated. Following primary inoculation with attenuated thymidine kinase-deficient (TK−) HSV-2, B cell-deficient (μMT) mice developed a local viraemia and transient genital inflammation, suggesting a role for B cells in the innate control of local infection and inflammation. Natural antibodies are implicated in this process, as passive transfer of normal serum into μMT mice significantly reduced HSV-2 TK− shedding in the vaginal lumen, although it did not affect subsequent inflammation. Protection against lethal HSV-2 challenge was noted in HSV-2-vaccinated wild-type, CD8+ T cell-deficient and μMT mice and was characterized by strong virus-specific IFN-γ responses in vitro and delayed type hypersensitivity (DTH) responses in vivo. In contrast, CD4+ T cell-deficient (CD4−/−) mice had impaired HSV-2-specific IFN-γ production and DTH responses and succumbed rapidly to genital HSV-2 challenge. However, protective responses to HSV-2 could be induced in HSV-2-vaccinated CD4−/− mice by treatment with recombinant IFN-γ. Taken together, these results suggest that CD4+ T cells secreting IFN-γ are critical for immune protection against lethal genital HSV-2 re-infection, whereas B cells/natural antibodies have anti-viral and -inflammatory effects in the innate control of a primary infection.

scholarly journals Herpes simplex virus type 2 induces secretion of IL-12 by macrophages through a mechanism involving NF-κB

2000 ◽  
Vol 81 (12) ◽  
pp. 3011-3020 ◽  
Author(s):  
Lene Malmgaard ◽  
Søren R. Paludan ◽  
Søren C. Mogensen ◽  
Svend Ellermann-Eriksen
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Neutralizing Antibodies ◽  
Parasitic Infections ◽  
Virus Infectivity ◽  
Ifn Γ ◽  
Simplex Virus

Interleukin (IL)-12 is an important proinflammatory and immunoregulatory cytokine expressed primarily by macrophages. Although IL-12 appears to be essential for clearance of many bacterial and parasitic infections, only little is known about the production and regulation of this cytokine during viral infections. In this study we have shown that infection of mouse macrophages with herpes simplex virus type 2 (HSV-2) induces secretion of the p40 subunit of IL-12, and this induction was synergistically enhanced by interferon (IFN)-γ. The production of IL-12 p40 was accompanied by production of bioactive IL-12 p70, since HSV-2-induced IFN-γ secretion was blocked by neutralizing antibodies against IL-12. The IL-12-inducing effect of HSV-2 was abrogated when virus infectivity was destroyed by heat or UV irradiation, indicating that a functional viral genome is required and that interaction of viral glycoproteins with cellular receptors is not sufficient. Production of IL-12 p40 was transcriptionally regulated and required de novo protein synthesis. Although IFN-α, IL-1β and tumour necrosis factor-α marginally influenced IL-12 production, they did not seem to constitute the endogenous factor(s) responsible for the effect of the virus infection. HSV-2 infection induced nuclear-binding activity to the κB halfsite of the IL-12 p40 promoter, and inhibitors of nuclear factor (NF)-κB activation significantly reduced IL-12 p40 production in infected cells. Collectively our data show that HSV-2 infection of murine macrophages induces production of IL-12 through a mechanism requiring intermediary synthesis of viral or host proteins and involving activation of NF-κB.

scholarly journals Clearance of Herpes Simplex Virus Type 2 by CD8+ T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

2005 ◽  
Vol 79 (23) ◽  
pp. 14546-14554 ◽  
Author(s):  
Melanie E. Dobbs ◽  
Jane E. Strasser ◽  
Chin-Fun Chu ◽  
Claudia Chalk ◽  
Gregg N. Milligan
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Gamma Interferon ◽  
Wild Type ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT The T-cell-mediated resolution of herpes simplex virus type 2 (HSV-2) genital infections is not fully understood. In these studies, the mechanisms by which CD8+ T cells clear virus from the genital epithelium were examined. Ovalbumin (OVA)-specific CD8+ T cells from OT-I transgenic mice cleared a thymidine kinase-deficient, ovalbumin-expressing HSV-2 virus (HSV-2 tk− OVA) from the genital epithelium of recipient mice, and clearance was abrogated by in vivo neutralization of gamma interferon (IFN-γ). Further, CD8+ OT-I T cells deficient in IFN-γ were unable to clear HSV-2 tk− OVA from the vaginal epithelium. The requirement for cytolytic mechanisms in HSV-2 tk− OVA clearance was tested in radiation chimeras by adoptive transfer of wild-type or perforin-deficient OT-I T cells to irradiated Fas-defective or wild-type recipients. Although a dramatic decrease in viral load was observed early after challenge with HSV-2 tk− OVA, full resolution of the infection was not achieved in recipients lacking both perforin- and Fas-mediated cytolytic pathways. These results suggest that IFN-γ was responsible for an early rapid decrease in HSV-2 virus titer. However, either perforin- or Fas-mediated cytolytic mechanisms were required to achieve complete clearance of HSV-2 from the genital epithelium.

scholarly journals Prolonged Exposure to Progesterone Prevents Induction of Protective Mucosal Responses following Intravaginal Immunization with Attenuated Herpes Simplex Virus Type 2

2003 ◽  
Vol 77 (18) ◽  
pp. 9845-9851 ◽  
Author(s):  
Amy E. Gillgrass ◽  
Ali A. Ashkar ◽  
Kenneth L. Rosenthal ◽  
Charu Kaushic
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Prolonged Exposure ◽  
Viral Shedding ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT Depo-Provera (Depo) is a long-acting progestational formulation that is a popular form of contraception for women. In animal models of sexually transmitted diseases, it is used to facilitate infection. Here we report that treatment with Depo, in a mouse model of genital herpes simplex virus type 2 (HSV-2), altered immune responses depending on the length of time that animals were exposed to Depo prior to immunization. Mice immunized intravaginally (i.vag.) with an attenuated strain (TK−) of HSV-2 following longer (15 days) exposure to Depo (Depo 15 group) failed to show protection when challenged with wild-type HSV-2. In contrast, mice that were immunized shortly after Depo treatment (5 days; Depo 5 group) were fully protected and showed no genital pathology after HSV-2 challenge. High viral titers were detected in the vaginal washes of the Depo 15 group up to 6 days postchallenge. In contrast, no viral shedding was observed beyond day 3 postchallenge in the Depo 5 group. Following i.vag. TK− immunization, high levels of gamma interferon (IFN-γ) were detected locally in vaginal washes of the Depo 5 group but not the Depo 15 group. After HSV-2 challenge, an early peak of IFN-γ in the Depo 5 group coincided with clearance of the virus. In Depo 15 animals IFN-γ was present throughout the 6 days postinfection. HSV-2-specific T-cell cytokine responses measured in the lymph node cells of Depo 5 TK−-immunized mice indicated a significantly higher Th1 response than that of Depo 15 TK−-immunized mice. The protection after HSV-2 challenge in the Depo 5 group correlated with increased local HSV-2 glycoprotein B (gB)-specific immunoglobulin G (IgG) and IgA responses seen in the vaginal secretions. The Depo 15 group had poor gB-specific antibody responses in the genital tract after HSV-2 challenge. These results indicate that longer exposure to Depo leads to poor innate and adaptive immune responses to HSV-2 that fail to protect mice from subsequent genital challenges.

scholarly journals Interleukin-15 and Natural Killer and NKT Cells Play a Critical Role in Innate Protection against Genital Herpes Simplex Virus Type 2 Infection

2003 ◽  
Vol 77 (18) ◽  
pp. 10168-10171 ◽  
Author(s):  
Ali A. Ashkar ◽  
Kenneth L. Rosenthal
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Natural Killer ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Nkt Cells ◽  
Interleukin 15 ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT Interleukin-15 (IL-15), natural killer (NK) cells, and NK T (NKT) cells, components of the innate immune system, are known to contribute to defense against pathogens, including viruses. Here we report that IL-15−/− (NK− and NKT−/+) mice and RAG-2−/−/γc −/− (NK− and NKT−) mice that lack all lymphoid cells were very susceptible to vaginal infection with a low dose of herpes simplex virus type 2 (HSV-2). IL-15−/− and RAG-2−/−/γc −/− mice were 100-fold more susceptible and RAG-2−/−, CD-1−/− (NKT−), and gamma interferon (IFN-γ)−/− mice were 10-fold more susceptible to vaginal HSV-2 infection than control C57BL/6 mice. NK and/or NKT cells were the early source of IFN-γ in vaginal secretions following genital HSV-2 infection. This study demonstrates that IL-15 and NK-NKT cells are critical for innate protection against genital HSV-2.

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