{"version":"1.0","provider_name":"TBE Book","provider_url":"https:\/\/tbenews.com\/tbe","author_name":"IT","author_url":"https:\/\/tbenews.com\/tbe\/author\/brianong\/","title":"Chapter 7: Immunology of TBEV Infection - TBE Book","type":"rich","width":600,"height":338,"html":"<blockquote class=\"wp-embedded-content\" data-secret=\"qO0FvZw34i\"><a href=\"https:\/\/tbenews.com\/tbe\/chapter-7-immunology-of-tbev-infection\/\">Chapter 7: Immunology of TBEV Infection<\/a><\/blockquote><iframe sandbox=\"allow-scripts\" security=\"restricted\" src=\"https:\/\/tbenews.com\/tbe\/chapter-7-immunology-of-tbev-infection\/embed\/#?secret=qO0FvZw34i\" width=\"600\" height=\"338\" title=\"&#8220;Chapter 7: Immunology of TBEV Infection&#8221; &#8212; TBE Book\" data-secret=\"qO0FvZw34i\" frameborder=\"0\" marginwidth=\"0\" marginheight=\"0\" scrolling=\"no\" class=\"wp-embedded-content\"><\/iframe><script>\n\/*! This file is auto-generated *\/\n!function(d,l){\"use strict\";l.querySelector&&d.addEventListener&&\"undefined\"!=typeof URL&&(d.wp=d.wp||{},d.wp.receiveEmbedMessage||(d.wp.receiveEmbedMessage=function(e){var t=e.data;if((t||t.secret||t.message||t.value)&&!\/[^a-zA-Z0-9]\/.test(t.secret)){for(var s,r,n,a=l.querySelectorAll('iframe[data-secret=\"'+t.secret+'\"]'),o=l.querySelectorAll('blockquote[data-secret=\"'+t.secret+'\"]'),c=new RegExp(\"^https?:$\",\"i\"),i=0;i<o.length;i++)o[i].style.display=\"none\";for(i=0;i<a.length;i++)s=a[i],e.source===s.contentWindow&&(s.removeAttribute(\"style\"),\"height\"===t.message?(1e3<(r=parseInt(t.value,10))?r=1e3:~~r<200&&(r=200),s.height=r):\"link\"===t.message&&(r=new URL(s.getAttribute(\"src\")),n=new URL(t.value),c.test(n.protocol))&&n.host===r.host&&l.activeElement===s&&(d.top.location.href=t.value))}},d.addEventListener(\"message\",d.wp.receiveEmbedMessage,!1),l.addEventListener(\"DOMContentLoaded\",function(){for(var e,t,s=l.querySelectorAll(\"iframe.wp-embedded-content\"),r=0;r<s.length;r++)(t=(e=s[r]).getAttribute(\"data-secret\"))||(t=Math.random().toString(36).substring(2,12),e.src+=\"#?secret=\"+t,e.setAttribute(\"data-secret\",t)),e.contentWindow.postMessage({message:\"ready\",secret:t},\"*\")},!1)))}(window,document);\n\/\/# sourceURL=https:\/\/tbenews.com\/tbe\/wp-includes\/js\/wp-embed.min.js\n<\/script>\n","thumbnail_url":"https:\/\/tbenews.com\/tbe\/wp-content\/uploads\/2024\/06\/Chapter-7-IMMUnOLOGY_-scaled.jpg","thumbnail_width":2560,"thumbnail_height":1709,"description":"Chapter 7:Immunology of TBEV infection Kyra D. Zens and Rahel Ackermann-G\u00e4umann Key points Introduction Tick-borne Encephalitis (TBE) is a severe, vaccine-preventable disease of the Central Nervous System (CNS) caused by the tick-borne encephalitis virus (TBEV). The virus is primarily transmitted to humans through the bite of infected Ixodid ticks, though an estimated 1% of cases occur via alimentary transmission1,2 and rare cases of transmission through organ or blood donation have been documented.3,4 An estimated 70% of TBEV exposures are asymptomatic.5-7 The remaining 30% of individuals experience a brief, asymptomatic incubation phase,1,2,8 followed by a period of viremia accompanied by febrile, influenza-like illness. While most individuals recover without further symptoms, approximately 30% progress to a second phase of illness characterized by CNS involvement.1,2,8,9 While some individuals transition directly from the first systemic phase to the second CNS phase, referred to as \u201cmonophasic\u201d disease, most experience a short symptom-free interval of approximately 1 week between these two phases, which is referred to as \u201cbiphasic\u201d disease. Factors driving a monophasic versus biphasic disease course are not completely clear. Data clearly linking viral subtype to clinical disease course are lacking, though it is believed that monophasic disease, as well as a more severe disease course, are more common after infection with the Siberian (TBEV-Sib) and Far Eastern (TBEV-FE) viral subtypes compared to the European (TBEV-Eu) subtype.1,10 Differences in virulence factors responsible for distinct pathologies between viral subtypes, however, have yet to be described and confounding factors, such as age, chronic conditions, or possibly even regional differences in medical practices could further play roles. The immune responses which protect individuals against disease represent a complex interplay between many distinct cell types at various times and over different locations. Innate immunity comprises the \u201cfirst line\u201d defenses following pathogen exposure, acting broadly within the first hours to days following infection to protect against invaders. TBEV belongs to the genus Orthoflavivirus, which also includes the clinically-relevant, arthropod-borne viruses Dengue, West Nile, Yellow Fever, Japanese Encephalitis, and Zika1,2,11 and early immune responses to TBEV infection share many features with these viruses.12 Adaptive immune responses, comprised by both humoral (i.e. antibody), and cell-mediated (i.e. T cell) responses, take more time to be established, on the order of days to weeks, as they require the initial activation of the innate immune system. Adaptive immunity, however, provides highly-specific protection against invading pathogens, and further offers immune memory \u2013 a subset of cells which are maintained long-term (up to decades), and provide rapid protection upon later re-exposure to the same pathogen. In this chapter, we summarize the early innate and adaptive immune responses to TBEV infection as well as discuss potential mediators of long-term immune memory protective against later viral reinfection. TBEV transmission and early local innate immune responses Skin is perhaps the most important immune organ in that it acts as an initial physical barrier to many infectious organisms. The skin further contains many specialized immune cells, including resident dendritic cell (DC) subsets, natural killer (NK) cells, and T cell subsets, among others (Figures 1, 2). Transmission of TBEV through tick bites helps the virus to partially circumvent skin\u2019s role as a protective physical barrier. Furthermore, factors present within the tick\u2019s saliva, including various compounds which help to suppress local innate responses as well as the initiation of adaptive immunity,13-15 further facilitate viral transmission. Figure 1: TBEV transmission and timeline of viral and host immune response Click the image above to enlarge 1) TBEV is transmitted by the bite of an infected tick. 2) The virus infects dendritic cells (DCs) within the kin which traffic to the draining lymph node where the virus replicates further. 3) Presentation of TBEV-derived antigens by infected DCs results in the activation of adaptive immune responses; these take, however weeks to fully develop. 4) The virus is able to spread from the draining lymph node into the blood; during this primary viremia, the host experiences the first symptomatic phase of illness. 5) During primary viremia the virus seeds peripheral organs and replicates further within the tissues. This leads to 6) a second period of virema during which the virus is able to 7) cross the blood brain barrier (BBB). 8) Involvement of the CNS leads to the second phase of disease (in individuals experiencing biphasic illness), neutrophils, T cells, NK cells and B cells can be detected in the CNS. The innate immune system is the first line of defense against infection and is especially crucial for so-called \u201cna\u00efve\u201d hosts that have not yet encountered a specific pathogen and developed corresponding adaptive immune memory. Following exposure to TBEV-infected ticks, local skin inflammatory responses begin within 1-3 hours of attachment.16-18 Pathogen recognition by the innate immune system depends on the host&#8217;s expression of pattern recognition receptors (PRRs), which identify conserved moieties expressed by invading microorganisms. Toll-Like Receptors (TLRs) and Retinoic Acid-Inducible Gene I (RIG-I)-Like Receptors (RLRs), including RIG-I and Melanoma Differentiation-Associated protein 5 (MDA5), are important in the detection of RNA viruses. Upon activation in this context, PRRs initiate signaling cascades that activate the Interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway, leading to the production of IFN. The role of TLR signaling in protecting against TBEV infection is not well-defined, although TLR-3 and possibly TLR-7, may be involved.19,20 Roles for RIG-I and MDA5 in the innate immune recognition of TBEV proteins, including non-structural protein 5 (NS5) have been demonstrated.17 This recognition leads to an early immune response dominated by type I IFN (IFN-a and IFN-b), which seems to be the key mediator of protection during early infection in both in vitro and in vivo models.21,22 In line with this, mice that lack the IFN-\u03b1\/\u03b2 receptor (IFNAR) are unable to control TBEV infection and studies of polymorphisms in innate immune response genes in patients have identified variations in the interferon-induced antiviral proteins oligoadenylate synthetase 2 (OAS2) and 3 (OAS3), which may predispose individuals to the development of clinical TBE.23 While it has been established that differing strains of TBEV can elicit distinct symptoms in mouse models of"}