一個國際研究小組日前發(fā)現(xiàn),，人體細胞內(nèi)的一種跨膜蛋白在麻疹病毒入侵人體時充當了“內(nèi)鬼”的角色,，為病毒進入細胞敞開大門。這一發(fā)現(xiàn)有可能幫助研究人員利用麻疹病毒對抗腫瘤細胞,。
麻疹是常見于兒童的急性呼吸道傳染病,。盡管相關(guān)疫苗早已問世，全球目前每年仍有約12萬人死于麻疹,。麻疹的傳染性很強,，未接種疫苗者如與麻疹患者接觸，其患病幾率可超過90％,。
通過對麻疹感染機制的多年研究,，科研人員已發(fā)現(xiàn)麻疹病毒能在特殊受體的協(xié)助下進入一些呼吸道細胞，攜帶該病毒的細胞隨后通過淋巴結(jié)將麻疹病毒帶至各淋巴器官,。不過,，至于麻疹病毒如何重返呼吸道，此后怎樣離開人體,、尋找新宿主卻難以說清,。有學者推測，可能是人體細胞內(nèi)的某種物質(zhì)充當了協(xié)助麻疹病毒進出人體的“內(nèi)鬼”,。
由德國,、美國、加拿大,、新加坡和法國研究者組成的一個小組在新一期英國學術(shù)周刊《自然》上報告說,，為了揪出這一“內(nèi)鬼”，他們選取肺腫瘤細胞等易受麻疹病毒感染的細胞,，研究它們內(nèi)部是否有一些“與眾不同”的蛋白,。隨后，研究人員將那些可疑蛋白分別放入正常情況下不會感染麻疹病毒的細胞內(nèi),，看它們會不會有協(xié)助麻疹病毒“作案”的異常舉動,。
經(jīng)過層層篩查，一種名為Nectin-4的跨膜蛋白終于“暴露身份”,。據(jù)德國保羅·埃爾利希研究所的米夏埃爾·米勒巴赫博士介紹,，Nectin-4跨膜蛋白位于上皮細胞內(nèi)側(cè)，可接觸麻疹病毒并幫助其穿過上皮細胞,。研究人員還阻斷了指導合成Nectin-4跨膜蛋白的基因表達,，結(jié)果易感染麻疹病毒的細胞不再感染這種病毒。
不過,，研究人員仍不放心,，因為他們選取的細胞源自較特殊的腫瘤細胞,。為了不“冤枉”Nectin-4跨膜蛋白，研究者又利用正常人的呼吸道上皮細胞進行實驗,，結(jié)果證實Nectin-4跨膜蛋白的確在麻疹病毒進出人體呼吸道時起到了關(guān)鍵作用,。
據(jù)悉，這一發(fā)現(xiàn)不僅有助于麻疹預防研究,，而且有望為抗癌研究提供新思路,。實際上，麻疹病毒此前已在一些研究中被用作抗癌的“溶瘤病毒”,，即利用該病毒自身的不斷繁殖殺死腫瘤細胞,。不過，這種方法的具體效果還有待進一步檢驗,。(生物谷 Bioon.com)
doi:10.1038/nature10639
PMC:
PMID:
Adherens junction protein nectin-4 is the epithelial receptor for measles virus
Michael D. Mühlebach1 Mathieu Mateo2 Patrick L. Sinn3 Steffen Prüfer1 Katharina M. Uhlig1 Vincent H. J. Leonard2 Chanakha K. Navaratnarajah2 Marie Frenzke2 Xiao X. Wong4 Bevan Sawatsky4 Shyam Ramachandran3 Paul B. McCray3 Klaus Cichutek1 Veronika von Messling4, 5 Marc Lopez6 Roberto Cattaneo2
Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously. How and where the virus crosses back into the airways has remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, here we identify nectin-4 (ref. ; also called poliovirus-receptor-like-4 (PVRL4)) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains measles virus entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is downregulated in infected epithelial cells, including those of macaque tracheae. Although other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that measles virus targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer, which has implications for ongoing measles-virus-based clinical trials of oncolysis. was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made
