scholarly journals Crosstalk Between Epithelial Cells, Neurons and Immune Mediators in HSV-1 Skin Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Luisa F. Duarte ◽  
Antonia Reyes ◽  
Mónica A. Farías ◽  
Claudia A. Riedel ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Immune Responses ◽  
World Population ◽  
Immune Mediators ◽  
Secondary Infections ◽  
Neuron Cell Body ◽  
Latently Infected ◽  
And Migration ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) infection is highly prevalent in humans, with approximately two-thirds of the world population living with this virus. However, only a fraction of those carrying HSV-1, which elicits lifelong infections, are symptomatic. HSV-1 mainly causes lesions in the skin and mucosae but reaches the termini of sensory neurons innervating these tissues and travels in a retrograde manner to the neuron cell body where it establishes persistent infection and remains in a latent state until reactivated by different stimuli. When productive reactivations occur, the virus travels back along axons to the primary infection site, where new rounds of replication are initiated in the skin, in recurrent or secondary infections. During this process, new neuron infections occur. Noteworthy, the mechanisms underlying viral reactivations and the exit of latency are somewhat poorly understood and may be regulated by a crosstalk between the infected neurons and components of the immune system. Here, we review and discuss the immune responses that occur at the skin during primary and recurrent infections by HSV-1, as well as at the interphase of latently-infected neurons. Moreover, we discuss the implications of neuronal signals over the priming and migration of immune cells in the context of HSV-1 infection.

scholarly journals Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons

2000 ◽  
Vol 191 (9) ◽  
pp. 1459-1466 ◽  
Author(s):  
Ting Liu ◽  
Kamal M. Khanna ◽  
XiaoPing Chen ◽  
David J. Fink ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Sensory Neurons ◽  
Cd8 T Cells ◽  
Early Proteins ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.

scholarly journals Level of Herpes Simplex Virus Type 1 Latency Correlates with Severity of Corneal Scarring and Exhaustion of CD8+ T Cells in Trigeminal Ganglia of Latently Infected Mice

2008 ◽  
Vol 83 (5) ◽  
pp. 2246-2254 ◽  
Author(s):  
Kevin R. Mott ◽  
Catherine J. Bresee ◽  
Sariah J. Allen ◽  
Lbachir BenMohamed ◽  
Steven L. Wechsler ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Individual ◽  
Trigeminal Ganglia ◽  
Corneal Scarring ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT A hallmark of infection with herpes simplex virus type 1 (HSV-1) is the establishment of latency in ganglia of the infected individual. During the life of the latently infected individual, the virus can occasionally reactivate, travel back to the eye, and cause recurrent disease. Indeed, a major cause of corneal scarring (CS) is the scarring induced by HSV-1 following reactivation from latency. In this study, we evaluated the relationship between the amount of CS and the level of the HSV-1 latency-associated transcript (LAT) in trigeminal ganglia (TG) of latently infected mice. Our results suggested that the amount of CS was not related to the amount of virus replication following primary ocular HSV-1 infection, since replication in the eyes was similar in mice that did not develop CS, mice that developed CS in just one eye, and mice that developed CS in both eyes. In contrast, mice with no CS had significantly less LAT, and thus presumably less latency, in their TG than mice that had CS in both eyes. Higher CS also correlated with higher levels of mRNAs for PD-1, CD4, CD8, F4/80, interleukin-4, gamma interferon, granzyme A, and granzyme B in both cornea and TG. These results suggest that (i) the immunopathology induced by HSV-1 infection does not correlate with primary virus replication in the eye; (ii) increased CS appears to correlate with increased latency in the TG, although the possible cause-and-effect relationship is not known; and (iii) increased latency in mouse TG correlates with higher levels of PD-1 mRNA, suggesting exhaustion of CD8+ T cells.

scholarly journals Infection of dendritic cells with herpes simplex virus type 1 induces rapid degradation of CYTIP, thereby modulating adhesion and migration

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 107-115 ◽  
Author(s):  
Alexandros A. Theodoridis ◽  
Christina Eich ◽  
Carl G. Figdor ◽  
Alexander Steinkasserer
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Lymphoid Tissues ◽  
Simplex Virus ◽  
Hsv 1

Abstract Immune responses require spatial and temporal coordinated interactions between different cell types within distinct microenvironments. This dynamic interplay depends on the competency of the involved cells, predominantly leukocytes, to actively migrate to defined sites of cellular encounters in various tissues. Because of their unique capacity to transport antigen from the periphery to secondary lymphoid tissues for the activation of naive T cells, dendritic cells (DCs) play a key role in the initiation and orchestration of adaptive immune responses. Therefore, pathogen-mediated interference with this process is a very effective way of immune evasion. CYTIP (cytohesin-interacting protein) is a key regulator of DC motility. It has previously been described to control LFA-1 deactivation and to regulate DC adherence. CYTIP expression is up-regulated during DC maturation, enabling their transition from the sessile to the motile state. Here, we demonstrate that on infection of human monocyte-derived DCs with herpes simplex virus type 1 (HSV-1), CYTIP is rapidly degraded and as a consequence β-2 integrins, predominantly LFA-1, are activated. Furthermore, we show that the impairment of migration in HSV-1-infected DCs is in part the result of this increased integrin-mediated adhesion. Thus, we propose a new mechanism of pathogen-interference with central aspects of leukocyte biology.

scholarly journals Reevaluating the CD8 T-Cell Response to Herpes Simplex Virus Type 1: Involvement of CD8 T Cells Reactive to Subdominant Epitopes

2008 ◽  
Vol 83 (5) ◽  
pp. 2237-2245 ◽  
Author(s):  
Brian S. Sheridan ◽  
Thomas L. Cherpes ◽  
Julie Urban ◽  
Pawel Kalinski ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
T Cell Response ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In C57BL/6 (B6) mice, most herpes simplex virus (HSV)-specific CD8 T cells recognize a strongly immunodominant epitope on glycoprotein B (gB498) and can inhibit HSV type 1 (HSV-1) reactivation from latency in trigeminal ganglia (TG). However, half of the CD8 T cells retained in latently infected TG of B6 mice are not gB498 specific and have been largely ignored. The following observations from our current study indicate that these gB498-nonspecific CD8 T cells are HSV specific and may contribute to the control of HSV-1 latency. First, following corneal infection, OVA257-specific OT-1 CD8 T cells do not infiltrate the infected TG unless mice are simultaneously immunized with OVA257 peptide, and then they are not retained. Second, 30% of CD8 T cells in acutely infected TG that produce gamma interferon in response to HSV-1 stimulation directly ex vivo are gB498 nonspecific, and these cells maintain an activation phenotype during viral latency. Finally, gB498-nonspecific CD8 T cells are expanded in ex vivo cultures of latently infected TG and inhibit HSV-1 reactivation from latency in the absence of gB498-specific CD8 T cells. We conclude that many of the CD8 T cells that infiltrate and are retained in infected TG are HSV specific and potentially contribute to maintenance of HSV-1 latency. Identification of the viral proteins recognized by these cells will contribute to a better understanding of the dynamics of HSV-1 latency.

scholarly journals Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

2013 ◽  
Vol 6 ◽  
pp. JCD.S10803 ◽  
Author(s):  
Clinton Jones
Keyword(s):  
Sensory Neurons ◽  
Viral Gene Expression ◽  
Productive Infection ◽  
Viral Gene ◽  
Viral Transcription ◽  
Latently Infected ◽  
Simplex Virus ◽  
Cellular Transcription ◽  
Hsv 1

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts.

Multiple sclerosis: reduced proportion of circulating plasmacytoid dendritic cells expressing BDCA-2 and BDCA-4 and reduced production of IL-6 and IL-10 in response to herpes simplex virus type 1

2008 ◽  
Vol 14 (9) ◽  
pp. 1199-1207 ◽  
Author(s):  
A Sanna ◽  
YM Huang ◽  
G Arru ◽  
ML Fois ◽  
H Link ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Cytokine Production ◽  
Type I ◽  
Simplex Virus ◽  
Hsv 1

Objective We hypothesized that autoaggressive immune responses observed in multiple sclerosis (MS) could be associated with an imbalance in proportion of immune cell subsets and in cytokine production in response to infection, including viruses. Methods We collected blood mononuclear cells (MNC) from 23 patients with MS and 23 sex- and age-matched healthy controls (HC) from the island of Sardinia, Italy, where the prevalence of MS is extraordinarily high. Using flow cytometry, we studied MNC for expression of blood dendritic cell antigens (BDCA)-2 and BDCA-4 surface markers reflecting the proportion of plasmacytoid dendritic cells (pDC) that produce type I interferons (IFNs) after virus challenge and promote Th2/anti-inflammtory cytokine production. In parallel, pro-inflammatory (interleukin [IL]-2, IL-12, IFN-γ), anti-inflammatory (IL-4, IL-10), and immuno-regulatory/pleiotropic cytokines (type I IFNs including IFN-α and β, IL-6) were measured before and after an in vitro exposure to herpes simplex virus type 1 (HSV-1). Results The subset of lineage negative (lin−), BDCA-2+ cells was lower in patients with MS compared with HC (0.08 ± 0.02% vs 0.24 ± 0.02%; P < 0.001). A similar pattern was observed for lin−BDCA-4+ cells (0.08 ± 0.02% vs 0.17% ± 0.03; P < 0.01). Spontaneous productions of IL-6 (45 ± 10 pg/mL vs 140 ± 26 pg/mL; P < 0.01) and IL-10 (17 ± 0.4 pg/mL vs 21 ± 1 pg/mL; P < 0.05) by MNC were lower in patients with MS compared with HC. Spontaneous production of IL-6 (6.5 ± 0.15 pg/mL vs 21 ± 5 pg/mL; P < 0.01 and IL-10 (11 ± 1 pg/mL vs 14 ± 3 pg/mL; P < 0.05) by pDC was also lower in patients with MS compared with HC. Exposure of MNC to HSV-1 showed, in both patients with MS and HC, increased production of IFN-α, IL-6, and IL-10 but decreased production of IL-4. In response to HSV-1 exposure, productions of IL-6 (165 ± 28 pg/mL vs 325 ± 35 pg/mL; P < 0.01) and IL-10 (27 ± 3 vs 33 ± 3 P < 0.05) by MNC as well as by pDC (IL-6: 28 ± 7 vs 39 ± 12 P < 0.05; IL-10: 14 ± 1 vs 16 ± 3 P < 0.05) were lower in patients with MS compared with HC. Conclusion The results implicate a new evidence for altered immune cells and reduced immune responses in response to viral challenge in MS.

scholarly journals Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity

2005 ◽  
Vol 86 (9) ◽  
pp. 2401-2410 ◽  
Author(s):  
Henning Lauterbach ◽  
Christine Ried ◽  
Alberto L. Epstein ◽  
Peggy Marconi ◽  
Thomas Brocker
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Host Immunity ◽  
Vaccine Vectors ◽  
Simplex Virus ◽  
Hsv 1

Due to the continuous need for new vaccines, viral vaccine vectors have become increasingly attractive. In particular, herpes simplex virus type 1 (HSV-1)-based vectors offer many advantages, such as broad cellular tropism, large DNA-packaging capacity and the induction of pro-inflammatory responses. However, despite promising results obtained with HSV-1-derived vectors, the question of whether pre-existing virus-specific host immunity affects vaccine efficacy remains controversial. For this reason, the influence of pre-existing HSV-1-specific immunity on the immune response induced with a replication-defective, recombinant HSV-1 vaccine was investigated in vivo. It was shown that humoral as well as cellular immune responses against a model antigen encoded by the vaccine were strongly diminished in HSV-1-seropositive mice. This inhibition could be observed in mice infected with wild-type HSV-1 or with a replication-defective vector. Although these data clearly indicate that pre-existing antiviral host immunity impairs the efficacy of HSV-1-derived vaccine vectors, they also show that vaccination under these constraints might still be feasible.

scholarly journals The Latency-Associated Transcript Gene Enhances Establishment of Herpes Simplex Virus Type 1 Latency in Rabbits

2000 ◽  
Vol 74 (4) ◽  
pp. 1885-1891 ◽  
Author(s):  
Guey-Chuen Perng ◽  
Susan M. Slanina ◽  
Ada Yukht ◽  
Homayon Ghiasi ◽  
Anthony B. Nesburn ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Fluorescent Protein ◽  
Ocular Infection ◽  
Latently Infected ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The latency-associated transcript (LAT) gene the only herpes simplex virus type 1 (HSV-1) gene abundantly transcribed during neuronal latency, is essential for efficient in vivo reactivation. Whether LAT increases reactivation by a direct effect on the reactivation process or whether it does so by increasing the establishment of latency, thereby making more latently infected neurons available for reactivation, is unclear. In mice, LAT-negative mutants appear to establish latency in fewer neurons than does wild-type HSV-1. However, this has not been confirmed in the rabbit, and the role of LAT in the establishment of latency remains controversial. To pursue this question, we inserted the gene for the enhanced green fluorescent protein (EGFP) under control of the LAT promoter in a LAT-negative virus (ΔLAT-EGFP) and in a LAT-positive virus (LAT-EGFP). Sixty days after ocular infection, trigeminal ganglia (TG) were removed from the latently infected rabbits, sectioned, and examined by fluorescence microscopy. EGFP was detected in significantly more LAT-EGFP-infected neurons than ΔLAT-EGFP-infected neurons (4.9% versus 2%, P < 0.0001). The percentages of EGFP-positive neurons per TG ranged from 0 to 4.6 for ΔLAT-EGFP and from 2.5 to 11.1 for LAT-EGFP (P = 0.003). Thus, LAT appeared to increase neuronal latency in rabbit TG by an average of two- to threefold. These results suggest that LAT enhances the establishment of latency in rabbits and that this may be one of the mechanisms by which LAT enhances spontaneous reactivation. These results do not rule out additional LAT functions that may be involved in maintenance of latency and/or reactivation from latency.

scholarly journals miR-23a/b suppress cGAS-mediated innate and autoimmunity

2021 ◽  
Author(s):  
Qiuya Yu ◽  
Lei Chu ◽  
Yongxing Li ◽  
Quanyi Wang ◽  
Juanjuan Zhu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Autoimmune Diseases ◽  
Regulatory Mechanism ◽  
Disease Model ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Simplex Virus ◽  
Increased Susceptibility ◽  
Hsv 1

AbstractCyclic GMP-AMP synthase (cGAS), a key sensor of intracellular DNA, is essential for eliciting innate immunity against infection, whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases. However, it is largely unknown how cGAS expression is regulated during pathogen infection and autoimmunity. Here, we report that during herpes simplex virus type 1 (HSV-1) infection, two microRNAs (miR-23a and miR-23b) whose levels significantly decrease due to their interaction with the lncRNA Oasl2-209 directly regulate the expression of cGAS. Overexpression of miR-23a/b markedly dampens cytosolic DNA-induced innate immune responses, whereas inhibition of miR-23a/b enhances these responses. Mice treated with miR-23a/b agomirs exhibit increased susceptibility to HSV-1 infection. Moreover, cGAS is significantly upregulated in the Trex1−/− mouse autoimmune disease model. Administration of miR-23a/b blunts self DNA-induced autoinflammatory responses in Trex1−/− mice. Collectively, our study not only reveals a novel regulatory mechanism of cGAS expression by miRNAs but also identifies a potential therapy for cGAS-related autoimmune diseases.

scholarly journals Primary herpes simplex virus type 1 infection of the eye triggers similar immune responses in the cornea and the skin of the eyelids

2002 ◽  
Vol 83 (7) ◽  
pp. 1579-1590 ◽  
Author(s):  
Thomas H. Stumpf ◽  
Rachel Case ◽  
Carolyn Shimeld ◽  
David L. Easty ◽  
Terry J. Hill
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Disease Process ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

Herpetic stromal keratitis (HSK) and blepharoconjunctivitis in humans are thought partly to result from immunopathological responses to herpes simplex virus type 1 (HSV-1). The corneas of NIH mice were inoculated with HSV-1 (strain McKrae) and mice were examined for signs of disease and infection on days 1, 4, 7, 10, 14 and 21. The eyes and eyelids of infected and control mice were processed for immunohistochemistry and double stained for viral antigens and one of the following cell surface markers (Gr-1, F4/80, CD4, CD8, CD45R or MHC class II) or one of the following cytokines (IL-2, IL-4, IL-6, IL-10, IL-12 or IFN-γ). All infected mice developed signs of HSK by day 4 and blepharitis by day 7 and these both persisted until day 21, when signs of resolution where apparent. Virus was detected during the first week of infection and became undetectable by day 10. Large numbers of Gr-1+ cells (neutrophils) infiltrated infected corneas and eyelids in areas of viral antigen and CD4+ T cells increased significantly in number after virus clearance. In both sites, the predominant cytokines were IL-6, IL-10, IL-12 and IFN-γ, with few IL-2+ and IL-4+ cells. These observations suggest that the immune responses in the cornea are similar to those in the eyelids but, overall, the responses are not clearly characterized as either Th1 or Th2. In both sites, the neutrophil is the predominant infiltrating cell type and is a likely source of the cytokines observed and a major effector of the disease process.

Sign in / Sign up

Export Citation Format

Share Document