First they examined WNV, which causes tens of thousands of cases of encephalitis every year. It moves from the skin to the lymph nodes and spleen, causing fever and other symptoms. Most human immune systems conquer the virus at that stage, but for another 5% of people, some with inborn errors of immunity that render them vulnerable, WNV slips past the blood-brain barrier into the CNS, where it replicates in neurons, leading to severe inflammation and sometimes death.\u00a0<\/p>\n
To see whether the brain responds to any of the intermediary stages of infection, the researchers injected the footpads of mice with WNV and then examined their brains at different time intervals. Within hours, they found interferon-stimulated antiviral genes (ISGs) in the brain had been activated even though there was no virus nearby. \u201cThe virus was not detectable in the brain at this stage, and yet the CNS mounted a robust and distinct antiviral immune response,\u201d says co-senior author Alexander Lercher. \u201cThat led us to hypothesize that the CNS was recognizing signals sent from the periphery.\u201d\u00a0<\/p>\n
To characterize this signaling network, the team tested a battery of footpad-administered pathogen-associated molecular patterns (PAMPs) \u2013conserved molecules found across pathogens that the immune system has evolved to readily recognize \u2013 and found the brain was highly specific in its response. \u201cIt\u2019s finely tuned, depending on the PAMP,\u201d Lercher adds. \u201cWe tried agonists that looked like bacteria or viruses, and, depending on the PAMP, the brain activated distinct transcriptomic programs.\u201d\u00a0<\/p>\n
Intrigued, they challenged mice again with footpad PAMPs, then infected them with WNV directly in the brain, and let the virus run its course for several days. Only mice that had received poly(I:C), a potent viral simulant, had a robust rate of survival. They then repeated the experiments with other encephalitic viruses in the same viral family as WNV, including Powassan virus (which causes tick-borne encephalitis) as well as unrelated viruses such as herpes simplex. All benefitted from poly(I:C)-induced triggering of the early warning system. \u201cIt wasn\u2019t very surprising that they got a boost in surviving Powassan virus, which is basically West Nile\u2019s cousin, but the fact that it was effective against herpes virus is pretty notable, because genetically these viruses are as different as a sequoia and a house mouse,\u201d Lewy says. \u201cWe didn\u2019t exhaustively try every single encephalitic virus, but I think from this evidence we can conclude that it\u2019s a pretty broad mechanism.\u201d\u00a0<\/p>\n
Further experiments revealed that the viral PAMP poly(I:C) triggered a particularly robust systemic response of type I interferons, which activated ISGs in brain microvascular endothelial cells (BMECs) located in the blood-brain barrier. Bioinformatic analyses suggests that these cells then pass the information along to the CNS, which prompted the brain\u2019s immune cells \u2013 especially innate immune cells called microglia \u2013 to prepare for a potential viral invasion. \u201cIn interpreting these immune signals, the blood-brain barrier is a bit like an infection sensor for the brain,\u201d Lewy says. \u201cThrough the BBB\u2019s early detection of infection signals in the periphery, the brain is able to mount a robust prophylactic response, ultimately preventing encephalitis in most cases.\u201d\u00a0<\/p>\n
Rice says the basic science research, which was partly supported by the Stavros Niarchos Foundation (SNF) Institute for Global Infectious Disease Research at Rockefeller, could inform new approaches to preventing vector-borne neuroinflammation. \u201cThe right therapeutic could goose the immune system early, shifting the brain into this preventative state,\u201d he says. \u201cThat might look like either some kind of adjuvant or even an interferon-based therapy like the ones that were used to treat chronic hepatitis C before the advent of more potent, curative regimens.\u201d\u00a0<\/p>\n
Source: Rockefeller University\u00a0<\/p>\n","protected":false},"excerpt":{"rendered":"First they examined WNV, which causes tens of thousands of cases of encephalitis every year. It moves from…\n","protected":false},"author":2,"featured_media":552609,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[103,61,60,233830,233829],"class_list":["post-552608","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-health","tag-ie","tag-ireland","tag-published-in-cp-immunity-bsky-social","tag-x-ricelaboratory-at-rockefelleruniv-brrockefelleruniversity-brrockefeller-edu"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/552608","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=552608"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/552608\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/552609"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=552608"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=552608"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=552608"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}