Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 31 Records) |
Query Trace: Blair CD [original query] |
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Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota)
Kuhn JH , Abe J , Adkins S , Alkhovsky SV , Avšič-Županc T , Ayllón MA , Bahl J , Balkema-Buschmann A , Ballinger MJ , Kumar Baranwal V , Beer M , Bejerman N , Bergeron É , Biedenkopf N , Blair CD , Blasdell KR , Blouin AG , Bradfute SB , Briese T , Brown PA , Buchholz UJ , Buchmeier MJ , Bukreyev A , Burt F , Büttner C , Calisher CH , Cao M , Casas I , Chandran K , Charrel RN , Kumar Chaturvedi K , Chooi KM , Crane A , Dal Bó E , Carlos de la Torre J , de Souza WM , de Swart RL , Debat H , Dheilly NM , Di Paola N , Di Serio F , Dietzgen RG , Digiaro M , Drexler JF , Duprex WP , Dürrwald R , Easton AJ , Elbeaino T , Ergünay K , Feng G , Firth AE , Fooks AR , Formenty PBH , Freitas-Astúa J , Gago-Zachert S , Laura García M , García-Sastre A , Garrison AR , Gaskin TR , Gong W , Gonzalez JJ , de Bellocq J , Griffiths A , Groschup MH , Günther I , Günther S , Hammond J , Hasegawa Y , Hayashi K , Hepojoki J , Higgins CM , Hongō S , Horie M , Hughes HR , Hume AJ , Hyndman TH , Ikeda K , Jiāng D , Jonson GB , Junglen S , Klempa B , Klingström J , Kondō H , Koonin EV , Krupovic M , Kubota K , Kurath G , Laenen L , Lambert AJ , Lǐ J , Li JM , Liu R , Lukashevich IS , MacDiarmid RM , Maes P , Marklewitz M , Marshall SH , Marzano SL , McCauley JW , Mirazimi A , Mühlberger E , Nabeshima T , Naidu R , Natsuaki T , Navarro B , Navarro JA , Neriya Y , Netesov SV , Neumann G , Nowotny N , Nunes MRT , Ochoa-Corona FM , Okada T , Palacios G , Pallás V , Papa A , Paraskevopoulou S , Parrish CR , Pauvolid-Corrêa A , Pawęska JT , Pérez DR , Pfaff F , Plemper RK , Postler TS , Rabbidge LO , Radoshitzky SR , Ramos-González PL , Rehanek M , Resende RO , Reyes CA , Rodrigues TCS , Romanowski V , Rubbenstroth D , Rubino L , Runstadler JA , Sabanadzovic S , Sadiq S , Salvato MS , Sasaya T , Schwemmle M , Sharpe SR , Shi M , Shimomoto Y , Kavi Sidharthan V , Sironi M , Smither S , Song JW , Spann KM , Spengler JR , Stenglein MD , Takada A , Takeyama S , Tatara A , Tesh RB , Thornburg NJ , Tian X , Tischler ND , Tomitaka Y , Tomonaga K , Tordo N , Tu C , Turina M , Tzanetakis IE , Maria Vaira A , van den Hoogen B , Vanmechelen B , Vasilakis N , Verbeek M , von Bargen S , Wada J , Wahl V , Walker PJ , Waltzek TB , Whitfield AE , Wolf YI , Xia H , Xylogianni E , Yanagisawa H , Yano K , Ye G , Yuan Z , Zerbini FM , Zhang G , Zhang S , Zhang YZ , Zhao L , Økland AL . J Gen Virol 2023 104 (8) In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV. |
2022 taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.
Kuhn JH , Adkins S , Alkhovsky SV , Avi-upanc T , Aylln MA , Bahl J , Balkema-Buschmann A , Ballinger MJ , Bandte M , Beer M , Bejerman N , Bergeron , Biedenkopf N , Bigarr L , Blair CD , Blasdell KR , Bradfute SB , Briese T , Brown PA , Bruggmann R , Buchholz UJ , Buchmeier MJ , Bukreyev A , Burt F , Bttner C , Calisher CH , Candresse T , Carson J , Casas I , Chandran K , Charrel RN , Chiaki Y , Crane A , Crane M , Dacheux L , B ED , delaTorre JC , deLamballerie X , deSouza WM , deSwart RL , Dheilly NM , DiPaola N , DiSerio F , Dietzgen RG , Digiaro M , Drexler JF , Duprex WP , Drrwald R , Easton AJ , Elbeaino T , Ergnay K , Feng G , Feuvrier C , Firth AE , Fooks AR , Formenty PBH , Freitas-Asta J , Gago-Zachert S , Garca ML , Garca-Sastre A , Garrison AR , Godwin SE , Gonzalez JJ , deBellocq JG , Griffiths A , Groschup MH , Gnther S , Hammond J , Hepojoki J , Hierweger MM , Hong S , Horie M , Horikawa H , Hughes HR , Hume AJ , Hyndman TH , Jing D , Jonson GB , Junglen S , Kadono F , Karlin DG , Klempa B , Klingstrm J , Koch MC , Kond H , Koonin EV , Krsov J , Krupovic M , Kubota K , Kuzmin IV , Laenen L , Lambert AJ , L J , Li JM , Lieffrig F , Lukashevich IS , Luo D , Maes P , Marklewitz M , Marshall SH , Marzano SL , McCauley JW , Mirazimi A , Mohr PG , Moody NJG , Morita Y , Morrison RN , Mhlberger E , Naidu R , Natsuaki T , Navarro JA , Neriya Y , Netesov SV , Neumann G , Nowotny N , Ochoa-Corona FM , Palacios G , Pallandre L , Palls V , Papa A , Paraskevopoulou S , Parrish CR , Pauvolid-Corra A , Pawska JT , Prez DR , Pfaff F , Plemper RK , Postler TS , Pozet F , Radoshitzky SR , Ramos-Gonzlez PL , Rehanek M , Resende RO , Reyes CA , Romanowski V , Rubbenstroth D , Rubino L , Rumbou A , Runstadler JA , Rupp M , Sabanadzovic S , Sasaya T , Schmidt-Posthaus H , Schwemmle M , Seuberlich T , Sharpe SR , Shi M , Sironi M , Smither S , Song JW , Spann KM , Spengler JR , Stenglein MD , Takada A , Tesh RB , Tkov J , Thornburg NJ , Tischler ND , Tomitaka Y , Tomonaga K , Tordo N , Tsunekawa K , Turina M , Tzanetakis IE , Vaira AM , vandenHoogen B , Vanmechelen B , Vasilakis N , Verbeek M , vonBargen S , Wada J , Wahl V , Walker PJ , Whitfield AE , Williams JV , Wolf YI , Yamasaki J , Yanagisawa H , Ye G , Zhang YZ , kland AL . Arch Virol 2022 167 (12) 2857-2906 In March 2022, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by two new families (bunyaviral Discoviridae and Tulasviridae), 41 new genera, and 98 new species. Three hundred forty-nine species were renamed and/or moved. The accidentally misspelled names of seven species were corrected. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV. |
Genetic Adaptation by Dengue Virus Serotype 2 to Enhance Infection of Aedes aegypti Mosquito Midguts.
Erb SM , Butrapet S , Roehrig JT , Huang CY , Blair CD . Viruses 2022 14 (7) Dengue viruses (DENVs), serotypes 1-4, are arthropod-borne viruses transmitted to humans by mosquitoes, primarily Aedes aegypti. The transmission cycle begins when Ae. aegypti ingest blood from a viremic human and the virus infects midgut epithelial cells. In studying viruses derived from the DENV2 infectious clone 30P-NBX, we found that when the virus was delivered to female Ae. aegypti in an infectious blood meal, the midgut infection rate (MIR) was very low. To determine if adaptive mutations in the DENV2 envelope (E) glycoprotein could be induced to increase the MIR, we serially passed 30P-NBX in Ae. aegypti midguts. After four passages, a single, non-conservative mutation in E protein domain II (DII) nucleotide position 1300 became dominant, resulting in replacement of positively-charged amino acid lysine (K) at position 122 with negatively-charged glutamic acid (E; K122E) and a significantly-enhanced MIR. Site directed mutagenesis experiments showed that reducing the positive charge of this surface-exposed region of the E protein DII correlated with improved Ae. aegypti midgut infection. |
Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection
Calvert AE , Bennett SL , Hunt AR , Fong RH , Doranz BJ , Roehrig JT , Blair CD . Virology 2021 565 13-21 Eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV) and Venezuelan equine encephalitis virus (VEEV) can cause fatal encephalitis in humans and equids. Some MAbs to the E1 glycoprotein are known to be cross-reactive, weakly neutralizing in vitro but can protect from disease in animal models. We investigated the mechanism of neutralization of VEEV infection by the broadly cross-reactive E1-specific MAb 1A4B-6. 1A4B-6 protected 3-week-old Swiss Webster mice prophylactically from lethal VEEV challenge. Likewise, 1A4B-6 inhibited virus growth in vitro at a pre-attachment step after virions were incubated at 37 °C and inhibited virus-mediated cell fusion. Amino acid residue N100 in the fusion loop of E1 protein was identified as critical for binding. The potential to elicit broadly cross-reactive MAbs with limited virus neutralizing activity in vitro but that can inhibit virus entry and protect animals from infection merits further exploration for vaccine and therapeutic developmental research. |
2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.
Kuhn JH , Adkins S , Agwanda BR , Al Kubrusli R , Alkhovsky Aльxoвcкий Cepгeй Bлaдимиpoвич SV , Amarasinghe GK , Avšič-Županc T , Ayllón MA , Bahl J , Balkema-Buschmann A , Ballinger MJ , Basler CF , Bavari S , Beer M , Bejerman N , Bennett AJ , Bente DA , Bergeron É , Bird BH , Blair CD , Blasdell KR , Blystad DR , Bojko J , Borth WB , Bradfute S , Breyta R , Briese T , Brown PA , Brown JK , Buchholz UJ , Buchmeier MJ , Bukreyev A , Burt F , Büttner C , Calisher CH , Cao 曹孟籍 M , Casas I , Chandran K , Charrel RN , Cheng Q , Chiaki 千秋祐也 Y , Chiapello M , Choi IR , Ciuffo M , Clegg JCS , Crozier I , Dal Bó E , de la Torre JC , de Lamballerie X , de Swart RL , Debat H , Dheilly NM , Di Cicco E , Di Paola N , Di Serio F , Dietzgen RG , Digiaro M , Dolnik O , Drebot MA , Drexler JF , Dundon WG , Duprex WP , Dürrwald R , Dye JM , Easton AJ , Ebihara 海老原秀喜 H , Elbeaino T , Ergünay K , Ferguson HW , Fooks AR , Forgia M , Formenty PBH , Fránová J , Freitas-Astúa J , Fu 付晶晶 J , Fürl S , Gago-Zachert S , Gāo 高福 GF , García ML , García-Sastre A , Garrison AR , Gaskin T , Gonzalez JJ , Griffiths A , Goldberg TL , Groschup MH , Günther S , Hall RA , Hammond J , Han 韩彤 T , Hepojoki J , Hewson R , Hong 洪健 J , Hong 洪霓 N , Hongo 本郷誠治 S , Horie 堀江真行 M , Hu JS , Hu T , Hughes HR , Hüttner F , Hyndman TH , Ilyas M , Jalkanen R , Jiāng 姜道宏 D , Jonson GB , Junglen S , Kadono 上遠野冨士夫 F , Kaukinen KH , Kawate M , Klempa B , Klingström J , Kobinger G , Koloniuk I , Kondō 近藤秀樹 H , Koonin EV , Krupovic M , Kubota 久保田健嗣 K , Kurath G , Laenen L , Lambert AJ , Langevin SL , Lee B , Lefkowitz EJ , Leroy EM , Li 李邵蓉 S , Li 李龙辉 L , Lǐ 李建荣 J , Liu 刘华珍 H , Lukashevich IS , Maes P , de Souza WM , Marklewitz M , Marshall SH , Marzano SL , Massart S , McCauley JW , Melzer M , Mielke-Ehret N , Miller KM , Ming TJ , Mirazimi A , Mordecai GJ , Mühlbach HP , Mühlberger E , Naidu R , Natsuaki 夏秋知英 T , Navarro JA , Netesov Heтёcoв Cepгeй Bиктopoвич SV , Neumann G , Nowotny N , Nunes MRT , Olmedo-Velarde A , Palacios G , Pallás V , Pályi B , Papa Άννα Παπά A , Paraskevopoulou Σοφία Παρασκευοπούλου S , Park AC , Parrish CR , Patterson DA , Pauvolid-Corrêa A , Pawęska JT , Payne S , Peracchio C , Pérez DR , Postler TS , Qi 亓立莹 L , Radoshitzky SR , Resende RO , Reyes CA , Rima BK , Luna GR , Romanowski V , Rota P , Rubbenstroth D , Rubino L , Runstadler JA , Sabanadzovic S , Sall AA , Salvato MS , Sang R , Sasaya 笹谷孝英 T , Schulze AD , Schwemmle M , Shi 施莽 M , Shí 石晓宏 X , Shí 石正丽 Z , Shimomoto 下元祥史 Y , Shirako Y , Siddell SG , Simmonds P , Sironi M , Smagghe G , Smither S , Song 송진원 JW , Spann K , Spengler JR , Stenglein MD , Stone DM , Sugano J , Suttle CA , Tabata A , Takada 高田礼人 A , Takeuchi 竹内繁治 S , Tchouassi DP , Teffer A , Tesh RB , Thornburg NJ , Tomitaka 冨高保弘 Y , Tomonaga 朝長啓造 K , Tordo N , Torto B , Towner JS , Tsuda 津田新哉 S , Tu 涂长春 C , Turina M , Tzanetakis IE , Uchida J , Usugi 宇杉富雄 T , Vaira AM , Vallino M , van den Hoogen B , Varsani A , Vasilakis Νίκος Βασιλάκης N , Verbeek M , von Bargen S , Wada 和田治郎 J , Wahl V , Walker PJ , Wang 王林发 LF , Wang 王国平 G , Wang 王雁翔 Y , Wang 王亚琴 Y , Waqas M , Wèi 魏太云 T , Wen 温少华 S , Whitfield AE , Williams JV , Wolf YI , Wu 吴建祥 J , Xu 徐雷 L , Yanagisawa 栁澤広宣 H , Yang 杨彩霞 C , Yang 杨作坤 Z , Zerbini FM , Zhai 翟立峰 L , Zhang 张永振 YZ , Zhang 张松 S , Zhang 张靖国 J , Zhang 张哲 Z , Zhou 周雪平 X . Arch Virol 2021 166 (12) 3513-3566 In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV. |
A monoclonal antibody specific for japanese encephalitis virus with high neutralizing capability for inclusion as a positive control in diagnostic neutralization tests
Calvert AE , Bennett SL , Dixon KL , Blair CD , Roehrig JT . Am J Trop Med Hyg 2019 101 (1) 233-236 Japanese encephalitis virus (JEV) is the most common cause of viral encephalitis in Asia, and it is increasingly a global public health concern because of its recent geographic expansion. Although commercial vaccines are available and used in some endemic countries, JEV continues to cause illness, with more than 60,000 cases reported annually. To develop a reproducible positive control antibody useable in diagnosis of JEV infections, murine hybridomas were developed from mice inoculated with a combination of IXIARO JEV vaccine and JEV domain III of the envelope protein (E-DIII). Monoclonal antibodies (MAbs) were characterized for their ability to neutralize virus in vitro. Monoclonal antibody 17BD3-2 was found to be JEV specific and highly neutralizing, with a plaque reduction neutralization test (PRNT)90 endpoint titer of 1.25 mug/mL. The functional epitopes were mapped using virus neutralization escape variants to amino acid residues S309, K312, and G333 in E-DIII. This MAb may be substituted for human immune sera used as a positive control in PRNT for distribution to public health laboratories worldwide in potential future outbreaks of JEV. |
Taxonomy of the order Bunyavirales: update 2019.
Abudurexiti A , Adkins S , Alioto D , Alkhovsky SV , Avsic-Zupanc T , Ballinger MJ , Bente DA , Beer M , Bergeron E , Blair CD , Briese T , Buchmeier MJ , Burt FJ , Calisher CH , Chang C , Charrel RN , Choi IR , Clegg JCS , de la Torre JC , de Lamballerie X , Deng F , Di Serio F , Digiaro M , Drebot MA , Duan X , Ebihara H , Elbeaino T , Ergunay K , Fulhorst CF , Garrison AR , Gao GF , Gonzalez JJ , Groschup MH , Gunther S , Haenni AL , Hall RA , Hepojoki J , Hewson R , Hu Z , Hughes HR , Jonson MG , Junglen S , Klempa B , Klingstrom J , Kou C , Laenen L , Lambert AJ , Langevin SA , Liu D , Lukashevich IS , Luo T , Lu C , Maes P , de Souza WM , Marklewitz M , Martelli GP , Matsuno K , Mielke-Ehret N , Minutolo M , Mirazimi A , Moming A , Muhlbach HP , Naidu R , Navarro B , Nunes MRT , Palacios G , Papa A , Pauvolid-Correa A , Paweska JT , Qiao J , Radoshitzky SR , Resende RO , Romanowski V , Sall AA , Salvato MS , Sasaya T , Shen S , Shi X , Shirako Y , Simmonds P , Sironi M , Song JW , Spengler JR , Stenglein MD , Su Z , Sun S , Tang S , Turina M , Wang B , Wang C , Wang H , Wang J , Wei T , Whitfield AE , Zerbini FM , Zhang J , Zhang L , Zhang Y , Zhang YZ , Zhang Y , Zhou X , Zhu L , Kuhn JH . Arch Virol 2019 164 (7) 1949-1965 In February 2019, following the annual taxon ratification vote, the order Bunyavirales was amended by creation of two new families, four new subfamilies, 11 new genera and 77 new species, merging of two species, and deletion of one species. This article presents the updated taxonomy of the order Bunyavirales now accepted by the International Committee on Taxonomy of Viruses (ICTV). |
Taxonomy of the order Bunyavirales: second update 2018
Maes P , Adkins S , Alkhovsky SV , Avsic-Zupanc T , Ballinger MJ , Bente DA , Beer M , Bergeron E , Blair CD , Briese T , Buchmeier MJ , Burt FJ , Calisher CH , Charrel RN , Choi IR , Clegg JCS , de la Torre JC , de Lamballerie X , DeRisi JL , Digiaro M , Drebot M , Ebihara H , Elbeaino T , Ergunay K , Fulhorst CF , Garrison AR , Gao GF , Gonzalez JJ , Groschup MH , Gunther S , Haenni AL , Hall RA , Hewson R , Hughes HR , Jain RK , Jonson MG , Junglen S , Klempa B , Klingstrom J , Kormelink R , Lambert AJ , Langevin SA , Lukashevich IS , Marklewitz M , Martelli GP , Mielke-Ehret N , Mirazimi A , Muhlbach HP , Naidu R , Nunes MRT , Palacios G , Papa A , Paweska JT , Peters CJ , Plyusnin A , Radoshitzky SR , Resende RO , Romanowski V , Sall AA , Salvato MS , Sasaya T , Schmaljohn C , Shi X , Shirako Y , Simmonds P , Sironi M , Song JW , Spengler JR , Stenglein MD , Tesh RB , Turina M , Wei T , Whitfield AE , Yeh SD , Zerbini FM , Zhang YZ , Zhou X , Kuhn JH . Arch Virol 2019 164 (3) 927-941 In October 2018, the order Bunyavirales was amended by inclusion of the family Arenaviridae, abolishment of three families, creation of three new families, 19 new genera, and 14 new species, and renaming of three genera and 22 species. This article presents the updated taxonomy of the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV). |
Bunyavirus taxonomy: Limitations and misconceptions associated with the current ICTV criteria used for species demarcation
Blitvich BJ , Beaty BJ , Blair CD , Brault AC , Dobler G , Drebot MA , Haddow AD , Kramer LD , LaBeaud AD , Monath TP , Mossel EC , Plante K , Powers AM , Tesh RB , Turell MJ , Vasilakis N , Weaver SC . Am J Trop Med Hyg 2018 99 (1) 11-16 The International Committee on Taxonomy of Viruses (ICTV) has implemented numerous changes to the taxonomic classification of bunyaviruses over the years. Whereas most changes have been justified and necessary because of the need to accommodate newly discovered and unclassified viruses, other changes are a cause of concern, especially the decision to demote scores of formerly recognized species to essentially strains of newly designated species. This practice was first described in the seventh taxonomy report of the ICTV and has continued in all subsequent reports. In some instances, viruses that share less than 75% nucleotide sequence identity across their genomes, produce vastly different clinical presentations, possess distinct vector and host associations, have different biosafety recommendations, and occur in nonoverlapping geographic regions are classified as strains of the same species. Complicating the matter is the fact that virus strains have been completely eliminated from ICTV reports; thus, critically important information on virus identities and their associated biological and epidemiological features cannot be readily related to the ICTV classification. Here, we summarize the current status of bunyavirus taxonomy and discuss the adverse consequences associated with the reclassification and resulting omission of numerous viruses of public health importance from ICTV reports. As members of the American Committee on Arthropod-borne Viruses, we encourage the ICTV Bunyavirus Study Group to reconsider their stance on bunyavirus taxonomy, to revise the criteria currently used for species demarcation, and to list additional strains of public and veterinary importance. |
Full genomic characterization of California serogroup viruses, genus Orthobunyavirus, family Peribunyaviridae including phylogenetic relationships.
Hughes HR , Lanciotti RS , Blair CD , Lambert AJ . Virology 2017 512 201-210 Thorough molecular characterization of reference viruses supports the detection of emerging human pathogens as well as studies of evolutionary relationships. However, full characterization of the tripartite RNA genomes of many viruses of the clinically important family Peribunyaviridae remains incomplete, making it difficult to identify emerging strains. Here, we report the full genome sequences of nine viruses belonging to the California serogroup and describe multi-segment analyses of these and previously published California serogroup strain data to determine the role of segment reassortment in the evolution of this serogroup. Phylogenetic trees from the small, medium, and large segments suggest long term, independent evolution of the majority of strains. However, trees from each segment were not entirely congruent and evidence of reassortment among some strains is presented. Of unique interest, the L segment phylogeny reveals divergent branching patterns for encephalitic versus non-encephalitic viruses in both major clades of the California serogroup. |
A humanized monoclonal antibody neutralizes yellow fever virus strain 17D-204 in vitro but does not protect a mouse model from disease
Calvert AE , Dixon KL , Piper J , Bennett SL , Thibodeaux BA , Barrett AD , Roehrig JT , Blair CD . Antiviral Res 2016 131 92-9 The yellow fever virus (YFV) vaccine 17D-204 is considered safe and effective, yet rare severe adverse events (SAEs), some resulting in death, have been documented following vaccination. Individuals exhibiting post-vaccinal SAEs are ideal candidates for antiviral monoclonal antibody (MAb) therapy; the time until appearance of clinical signs post-exposure is usually short and patients are quickly hospitalized. We previously developed a murine-human chimeric monoclonal antibody (cMAb), 2C9-cIgG, reactive with both virulent YFV and 17D-204, and demonstrated its ability to prevent and treat YF disease in both AG129 mouse and hamster models of infection. To counteract possible selection of 17D-204 variants that escape neutralization by treatment with a single MAb (2C9-cIgG), we developed a second cMAb, 864-cIgG, for use in combination with 2C9-cIgG in post-vaccinal therapy. MAb 864-cIgG recognizes/neutralizes only YFV 17D-204 vaccine substrain and binds to domain III (DIII) of the viral envelope protein, which is different from the YFV type-specific binding site of 2C9-cIgG in DII. Although it neutralized 17D-204 in vitro, administration of 864-cIgG had no protective capacity in the interferon receptor-deficient AG129 mouse model of 17D-204 infection. The data presented here show that although DIII-specific 864-cIgG neutralizes virus infectivity in vitro, it does not have the ability to abrogate disease in vivo. Therefore, combination of 864-cIgG with 2C9-cIgG for treatment of YF vaccination SAEs does not appear to provide an improvement on 2C9-cIgG therapy alone. |
Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies
Porta J , Jose J , Roehrig JT , Blair CD , Kuhn RJ , Rossmann MG . J Virol 2014 88 (17) 9616-23 Alphaviruses can be serious, sometimes lethal human pathogens that belong to the family Togaviridae. Structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy (cryo-EM) and homology modeling. Here we characterize these monoclonal antibody Fab fragments known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both these antibody Fab fragments cross-link the surface E2 glycoproteins and, therefore, probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain. IMPORTANCE: Alphaviral infections are transmitted mainly by mosquitoes. Venezuelan equine encephalitis virus (VEEV) is an alphavirus with a wide distribution across the globe. No effective vaccines exist for alphaviral infections. Therefore, a better understanding of VEEV and its associated neutralizing antibodies will help with the development of effective drugs and vaccines. |
Molecular determinants of dengue virus 2 envelope protein important for virus entry in Fc?RIIA-mediated antibody-dependent enhancement of infection.
Chotiwan N , Roehrig JT , Schlesinger JJ , Blair CD , Huang CYH . Virology 2014 456-457 (1) 238-246 Antibody-dependent enhancement (ADE) of infection may cause severe illness in patients suffering a secondary infection by a heterologous dengue virus (DENV) serotype. During ADE of infection, cross-reactive non- or poorly-neutralizing antibodies form infectious virus-Ab complexes with the newly infecting serotype and enhance virus infection by binding to the Fc receptors (FcR) on FcR-bearing cells. In this study, we determined that molecular determinants of DENV2 envelope protein critical for virus entry during non-ADE infection are also required for ADE infection mediated by FcRIIA, and binding of virus-Ab complexes with FcRIIA alone is not sufficient for ADE of infection. The FcRIIA mainly plays an auxiliary role in concentrating the virus-Ab complex to the cell surface, and other primary cellular receptors are required for virus entry. Understanding the viral entry pathway in ADE of DENV infection will greatly facilitate rational designs of anti-viral therapeutics against severe dengue disease associated with ADE. |
Humanized monoclonal antibody 2C9-cIgG has enhanced efficacy for yellow fever prophylaxis and therapy in an immunocompetent animal model
Julander JG , Thibodeaux BA , Morrey JD , Roehrig JT , Blair CD . Antiviral Res 2014 103c 32-38 Yellow fever virus (YFV) causes significant human disease and mortality in tropical regions of South and Central America and Africa, despite the availability of an effective vaccine. No specific therapy for YF is available. We previously showed that the humanized monoclonal antibody (MAb) 2C9-cIgG provided prophylactic and therapeutic protection from mortality in interferon receptor-deficient strain AG129 mice challenged with YF 17D-204 vaccine. In this study we tested the prophylactic and therapeutic efficacy of this MAb against virulent YFV infection in an immunocompetent hamster model. Intraperitoneal (ip) administration of a single dose of MAb 2C9-cIgG 24h prior to YFV challenge resulted in significantly improved survival rates in animals treated with 380 or 38mug of MAb compared to untreated animals. Treatment with the higher dose also resulted in significantly improved weight gain and reductions in serum alanine aminotransferase (ALT) and virus titers in serum and liver. Prophylactic treatment with 2C9-cIgG 24h prior to virus challenge prevented the development of a virus-neutralizing antibody (vnAb) response in hamsters. Administration of a single ip dose of 380mug of 2C9-cIgG as late as 72h post-YFV challenge also resulted in significant improvement in survival rates. Hamsters treated at 4-72h post-virus challenge developed a robust vnAb response. Enhanced survival and improvement of various disease parameters in the hamster model when MAb 2C9-cIgG is administered up to 3days after virus challenge demonstrate the clinical potential of specific antibody therapy for YF. |
Development of a small animal peripheral challenge model of Japanese encephalitis virus using interferon deficient AG129 mice and the SA14-14-2 vaccine virus strain
Calvert AE , Dixon KL , Delorey MJ , Blair CD , Roehrig JT . Vaccine 2013 32 (2) 258-64 Japanese encephalitis virus (JEV) is the most common cause of viral encephalitis in Asia, and it is increasingly a global public health concern due to its recent geographic expansion. While commercial vaccines are available and used in some endemic countries, JEV continues to be a public health problem, with 50,000 cases reported annually. Research with virulent JEV in mouse models to develop new methods of prevention and treatment is restricted to BSL-3 containment facilities, confining these studies to investigators with access to these facilities. We have developed an adult small animal peripheral challenge model using interferon-deficient AG129 mice and the JEV live-attenuated vaccine SA14-14-2, thus requiring only BSL-2 containment. A low dose of virus (10PFU/0.1ml) induced 100% morbidity in infected mice. Increased body temperatures measured by implantable temperature transponders correlated with an increase in infectious virus and viral RNA in serum, spleen and brain as well as an increase in pro-inflammatory markers measured by a 58-biomarker multi-analyte profile (MAP) constructed during the course of infection. In the future, the MAP measurements can be used as a baseline for comparison in order to better assess the inhibition of disease progression by other prophylactic and therapeutic agents. The use of the AG129/JEV SA14-14-2 animal model makes vaccine and therapeutic studies feasible for laboratories with limited biocontainment facilities. |
Mutation of the dengue virus type 2 envelope protein heparan sulfate binding sites or the domain III lateral ridge blocks replication in Vero cells prior to membrane fusion.
Roehrig JT , Butrapet S , Liss NM , Bennett SL , Luy BE , Childers T , Boroughs KL , Stovall JL , Calvert AE , Blair CD , Huang CY . Virology 2013 441 (2) 114-25 Using an infectious cDNA clone we engineered seven mutations in the putative heparan sulfate- and receptor-binding motifs of the envelope protein of dengue virus serotype 2, strain 16681. Four mutant viruses, KK122/123EE, E202K, G304K, and KKK305/307/310EEE, were recovered following transfection of C6/36 cells. A fifth mutant, KK291/295EE, was recovered from C6/36 cells with a compensatory E295V mutation. All mutants grew in and mediated fusion of virus-infected C6/36 cells, but three of the mutants, KK122/123EE, E202K, G304K, did not grow in Vero cells without further modification. Two Vero cell lethal mutants, KK291/295EV and KKK307/307/310EEE, failed to replicate in DC-SIGN-transformed Raji cells and did not react with monoclonal antibodies known to block DENV attachment to Vero cells. Additionally, both mutants were unable to initiate negative-strand vRNA synthesis in Vero cells by 72h post-infection, suggesting that the replication block occurred prior to virus-mediated membrane fusion. |
Immunization with Culex tarsalis mosquito salivary gland extract modulates West Nile virus infection and disease in mice
Machain-Williams C , Reagan K , Wang T , Zeidner NS , Blair CD . Viral Immunol 2013 26 (1) 84-92 Mosquito salivary proteins inoculated during blood feeding modulate the host immune response, which can contribute to the pathogenesis of viruses transmitted by mosquito bites. Previous studies with mosquito bite-naive mice indicated that exposure to arthropod salivary proteins resulted in a shift toward a Th2-type immune response in flavivirus-susceptible mice but not flavivirus-resistant animals. In the study presented here, we tested the hypothesis that immunization with high doses of Culex tarsalis salivary gland extracts (SGE) with an adjuvant would prevent Th2 polarization after mosquito bite and enhance resistance to mosquito-transmitted West Nile virus (WNV). Our results indicate that mice immunized with Cx. tarsalis SGE produced increased levels of Th1-type cytokines (IFNgamma and TNFalpha) after challenge with mosquito-transmitted WNV and exhibited both a delay in infection of the central nervous system (CNS) and significantly lower WNV brain titers compared to mock-immunized mice. Moreover, mortality was significantly reduced in the SGE-immunized mice, as none of these mice died, compared to mortality of 37.5% of mock-vaccinated mice by 8 days after infected mosquito bite. These results suggest that development of a mosquito salivary protein vaccine might be a strategy to control arthropod-borne viral pathogens such as WNV. |
Mutations in the West Nile prM protein affect VLP and virion secretion in vitro.
Calvert AE , Huang CY , Blair CD , Roehrig JT . Virology 2012 433 (1) 35-44 Mutation of the West Nile virus-like particle (WN VLP) prM protein (T20D, K31A, K31V, or K31T) results in undetectable VLP secretion from transformed COS-1 cells. K31 mutants formed intracellular prM-E heterodimers; however these proteins remained in the ER and ER-Golgi intermediary compartments of transfected cells. The T20D mutation affected glycosylation, heterodimer formation, and WN VLP secretion. When infectious viruses bearing the same mutations were used to infect COS-1 cells, K31 mutant viruses exhibited delayed growth and reduced infectivity compared to WT virus. Epitope maps of WN VLP and WNV prM were also different. These results suggest that while mutations in the prM protein can reduce or eliminate secretion of WN VLPs, they have less effect on virus. This difference may be due to the quantity of prM in WN VLPs compared to WNV or to differences in maturation, structure, and symmetry of these particles. |
A humanized IgG but not IgM antibody is effective in prophylaxis and therapy of yellow fever infection in an AG129/17D-204 peripheral challenge mouse model
Thibodeaux BA , Garbino NC , Liss NM , Piper J , Schlesinger JJ , Blair CD , Roehrig JT . Antiviral Res 2012 94 (1) 1-8 Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne virus found in tropical regions of Africa and South America that causes severe hepatic disease and death in humans. Despite the availability of effective vaccines, YFV is responsible for an estimated 200,000 cases and 30,000 deaths annually. There are currently no prophylactic or therapeutic strategies approved for use in human YFV infections. Furthermore, implementation of YFV 17D-204 vaccination campaigns has become problematic due to an increase in reported post-vaccinal adverse events. We have created human/murine chimeric MAbs of a YFV-reactive murine monoclonal antibody (mMAb), 2C9, that was previously shown to protect mice from lethal YFV infection and to have therapeutic activity. The new chimeric (cMAbs) were constructed by fusion of the m2C9 IgG gene variable regions with the constant regions of human IgG and IgM and expressed in Sp2 murine myelomas. The 2C9 cMAbs (2C9-cIgG and 2C9-cIgM) reacted with 17D-204 vaccine strain in an enzyme-linked immunosorbent assay and neutralized virus in vitro similarly to the parent m2C9. Both m2C9 and 2C9-cIgG when administered prophylactically 24h prior to infection protected AG129 mice from peripheral 17D-204 challenge at antibody concentrations 1.27mcg/mouse; however, the 2C9-cIgM did not protect even at a dose of 127mcg/mouse. The 17D-204 infection of AG129 mice is otherwise uniformly lethal. While the m2C9 was shown previously to be therapeutically effective in YFV-infected BALB/c mice at day 4 post-infection, the m2C9 and 2C9-cIgG demonstrated therapeutic activity only when administered 1 day post-infection in 17D-204-infected AG129 mice. |
A small animal peripheral challenge model of yellow fever using interferon-receptor deficient mice and the 17D-204 vaccine strain
Thibodeaux BA , Garbino NC , Liss NM , Piper J , Blair CD , Roehrig JT . Vaccine 2012 30 (21) 3180-7 Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne pathogen that requires wild-type (wt), virulent strains to be handled at biosafety level (BSL) 3, with HEPA-filtration of room air exhaust (BSL3+). YFV is found in tropical regions of Africa and South America and causes severe hepatic disease and death in humans. Despite the availability of effective vaccines (17D-204 or 17DD), YFV is still responsible for an estimated 200,000 cases of illness and 30,000 deaths annually. Besides vaccination, there are no other prophylactic or therapeutic strategies approved for use in human YF. Current small animal models of YF require either intra-cranial inoculation of YF vaccine to establish infection, or use of wt strains (e.g., Asibi) in order to achieve pathology. We have developed and characterized a BSL2, adult mouse peripheral challenge model for YFV infection in mice lacking receptors for interferons alpha, beta, and gamma (strain AG129). Intraperitoneal challenge of AG129 mice with 17D-204 is a uniformly lethal in a dose-dependent manner, and 17D-204-infected AG129 mice exhibit high viral titers in both brain and liver suggesting this infection is both neurotropic and viscerotropic. Furthermore the use of a mouse model permitted the construction of a 59-biomarker multi-analyte profile (MAP) using samples of brain, liver, and serum taken at multiple time points over the course of infection. This MAP serves as a baseline for evaluating novel therapeutics and their effect on disease progression. Changes (4-fold or greater) in serum and tissue levels of pro- and anti-inflammatory mediators as well as other factors associated with tissue damage were noted in AG129 mice infected with 17D-204 as compared to mock-infected control animals. |
Transmission dynamics of an insect-specific flavivirus in a naturally infected Culex pipiens laboratory colony and effects of co-infection on vector competence for West Nile virus
Bolling BG , Olea-Popelka FJ , Eisen L , Moore CG , Blair CD . Virology 2012 427 (2) 90-7 We established a laboratory colony of Culex pipiens mosquitoes from eggs collected in Colorado and discovered that mosquitoes in the colony are naturally infected with Culex flavivirus (CxFV), an insect-specific flavivirus. In this study we examined transmission dynamics of CxFV and effects of persistent CxFV infection on vector competence for West Nile virus (WNV). We found that vertical transmission is the primary mechanism for persistence of CxFV in Cx. pipiens, with venereal transmission potentially playing a minor role. Vector competence experiments indicated possible early suppression of WNV replication by persistent CxFV infection in Cx. pipiens. This is the first description of insect-specific flavivirus transmission dynamics in a naturally infected mosquito colony and the observation of delayed dissemination of superinfecting WNV suggests that the presence of CxFV may impact the intensity of enzootic transmission of WNV and the risk of human exposure to this important pathogen. |
Association of human immune response to Aedes aegypti salivary proteins with dengue disease severity
Machain-Williams C , Mammen MP Jr , Zeidner NS , Beaty BJ , Prenni JE , Nisalak A , Blair CD . Parasite Immunol 2011 34 (1) 15-22 Dengue viruses (DENV; family Flaviviridae, genus Flavivirus) are transmitted by Aedes aegypti mosquitoes and can cause dengue fever (DF), a relatively benign disease, or more severe dengue haemorrhagic fever (DHF). Arthropod saliva contains proteins delivered into the bite wound that can modulate the host haemostatic and immune responses to facilitate the intake of a blood meal. The potential effects on DENV infection of previous exposure to Ae. aegypti salivary proteins has not been investigated. We collected Ae. aegypti saliva, concentrated the proteins, and fractionated them by non-denaturing polyacrylamide gel electrophoresis (PAGE). By use of immunoblots we analysed reactivity with the mosquito salivary proteins (MSP) of sera from 96 Thai children diagnosed with secondary DENV infections leading either to DF or DHF, or with no DENV infection, and found that different proportions of each patient group had serum antibodies reactive to specific Ae. aegypti salivary proteins. Our results suggest that prior exposure to MSP might play a role in the outcome of DENV infection in humans. |
Distribution and phylogenetic comparisons of a novel mosquito flavivirus sequence present in Culex tarsalis mosquitoes from western Canada with viruses isolated in California and Colorado
Tyler S , Bolling BG , Blair CD , Brault AC , Pabbaraju K , Armijos MV , Clark DC , Calisher CH , Drebot MA . Am J Trop Med Hyg 2011 85 (1) 162-8 In a previous study, a new flavivirus genome sequence was identified in Culex tarsalis mosquitoes obtained in Alberta, Canada and was shown to be genetically related to but distinct from members of the insect-specific flaviviruses. Nonstructural protein 5-encoding sequences amplified from Cx. tarsalis pools from western Canada have shown a high similarity to genome sequences of novel flaviviruses isolated from mosquitoes in California and Colorado. Despite wide distribution of this virus, designated Calbertado virus, strains demonstrate a high degree of nonstructural protein 5 nucleotide (> 90%) and amino acid (> 97%) identity. The ecology and geographic range of Calbertado virus warrants further study because it may potentially influence transmission of mosquito-borne flaviviruses, including important human pathogens such as West Nile and Saint Louis encephalitis viruses. |
Insect-specific flaviviruses from culex mosquitoes in Colorado, with evidence of vertical transmission
Bolling BG , Eisen L , Moore CG , Blair CD . Am J Trop Med Hyg 2011 85 (1) 169-77 Mosquitoes were collected in Colorado during 2006 and 2007 to examine spatial and seasonal patterns of risk for exposure to Culex vectors and West Nile virus. We used universal flavivirus primers to test pools of Culex mosquitoes for viral RNA. This led to the detection and subsequent isolation of two insect-specific flaviviruses: Culex flavivirus (CxFV), which was first described from Japan, and a novel insect flavivirus, designated Calbertado virus (CLBOV), which has also been detected in California and Canada. We recorded both viruses in Cx. tarsalis and Cx. pipiens from Colorado. Furthermore, quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed the presence of CxFV RNA in Cx. pipiens eggs and larvae from a laboratory colony established in 2005 and naturally infected with CxFV, suggesting vertical transmission as a means of viral maintenance in natural Culex populations. Finally, we present phylogenetic analyses of the relationships between insect-specific flaviviruses and other selected flaviviruses. |
Treatment of mice with human monoclonal antibody 24h after lethal aerosol challenge with virulent Venezuelan equine encephalitis virus prevents disease but not infection
Hunt AR , Bowen RA , Frederickson S , Maruyama T , Roehrig JT , Blair CD . Virology 2011 414 (2) 146-52 We recently described a Venezuelan equine encephalitis virus (VEEV)-specific human monoclonal antibody (MAb), F5 nIgG, that recognizes a new neutralization epitope on the VEEV E2 envelope glycoprotein. In this study, we investigated the ability of F5 nIgG given prophylactically or therapeutically to protect mice from subcutaneous or aerosolized VEEV infection. F5 nIgG had potent ability to protect mice from infection by either route when administered 24h before exposure; however, mice treated 24h after aerosol exposure developed central nervous system infections but exhibited no clinical signs of disease. Infectious virus, viral antigen and RNA were detected in brains of both treated and untreated mice 2-6days after aerosol exposure but were cleared from the brains of treated animals by 14-28days after infection. This fully human MAb could be useful for prophylaxis or immediate therapy for individuals exposed to VEEV accidentally in the laboratory or during a deliberate release. |
Amino acid changes within the E protein hinge region that affect dengue virus type 2 infectivity and fusion
Butrapet S , Childers T , Moss KJ , Erb SM , Luy BE , Calvert AE , Blair CD , Roehrig JT , Huang CY . Virology 2011 413 (1) 118-27 Fifteen mutant dengue viruses were engineered and used to identify AAs in the molecular hinge of the envelope protein that are critical to viral infection. Substitutions at Q52, A54, or E133 reduced infectivity in mammalian cells and altered the pH threshold of fusion. Mutations at F193, G266, I270, or G281 affected viral replication in mammalian and mosquito cells, but only I270W had reduced fusion activity. T280Y affected the pH threshold for fusion and reduced replication in C6/36 cells. Three different mutations at L135 were lethal in mammalian cells. Among them, L135G abrogated fusion and reduced replication in C6/36 cells, but only slightly reduced the mosquito infection rate. Conversely, L135W replicated well in C6/36 cells, but had the lowest mosquito infection rate. Possible interactions between hinge residues 52 and 277, or among 53, 135, 170, 186, 265, and 276 required for hinge function were discovered by sequence analysis to identify compensatory mutations. |
Human monoclonal antibodies to West Nile virus identify epitopes on the prM protein.
Calvert AE , Kalantarov GF , Chang GJ , Trakht I , Blair CD , Roehrig JT . Virology 2011 410 (1) 30-7 Hybridoma cell lines (2E8, 8G8 and 5G12) producing fully human monoclonal antibodies (hMAbs) specific for the pre-membrane (prM) protein of West Nile virus (WNV) were prepared using a human fusion partner cell line, MFP-2, and human peripheral blood lymphocytes from a blood donor diagnosed with WNV fever in 2004. Using site-directed mutagenesis of a WNV-like particle (VLP) we identified 4 amino acid residues in the prM protein unique to WNV and important in the binding of these hMAbs to the VLP. Residues V19 and L33 are important epitopes for the binding of all three hMAbs. Mutations at residue, T20 and T24 affected the binding of hMAbs, 8G8 and 5G12 only. These hMAbs did not significantly protect AG129 interferon-deficient mice or Swiss Webster outbred mice from WNV infection. |
Domain-III FG loop of the dengue virus type 2 envelope protein is important for infection of mammalian cells and Aedes aegypti mosquitoes
Erb SM , Butrapet S , Moss KJ , Luy BE , Childers T , Calvert AE , Silengo SJ , Roehrig JT , Huang CY , Blair CD . Virology 2010 406 (2) 328-35 The FG extended loop in domain III of the dengue virus type 2 (DENV2) envelope protein is postulated to be a molecular determinant for host cell infectivity. To determine the contribution of the FG loop to virus infectivity, an infectious cDNA clone of DENV2 was manipulated by deleting amino acids in the loop (VEPGDelta) to mimic tick-borne flaviviruses or by substituting these AAs with RGD or RGDK/S to mimic motifs present in other mosquito-borne flaviviruses. We found the FG loop to be dispensable for infection of C6/36 cells but critical for infection of Aedes aegypti mosquito midguts and mammalian cells. All the FG loop mutants were able to bind to and enter mammalian cells but replication of VEPGDelta in Vero cells at 37 degrees C was delayed until acquisition of secondary mutations. Reduced binding of DENV2 type-specific monoclonal antibody 3H5 to mutant viruses confirmed the FG loop motif as its target epitope. |
La Crosse virus in Aedes albopictus mosquitoes, Texas, USA, 2009
Lambert AJ , Blair CD , D'Anton M , Ewing W , Harborth M , Seiferth R , Xiang J , Lanciotti RS . Emerg Infect Dis 2010 16 (5) 856-8 We report the arthropod-borne pediatric encephalitic agent La Crosse virus in Aedes albopictus mosquitoes collected in Dallas County, Texas, USA, in August 2009. The presence of this virus in an invasive vector species within a region that lies outside the virus's historically recognized geographic range is of public health concern. |
Toll-like receptor 7-induced immune response to cutaneous West Nile virus infection
Welte T , Reagan K , Fang H , Machain-Williams C , Zheng X , Mendell N , Chang GJ , Wu P , Blair CD , Wang T . J Gen Virol 2009 90 2660-8 The Toll-like receptor (TLR) 7 response represents a vital host-defence mechanism in a murine model of systemic West Nile virus (WNV) infection. Here, we investigated the role of the TLR7-induced immune response following cutaneous WNV infection. We found that there was no difference in susceptibility to WNV encephalitis between wild-type and TLR7(-/-) mice upon intradermal injection or infected mosquito feeding. Viral load analysis revealed similar levels of WNV RNA in the peripheral tissues and brains of these two groups of mice following intradermal infection. There was a higher level of cytokines in the blood of wild-type mice at early stages of infection; however, this difference was diminished in the blood and brains at later stages. Langerhans cells (LCs) are permissive to WNV infection and migrate from the skin to draining lymph nodes upon intradermal challenge. Our data showed that WNV infection of TLR7(-/-) keratinocytes was significantly higher than that of wild-type keratinocytes. Infection of wild-type keratinocytes induced higher levels of alpha interferon and interleukin-1beta (IL-1beta), IL-6 and IL-12, which might promote LC migration from the skin. Co-culture of naive LCs of wild-type mice with WNV-infected wild-type keratinocytes resulted in the production of more IL-6 and IL-12 than with TLR7(-/-) keratinocytes or by cultured LCs alone. Moreover, LCs in the epidermis were reduced in wild-type mice, but not in TLR7(-/-) mice, following intradermal WNV infection. Overall, our results suggest that the TLR7 response following cutaneous infection promotes LC migration from the skin, which might compromise its protective effect in systemic infection. |
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