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Advances in Research on the Pathogenesis of Varicella-zoster Virus


Varicella-zoster virus(VZV) has neurotropic and cutaneous characteristics. The initial infection of the virus manifests as varicella and latent state. When stimulated by various incentives, the latent VZV reactivates and replicates a lot, and the peripheral sensory nerve and the unilateral cutaneous ganglion innervated by the nerve react with each other, causing erythema and clustering. Blisters and neuralgia. The manifestation of herpes zoster(HZ) as a reactivation of varicella infection can occur in approximately 20% of healthy adults and 50% of immunocompromised populations. Children with improved immune system and adults often have no complications after HZ healing. Patients with low cellular immune function are prone to complicated systemic involvement, common pneumonia, hepatitis, encephalomyelitis and vascular disease, and postherpeticneuralgia(PHN) seriously affects the physical and mental health and quality of life of patients.

After VZV infects neuronal cells, the virus begins to replicate. When neuronal cells no longer undergo apoptosis, latent infections are established. When the host is exposed to external factors and the immune function is low, VZV begins to replicate, activate, and spread to the skin or other organ tissues, causing HZ. At present, some signal molecules such as open reading frame (ORF), microRNA (miRNA) and pattern recognition receptor of VZV regulate VZV replication and participate in the latency and activation of VZV; Cellular immunity plays a leading role in the pathogenesis of VZV activation. The type and prognosis of herpes zoster are determined according to the degree of VZV dissemination and the intensity of antiviral immune response. In-depth explanation of the VZV-specific cellular immune response after VZV latency, activation and onset is particularly important for a comprehensive understanding of the pathogenesis of HZ.

1. Molecular biological characteristics of varicella-zoster virus

VZV consists of double-stranded DNA, capsid, cortex and capsule. The innermost layer is the nucleocapsid containing the DNA genome, and the outermost layer is the capsule from the host cell membrane containing the viral glycoprotein, with the cortex in the middle. It is mainly composed of three immediate earlyprotein (IE), which are encoded by ORF4, ORF62 and ORF63. The VZV genome can be divided into four parts: unique long sequence (UL), unique short sequence (US), internal repeat (IR) and terminal repeat (TR), containing 71 ORFs and promoter-related sequences. The 2/3 ORF and 8 glycoproteins are involved in viral DNA replication, splicing, packaging, metabolism, and nucleocapsid assembly. Most of the VZV genes are involved in viral replication, and the encoded products are expressed in IE, early protein, and late protein sequences. When the virus is latently infected, only IE62 and IE63 encoded by the early protein gene are expressed. The late protein gene mainly encodes some capsids and glycoproteins, and is not expressed when latent infection. Viral glycoproteins mediate viral adsorption, enter human host cells, express on the cell membrane of infected cells and promote the spread of viruses between cells.

2. Pathogenic process of varicella-zoster virus

In the case of primary VZV infection, the virus is first inoculated into the upper respiratory tract mucosa, then replicated in the local lymph nodes and released into the blood to form the first viremia. When the virus was transported to the reticuloendothelial system organs such as the liver and spleen, the second round of replication was completed, and a second viremia was formed, which spread widely to the whole body. After about 14 to 16 days of infection, the virus can reach the epidermis by invading the capillary endothelial cells, and then move toward the center along the nerve fibers of the posterior root of the spinal cord or the trigeminal ganglion, and persistently lurk in the neurons of the posterior root ganglia of the spinal cord. The onset of HZ is usually divided into three phases: The first phase is in the incubation period, the latent VZV is reactivated in neurons and the immune surveillance function is impaired; the second phase is in the clinical rash phase, and the virus is released from the ganglion along the nerve pathway to the skin. At this time, the memory immune response of the host is enhanced, and the VZV infection is confined to the cutaneous node of the first onset. Once the memory immune response is weakened, it progresses to the third stage; the third stage is in the clinical dissemination period, and the virus not only involves the virus. To the skin, and spread to the central nervous system and other internal organs. VZV Latent Mechanism All herpes viruses have latent ability, and the latency is almost lifelong. The latentity of most herpesviruses is an important form of escaping immune surveillance. The study found that when the virus is latently infected, VZV DNA exists in the cell as an episome, and there are viral gene transcripts and synthetic proteins. VZV ORFs and miRNAs play an important role in maintaining VZV latent infection.

3. The role in varicella-zoster virus latency

3.1 The role of IE in VZV latency

Most of the IEs in the VZV genome play an important role in viral replication, mainly by silencing the transcription and expression of related genes to maintain latency. ORF61 can induce ND-10 structural dispersion in the host that promotes viral replication. In the study of the latent and activating mechanisms of VZV in the nervous system, it was found that IE4, IE62 and IE63 can be expressed in VZV latently infected neurons and mainly distributed in the cytoplasm, suggesting that these IEs may be restricted for some reason during VZV latency. Nucleation, limiting their transactivation of genes and affecting VZV self-replication. It was found that ORF66 inhibits the transactivation of IE62 into the nucleus by phosphorylation, and participates in viral immune escape by down-regulating the expression of major histocompatibility complex (MHC)-I on the cell surface. IE4 and IE63 are essential for the establishment of VZV latent infections. Some scholars have used SCID human-chicken chimeric infection model to study IE, and found that the expression of IE62 and IE63 is down-regulated in latent infection. The reason is that IE has the ability to resist neuronal apoptosis, so that the virus can survive the nerve when it first invades. Meta cells, the virus can be replicated in the host cell.

3.2 The role of miRNAs in VZV latency

A miRNA is a non-coding single-stranded RNA consisting of 22 nucleotides that, by complementary binding to a targeted messenger RNA, causes mR-NA to degrade or inhibit the translation process of the protein. The study found that the VZV miRNA lacks a targeting site that binds to the latent-related homologous region gene, so that the latent-related ORF encodes mRNA that is not degraded, maintaining viral latency. There are hundreds of miRNAs, and different miRNAs play different regulatory roles. It is found that the changes in the levels of the seven miRNA molecules miR-190b, 571, 1276, 1303, 943 and 661 can be used as potential markers of HZ. Some scholars believe that miRNAs in the circulatory system of HZ patients can regulate multiple signaling pathways to induce viral replication and participate in the inflammatory response and neurological damage of the disease. For example, when miRNA21 expression is up-regulated, VZV replication is promoted by activation of signal transducer-sand activators of transcription (STAT3) signaling pathway. Further studies have found that VZV-encoded miR-NA can regulate nuclear factor-κB. The pathway inhibits the expression of antiviral cytokines such as IL-6 and IL-10, evading host immune surveillance.

4. Activation mechanism of varicella-zoster virus

Neuronal cells and keratinocytes act not only as target cells for VZV infection, but also as antigen-presenting cells to mediate immune responses. VZV down-regulates the expression of MHC-I, MHC-II and intercellular adhe-synthesis molecule-1 (ICAM-1) on the surface of target cells through immunoregulatory mechanisms, and reduces the expression of T cell activation-related signaling molecules. The activation and proliferation of T lymphocytes decreased, and the target cells infected with VZV escaped the immune recognition of T cells, and the virus was activated again. VZV activation is the key to the occurrence of HZ, followed by pattern recognition receptor recognition virus, immune cell infiltration, cytokine release and T lymphocyte subsets interaction, and finally lead to damage to nerve and skin tissue.

4.1 Pattern recognition receptor

After VZV activation, the innate immune system acts as the first line of defense against pathogens, and recognizes and binds to VZV pathogen-associated molecular patterns through pattern recognition receptors, activates downstream signal transduction pathways, and secretes cytokines to produce immune responses. Pattern recognition receptors include Toll-like receptors (TLRs), C-type lectin-like receptors, NOD-like receptors, and retinoic acid-induced I-like receptors, among which TLRs are the most in-depth pattern recognition. Receptors, which recognize multiple pathogens to activate the body’s immune response, are a bridge between non-specific immunity and specific immunity. The study found that TLR9 acts as a “sensor” for VZV cell signaling, recognizing that VZV induces type I interferon-mediated non-specific immune responses; in addition, TLR9 mediates IFN-α release via a MYD88-dependent signaling pathway, and aids in the specific immune response of Th1 cells.

4.2 CD4+ T cells and CD8

The low immune function of +T cells is the main reason for the reactivation of VZV to HZ. Histologically, the incidence of HZ mainly manifests as infiltration of inflammatory cells mainly composed of lymphocytes and lymphocytes around the neurons, mainly T lymphocytes. Among them, CD4+ T cells and CD8+ T cells are considered to be the most important cell subpopulations that determine VZV reactivation and dissemination. The cell number and immune function play a role in HZ latent infection, rash, and virus dissemination. Different effects. After VZV activation, the proportion of CD4+ T cells increased; when CD4+ T cells were extremely deficient, the lesions spread, the viral load in the body increased, and the viremia time prolonged, and generalized skin lesions appeared. CD8+ T cell-mediated immune response plays an important role in immune defense in HZ patients. Steain et al. found that there is a large amount of memory CD8+ T cell infiltration around the dorsal root ganglia of HZ patients, due to low expression of cell surface signal molecules. The ability to cause CD8+ T cells to lose cytotoxicity. An imbalance in the proportion of CD4+/CD8+ T cells causes the body’s immune level to be abnormal and induces the occurrence of HZ. The study found that the ratio of CD4+T and CD8+ T cells decreased significantly after VZV activation until the appearance of typical rash. When the rash began to appear, the ratio of CD4+T/CD8+T began to increase gradually until the ratio of skin lesions subsided. To the normal range. In addition, scholars found that the ratio of CD4+T/CD8+T in the acute phase of HZ was negatively correlated with the occurrence of PHN. Therefore, some scholars believe that the CD4+T/CD8+T ratio inversion can be used as an immune surveillance indicator for HZ patients and high-risk groups.

4.3 CD4 helper T lymphocyte subset

CD4 helper cells include Th1, Th2, Th17 and regulatory T cells (Treg). One of the reasons for the current HZ is that the balance of the immune system is broken and the Th cells are shifted. Some scholars have found that the secretion of Th1 and Th2 cytokines in serum of patients with HZ is increased, and the blister fluid of HZ patients by Zhang et al. showed different results. The results showed that the expression of Th1 type cytokines IL-2 and TNF-a was low. The Th2 type cytokines IL-4 and IL-10 are highly expressed, and the Th1/Th2 ratio shifts. The above conclusions indicate that the immune response mechanisms of Th1 and Th2 cells in different parts of HZ patients are similar, but the intensity of immune responses is different. Th1 cells mediate immune defenses stronger than Th2 cell immunity cause local skin and nerve tissues. Pathological damage. Th17 is a distinct subset of CD4+ T cells that differs from Th1 and Th2 cells. Cytokines such as IL-4, IL-10 and IL-13 secreted by Th2 cells can inhibit the differentiation and development of Th17 cells. However, Agata et al found that the levels of Th17-type cytokines IL-17, IL-23, IL-21 and Th2 cytokines IL-4 and IL-12 were elevated in serum of HZ patients. This indicates that Th2, which has a prominent advantage in the pathogenesis of HZ, has a decreased inhibitory effect on Th17, showing high expression of Th2 type and Th17 type cytokines, and the body is in an immune tolerance state. Recently, Treg cells have attracted much attention. They play an important role in autoimmune diseases, inflammatory diseases, organ transplants, tumors, and various infectious diseases. They also regulate each other in virus-infected diseases together with Th17. Together to maintain the body’s immune balance. Treg cells indirectly participate in the occurrence and development of HZ by regulating the function of CD4+ T cells. Xing et al selected 76 patients with acute HZ, according to the severity of the disease, divided into mild, moderate and severe groups, respectively, to detect the distribution of T lymphocyte subsets in each group. The results showed that compared with the healthy control group, the CD4+ T cells in the HZ group decreased, the Treg cells increased significantly, and the CD4+ T cells were negatively correlated with the Treg cells; compared with the other two groups, the severe group CD4+CD25+ T cells The expression of Foxp3+ was significantly enhanced. This indicates that Treg cells in HZ patients are activated in a large amount to inhibit the proliferation and activation of CD4+ T cells, and the severity of the disease is positively correlated with the inhibition intensity of Treg cells.

5. Conclusion of varicella-zoster virus

The prevention and treatment of HZ is based on the deepening of the research on the pathogenesis of this disease. Recently, the research on the pathogenesis of HZ immunology has provided a new entry point for HZ prevention and treatment. Studying the structure and function of VZV gene and protein will help to develop small molecule inhibitors with antiviral effects and preventing postherpetic neuralgia. Understanding the pathogenesis of HZ from the cellular and molecular levels can provide more effective treatment for the prevention and treatment of HZ. Methods and drugs.

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