{"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 6: Pathogenesis of TBEV-diseases - TBE Book","type":"rich","width":600,"height":338,"html":"<blockquote class=\"wp-embedded-content\" data-secret=\"WrFPRYf0pF\"><a href=\"https:\/\/tbenews.com\/tbe\/chapter-6-pathogenesis-of-tbev-diseases\/\">Chapter 6: Pathogenesis of TBEV-diseases<\/a><\/blockquote><iframe sandbox=\"allow-scripts\" security=\"restricted\" src=\"https:\/\/tbenews.com\/tbe\/chapter-6-pathogenesis-of-tbev-diseases\/embed\/#?secret=WrFPRYf0pF\" width=\"600\" height=\"338\" title=\"&#8220;Chapter 6: Pathogenesis of TBEV-diseases&#8221; &#8212; TBE Book\" data-secret=\"WrFPRYf0pF\" 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-6-scaled.jpg","thumbnail_width":2560,"thumbnail_height":1709,"description":"Chapter 6:Pathogenesis of TBEV-diseases Anna K \u00d6verby, Saravanan Thangamani Key points Transmission and entry:Tick vectors and tick-host interface The Ixodes ricinus tick serves as the primary carrier of TBEV-Eu in nature, while the Ixodes persulcatus tick is the primary vector for TBEV-Sib and TBEV-FE.1 I. ricinus is widely spread across Europe, reaching into Turkey and northern Iran, whereas I. persulcatus is found in the Urals, Siberia, Far-Eastern Russia, as well as parts of China and Japan.2,3 A zone of sympatry exists in the northern Baltics, western Finland, and northwestern Russia, where the habitats of I. ricinus and I. persulcatus overlap, leading to the presence of multiple TBEV subtypes.3-5 TBEV is maintained within natural transmission cycles involving ixodid ticks and wild-living mammalian hosts. Infected ticks are presumed to remain infected throughout their life cycle.2 While transovarial transmission of TBEV from an infected female tick to the egg mass is possible, this mode of infection is not entirely efficient in sustaining TBEV within the natural tick population.6 The transmission of tick-borne encephalitis virus (TBEV) from an infected tick to a host involves a complex interplay between the tick&#8217;s feeding process and the immunomodulatory properties of its saliva. This process begins shortly after the tick attaches itself to the host. TBEV is transmitted to the vertebrate host along with the tick&#8217;s saliva as early as one hour after the tick attaches7 and POWV is transmitted as fast as 15 minutes after attachment.8 Tick feeding is a sophisticated process, and successful feeding is facilitated by various components present in the tick&#8217;s saliva, which possess immunomodulatory properties. Notably, tick salivary factors not only aid in blood feeding but also modulate the host environment, thereby promoting the transmission and establishment of TBEV.9 Seminal studies conducted by Labuda et al. (1993) demonstrated the significance of saliva-assisted transmission (SAT) of TBEV.10 They observed that when na\u00efve guinea pigs were inoculated with a mixture of TBEV and salivary gland extract (SGE) obtained from partially fed uninfected female ticks of species like Ixodes ricinus, Dermacentor reticulatus, or Rhipicephalus appendiculatus, and subsequently, uninfected Rhipicephalus appendiculatus nymphs fed on these guinea pigs, there was an increased acquisition of the virus by ticks feeding on animals inoculated with the mixture of SGE and virus compared to those inoculated with the virus alone. This research underscores the crucial role of tick saliva in facilitating the transmission of TBEV and sheds light on the mechanisms involved in the transmission dynamics between ticks and hosts. Observations of pathogens being transmitted from infected ticks to uninfected ticks co-feeding on the same host have offered indirect evidence of what is known as &#8220;sequential acquisition of tick-borne pathogens,&#8221; as noted by Nuttall and Labuda in 2004.9 It is also referred to as co-feeding transmission. In natural environments, it&#8217;s common for infected ticks to co-feed alongside uninfected ticks on a single host. Labuda et al. conducted experiments where TBEV-infected I. ricinus ticks and uninfected ticks co-fed on na\u00efve, natural host species. Intriguingly, they found that the highest numbers of TBEV-infected ticks originated from susceptible host species with very low levels of viremia, providing compelling evidence that non-viremic co-feeding transmission of TBEV is a primary mechanism for maintaining the virus in natural foci.11,12 Tick-host-virus interface during TBEV transmission: Skin acts as the primary barrier against various forms of damage, including mechanical stress, environmental factors, and potential infections. It serves as the frontline defense between a tick and its host, making it the first point of contact for both TBEV and tick saliva during feeding. Throughout the feeding process, a tick&#8217;s mouthparts and saliva interact with the host&#8217;s blood and lymphatic vessels, as well as various cellular components such as fibroblasts, keratinocytes, Langerhans cells, dendritic cells, macrophages, mast cells, natural killer cells, T lymphocytes, and soluble mediators like cytokines, chemokines, complement proteins, and lectins.13 These cutaneous immune cells play a pivotal role in initiating the host&#8217;s immune response and inflammatory reactions against tick feeding and potential pathogen transmission. The significance of skin infection in the transmission of TBEV is paramount. Skin acts as the primary interface where these viruses establish infection in the host.9 Labuda et al. thoroughly investigated the initial stages of TBEV replication within the skin of two natural host species: bank voles (Clethrionomys glareolus) and yellow-necked field mice (Apodemus flavicollis). Their experimental setup mirrored natural conditions, with infected and uninfected Ixodes ricinus ticks placed on specific areas of the host&#8217;s skin. Their findings revealed a correlation between TBEV detection in feeding ticks and the transmission dynamics from infected to uninfected ticks.14 Additionally, TBEV exhibited a preference for skin sites where ticks were actively feeding. To characterize TBEV-infected cells, Labuda et al. infested laboratory mice with TBEV-infected ticks and cultured skin explants from the infestation sites. They observed the migration of leukocytes from these explants, with viral antigens present in migrating Langerhans cells and neutrophils, indicating their role in viral dissemination.14 In vitro studies suggest that dendritic cell populations at the tick feeding site are among the early targets of TBEV infection. Recent research indicates that exposure of bone marrow-derived dendritic cells to tick saliva enhances TBEV replication, partly through activation of the pro-survival Akt pathway.15 These results underscore the importance of localized skin infection in the early transmission of the virus from infected ticks and its acquisition by uninfected co-feeding ticks.11,16 Immune cells infiltrating the skin during tick feeding act as carriers for virus transmission between co-feeding ticks, independent of systemic viremia.14 Langerhans cells, the primary dendritic cell population in the epidermis, likely play a crucial role in virus dissemination, as evidenced by their migration to draining lymph nodes in response to cutaneous infections with other arthropod-borne viruses.17 Thus, the presence of TBE viral antigen in emigrating Langerhans cells suggests their involvement in transporting TBEV to the lymphatic system, contributing to overall viral dissemination. The importance of virus-infected cells at the tick feeding site and their contribution to initial viral replication and dissemination was further supported by in vitro experiments where I. ricinus tick saliva was shown to"}