scholarly journals Susceptibility of CCR5-Deficient Mice to Genital Herpes Simplex Virus Type 2 Is Linked to NK Cell Mobilization

2007 ◽  
Vol 81 (8) ◽  
pp. 3704-3713 ◽  
Author(s):  
Manoj Thapa ◽  
William A. Kuziel ◽  
Daniel J. J. Carr
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Herpes Simplex ◽  
Nk Cells ◽  
Brain Stem ◽  
Nk Cell ◽  
Wild Type ◽  
Simplex Virus ◽  
The Brain

ABSTRACT Following genital herpes simplex virus type 2 (HSV-2) exposure, NK cells and T cells are mobilized to sites of infection to control viral replication and spread. The present investigation sought to determine the role of the chemokine receptor CCR5 in this process. Mice deficient in CCR5 (CCR5−/−) displayed a significant reduction in cumulative survival following infection in comparison to wild-type, HSV-2-infected controls. Associated with decreased resistance to viral infection, CCR5−/− mice yielded significantly more virus and expressed higher levels of tumor necrosis factor alpha, CXCL1, CCL2, CCL3, and CCL5 in the vagina, spinal cord, and/or brain stem than did wild-type mice. Whereas there was no difference in absolute number of leukocytes (CD45high), CD4 T cells, or CD8 T cells residing in the draining lymph nodes, spleen, spinal cord, or brain stem comparing HSV-2-infected wild-type to CCR5−/− mice prior to or after infection, there were significantly more NK cells (NK1.1+ CD3−) residing in the brain stem and spleen of infected wild-type mice. Functionally, NK activity from cells isolated from the brain stem of HSV-2-infected wild-type mice was greater than that from HSV-2-infected CCR5−/− mice. In addition, antibody-mediated depletion of NK cells resulted in an increase in HSV-2 levels in the vaginal, spinal cord, and brain stem tissue of wild-type but not CCR5−/− mice. Collectively, the absence of CCR5 expression significantly impacts the ability of the host to control genital HSV-2 infection, inflammation, and spread associated with a specific reduction in NK cell expansion, infiltration, and activity in the nervous system.

scholarly journals Natural Killer Cells as Novel Helpers in Anti-Herpes Simplex Virus Immune Response

2008 ◽  
Vol 82 (21) ◽  
pp. 10820-10831 ◽  
Author(s):  
Subhadra Nandakumar ◽  
Stacie N. Woolard ◽  
Dorothy Yuan ◽  
Barry T. Rouse ◽  
Uday Kumaraguru
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nk Cells ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Simplex Virus

ABSTRACT Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be the most relevant components of the innate reaction to herpes simplex virus (HSV) infection. We confirm that mice lacking or depleted of NK cells are susceptible to HSV-induced lesions. The quantity and quality of CD8+ cytotoxic T lymphocytes generated in the absence of NK cells were diminished, thereby contributing to susceptibility to HSV-induced encephalitis. We demonstrate a novel helper role for NK cells, in that NK cells compensate for the loss of CD4 helper T cells and NK cell supplementation enhances the function of wild type anti-HSV CD8 T cells. In addition, NK cells were able to partially rescue the dysfunctional CD8+ T cells generated in the absence of CD4 T helper cells, thereby performing a novel rescue function. Hence, NK cells may well be exploited for enhancing and rescuing the T-cell response in situations where the CD4 helper response is affected.

scholarly journals Age-Dependent Role for CCR5 in Antiviral Host Defense against Herpes Simplex Virus Type 2

2005 ◽  
Vol 79 (15) ◽  
pp. 9831-9841 ◽  
Author(s):  
Nina Ank ◽  
Klavs Petersen ◽  
Lene Malmgaard ◽  
Søren C. Mogensen ◽  
Søren R. Paludan
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Host Defense ◽  
Herpes Simplex Virus Type ◽  
Wild Type ◽  
Age Dependent ◽  
Simplex Virus

ABSTRACT Elimination of viral infections is dependent on rapid recruitment and activation of leukocytes with antiviral activities to infected areas. Chemokines constitute a class of cytokines that have regulatory effects on leukocyte migration and activity. In this study we have studied the role of CC chemokine receptor 1 (CCR1) and CCR5 in host defense during a generalized herpes simplex virus type 2 (HSV-2) infection. Whereas both 4- and 8-week-old CCR1−/− mice resembled wild-type mice (C57BL/6) with respect to defense against the infection, significantly higher virus titers were seen in the livers and brains of 4-week-old CCR5−/− mice. At the age of 8 weeks, CCR5−/− were indistinguishable from wild-type mice and cleared the infection from liver and spleen. Although 4-week-old CCR5−/− mice were able to recruit natural killer (NK) cells to the site of infection, these cells had reduced cytotoxic activity compared to NK cells from wild-type mice. This was not due to lower production of alpha/beta interferon or interleukin-12, two well-described activators of cytotoxic activity in NK cells. We also noted that the spleens of young CCR5−/− mice did not increase in size during infection as did the spleens of wild-type and CCR1−/− mice. This observation was accompanied by impaired proliferation of CCR5−/− splenocytes (SCs) ex vivo. Moreover, migration of CD8+ T cells to the liver in response to infection was impaired in CCR5−/− mice, and adoptive transfer of SCs from CCR5−/− mice infected for 6 days into newly infected wild-type mice did not improve antiviral activity in the liver, in contrast to what was seen in mice receiving immune SCs from wild-type mice. Altogether, this study shows that CCR5 plays an age-dependent role in host defense against HSV-2 by supporting both the innate and adaptive immune response.

scholarly journals Protective Role of Fas-FasL Signaling in Lethal Infection with Herpes Simplex Virus Type 2 in Mice

2009 ◽  
Vol 83 (22) ◽  
pp. 11777-11783 ◽  
Author(s):  
Takahiro Ishikawa ◽  
Hisakata Yamada ◽  
Akiko Oyamada ◽  
Fumi Goshima ◽  
Yukihiro Nishiyama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Target Cells ◽  
Lethal Infection ◽  
Simplex Virus

ABSTRACT Herpes simplex virus type 2 (HSV-2) induces acute local infection followed by latent infection in the nervous system and often leads to the development of lethal encephalitis in immunocompromised hosts. The mechanisms of immune protection against lethal HSV-2 infection, however, have not been clarified. In this study, we examined the roles of Fas-Fas ligand (FasL) signaling in lethal infection with HSV-2 by using mice with mutated Fas (lpr) or FasL (gld) in C57BL/6 background. Both lpr and gld mice exhibited higher mortality than wild-type (WT) C57BL/6 mice after infection with virulent HSV-2 strain 186 and showed significantly increased viral titers in the spinal cord compared with WT mice 9 days after infection, just before the mice started to die. There were no differences in the numbers of CD4+ and CD8+ T cells infiltrated in the spinal cord or in the levels of HSV-2-specific gamma interferon produced by those cells in a comparison of lpr and WT mice 9 days after infection. Adoptive transfer studies demonstrated that CD4+ T cells from WT mice protected gld mice from lethal infection by HSV-2. Furthermore, CD4+ T cells infiltrated in the spinal cord of HSV-2-infected WT mice expressed functional FasL that induced apoptosis of Fas-expressing target cells in vitro. These results suggest that FasL-mediated cytotoxic activity of CD4+ T cells plays an important role in host defense against lethal infection with HSV-2.

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 Mucosal Immunity to Herpes Simplex Virus Type 2 Infection in the Mouse Vagina Is Impaired by In Vivo Depletion of T Lymphocytes

1998 ◽  
Vol 72 (4) ◽  
pp. 2677-2685 ◽  
Author(s):  
Margaret B. Parr ◽  
Earl L. Parr
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Wild Type ◽  
Neurological Illness ◽  
Simplex Virus

ABSTRACT Intravaginal (IVAG) inoculation of wild-type herpes simplex virus type 2 (HSV-2) in mice causes epithelial infection followed by lethal neurological illness, while IVAG inoculation of attenuated HSV-2 causes epithelial infection followed by development of protective immunity against subsequent IVAG challenge with wild-type virus. The role of T cells in this immunity was studied by in vivo depletion of these cells with monoclonal antibodies. Three groups of mice were used for each experiment: nonimmune/challenged mice, immune/challenged mice, and immune depleted mice [immune mice depleted of a T-cell subset(s) shortly before challenge with HSV-2]. Mice were assessed for epithelial infection 24 h after challenge, virus protein in the vaginal lumen 3 days after challenge, and neurological illness 8 to 14 days after challenge. Monoclonal antibodies to CD4, CD8, or Thy-1 markedly reduced T cells in blood, spleen, and vagina, but major histocompatibility complex class II antigens were still partially upregulated in the vaginal epithelium after virus challenge, indicating that virus-specific memory T-cell function was not entirely eliminated from the vagina. Nevertheless, immune mice depleted of CD4+and CD8+ T cells, Thy-1+ T cells, or CD8+ T cells alone had greater viral infection in the vaginal epithelium than nondepleted immune mice, indicating that T cells contribute to immunity against vaginal HSV-2 infection. All immune depleted mice retained substantial immunity to epithelial infection and were immune to neurological illness, suggesting that other immune mechanisms such as virus-specific antibody may also contribute to immunity.

scholarly journals CD8+ T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3

2021 ◽  
Author(s):  
Liza Lind ◽  
Alexandra Svensson ◽  
Karolina Thörn ◽  
Malgorzata Krzyzowska ◽  
Kristina Eriksson
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Chemokine Receptors ◽  
The Central Nervous System ◽  
Simplex Virus

AbstractHerpes simplex virus type 2 (HSV-2) is a neurotropic virus that can cause meningitis, an inflammation of the meninges in the central nervous system. T cells are key players in viral clearance, and these cells migrate from peripheral blood into the central nervous system upon infection. Several factors contribute to T cell migration, including the expression of chemokines in the inflamed tissue that attract T cells through their expression of chemokine receptors. Here we investigated CD8+ T cell profile in the spinal cord in a mouse model of herpes simplex virus type 2 neuroinflammation. Mice were infected with HSV-2 and sacrificed when showing signs of neuroinflammation. Cells and/or tissue from spinal cord, spleen, and blood were analyzed for expression of activation markers, chemokine receptors, and chemokines. High numbers of CD8+ T cells were present in the spinal cord following genital HSV-2-infection. CD8+ T cells were highly activated and HSV-2 glycoprotein B -specific effector cells, some of which showed signs of recent degranulation. They also expressed high levels of many chemokine receptors, in particular CCR2, CCR4, CCR5, and CXCR3. Investigating corresponding receptor ligands in spinal cord tissue revealed markedly increased expression of the cognate ligands CCL2, CCL5, CCL8, CCL12, and CXCL10. This study shows that during herpesvirus neuroinflammation anti-viral CD8+ T cells accumulate in the CNS. CD8+ T cells in the CNS also express chemotactic receptors cognate to the chemotactic gradients in the spinal cord. This indicates that anti-viral CD8+ T cells may migrate to infected areas in the spinal cord during herpesvirus neuroinflammation in response to chemotactic gradients.

scholarly journals Herpes Simplex Virus Latency-Associated Transcript Sequence Downstream of the Promoter Influences Type-Specific Reactivation and Viral Neurotropism

2007 ◽  
Vol 81 (12) ◽  
pp. 6605-6613 ◽  
Author(s):  
Andrea S. Bertke ◽  
Amita Patel ◽  
Philip R. Krause
Keyword(s):  
Spinal Cord ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Acute Infection ◽  
Central Nervous System Infection ◽  
Sensory Nerve ◽  
Lumbar Spinal Cord ◽  
Wild Type ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus (HSV) establishes latency in sensory nerve ganglia during acute infection and may later periodically reactivate to cause recurrent disease. HSV type 1 (HSV-1) reactivates more efficiently than HSV-2 from trigeminal ganglia while HSV-2 reactivates more efficiently than HSV-1 from lumbosacral dorsal root ganglia (DRG) to cause recurrent orofacial and genital herpes, respectively. In a previous study, a chimeric HSV-2 that expressed the latency-associated transcript (LAT) from HSV-1 reactivated similarly to wild-type HSV-1, suggesting that the LAT influences the type-specific reactivation phenotype of HSV-2. To further define the LAT region essential for type-specific reactivation, we constructed additional chimeric HSV-2 viruses by replacing the HSV-2 LAT promoter (HSV2-LAT-P1) or 2.5 kb of the HSV-2 LAT sequence (HSV2-LAT-S1) with the corresponding regions from HSV-1. HSV2-LAT-S1 was impaired for reactivation in the guinea pig genital model, while its rescuant and HSV2-LAT-P1 reactivated with a wild-type HSV-2 phenotype. Moreover, recurrences of HSV-2-LAT-S1 were frequently fatal, in contrast to the relatively mild recurrences of the other viruses. During recurrences, HSV2-LAT-S1 DNA increased more in the sacral cord compared to its rescuant or HSV-2. Thus, the LAT sequence region, not the LAT promoter region, provides essential elements for type-specific reactivation of HSV-2 and also plays a role in viral neurotropism. HSV-1 DNA, as quantified by real-time PCR, was more abundant in the lumbar spinal cord, while HSV-2 DNA was more abundant in the sacral spinal cord, which may provide insights into the mechanism for type-specific reactivation and different patterns of central nervous system infection of HSV-1 and HSV-2.

scholarly journals Mechanism of Reduced T-Cell Effector Functions and Class-Switched Antibody Responses to Herpes Simplex Virus Type 2 in the Absence of B7 Costimulation

2003 ◽  
Vol 77 (4) ◽  
pp. 2426-2435 ◽  
Author(s):  
Lydia G. Thebeau ◽  
Lynda A. Morrison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Antibody Responses ◽  
Wild Type ◽  
Effector Functions ◽  
Lymphocyte Activity ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT T-cell costimulation molecules B7-1 and B7-2 play an important role in activation of T cells to cytolytic effector function and production of cytokines. Interaction with B7 also causes T cells to upregulate surface molecules, such as CD40L, that effectively stimulate antibody responses in conjunction with cytokines. We have shown that mice lacking both B7-1 and B7-2 (B7KO mice), when infected intravaginally with virulent herpes simplex virus type 2 (HSV-2), developed more severe disease and higher mortality than their wild-type counterparts. We have now investigated the effects of B7 costimulation deficiency on induction of immune responses to HSV-2 infection of the genital tract. Fewer gamma interferon (IFN-γ)-producing T cells were present in the genital lymph nodes of B7KO mice compared to wild-type mice, either acutely after primary infection or in recall responses. Less IFN-γ and especially interleukin-10 were produced by B7KO mice, and cytolytic T-lymphocyte activity was also attenuated. Reduced expression of CD25 on CD4+ T cells after infection of B7KO mice was consistent with deficits in T-cell activation to effector functions. Although HSV-specific immunoglobulin M (IgM) titers were comparable for both B7KO mice and wild-type mice, B7KO mice had significant deficits in HSV-specific serum IgG responses, with markedly reduced levels of IgG2a and IgG1. In addition, significantly less IgG was detected in the vaginal secretions of B7KO mice than in those from wild-type mice. CD4+ T-cell expression of CD40L was depressed in B7KO mice in vivo and in vitro. Together with reduced cytokine production, these results suggest a mechanism for decreased IgG class switching or production. Thus, in the absence of B7 costimulation, naïve T cells fail to undergo proper activation in response to HSV-2, which limits T-cell cytokine production, cytotoxic T lymphocyte activity, and provision of help for class-switched antibody responses.

scholarly journals Innate Immune Responses to Herpes Simplex Virus Type 2 Influence Skin Homing Molecule Expression by Memory CD4+ Lymphocytes

2006 ◽  
Vol 80 (6) ◽  
pp. 2863-2872 ◽  
Author(s):  
David M. Koelle ◽  
Jay Huang ◽  
Michael T. Hensel ◽  
Christopher L. McClurkan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd4 T Cells ◽  
Receptor Expression ◽  
Homing Receptor ◽  
Skin Homing ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) infections of humans are characterized by intermittent, lytic replication in epithelia. Circulating HSV-specific CD4 T cells express lower levels of preformed cutaneous lymphocyte-associated antigen (CLA), a skin-homing receptor, than do circulating HSV-specific CD8 T cells but, paradoxically, move into infected skin earlier than CD8 cells. Memory CD4 T cells develop strong and selective expression of CLA and E-selectin ligand while responding to HSV antigen in vitro. We now show that interleukin-12, type I interferon, and transforming growth factor beta are each involved in CLA expression by memory HSV type 2 (HSV-2)-specific CD4 T cells in peripheral blood mononuclear cells (PBMC). A reduction of the number of monocytes and dendritic cells from PBMC reduces CLA expression by HSV-2-responsive CD4 lymphoblasts, while their reintroduction restores this phenotype, identifying these cells as possible sources of CLA-promoting cytokines. Plasmacytoid dendritic cells are particularly potent inducers of CLA on HSV-reactive CD4 T cells. These observations are consistent with cooperation between innate and acquired immunity to promote a pattern of homing receptor expression that is physiologically appropriate for trafficking to infected tissues.

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