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5. Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency

Author

Ouwendijk, W.J.D. (Werner), Depledge, D.P. (Daniel P.), Rajbhandari, L. (Labchan), Lenac Rovis, T. (Tihana), Jonjic, S. (Stipan), Breuer, J. (Judith), Venkatesan, A. (Arun), Verjans, G.M.G.M. (George), Sadaoka, T. (Tomohiko), Ouwendijk, W.J.D. (Werner), Depledge, D.P. (Daniel P.), Rajbhandari, L. (Labchan), Lenac Rovis, T. (Tihana), Jonjic, S. (Stipan), Breuer, J. (Judith), Venkatesan, A. (Arun), Verjans, G.M.G.M. (George), and Sadaoka, T. (Tomohiko)

Abstract

Varicella-zoster virus (VZV) establishes lifelong neuronal latency in most humans world-wide, reactivating in one-third to cause herpes zoster and occasionally chronic pain. How VZV establishes, maintains and reactivates from latency is largely unknown. VZV transcription during latency is restricted to the latency-associated transcript (VLT) and RNA 63 (encoding ORF63) in naturally VZV-infected human trigeminal ganglia (TG). While significantly more abundant, VLT levels positively correlated with RNA 63 suggesting co-regulated transcription during latency. Here, we identify VLT-ORF63 fusion transcripts and confirm VLT-ORF63, but not RNA 63, expression in human TG neurons. During in vitro latency, VLT is transcribed, whereas VLT-ORF63 expression is induced by reactivation stimuli. One isoform of VLT-ORF63, encoding a fusion protein combining VLT and ORF63 proteins, induces broad viral gene transcription. Collectively, our findings show that VZV expresses a unique set of VLT-ORF63 transcripts, potentially involved in the transition from latency to lytic VZV infection.

Published
2020
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6. Repair of an attenuated low-passage murine cytomegalovirus bacterial artificial chromosome identifies a novel spliced gene essential for salivary gland tropism

Author

Redwood, A.J., Masters, L.L., Chan, B., Leary, S., Forbes, C., Jonjic, S., Juranić Lisnić, V., Lisnić, B., Smith, L.M., Jung, J.U., Redwood, A.J., Masters, L.L., Chan, B., Leary, S., Forbes, C., Jonjic, S., Juranić Lisnić, V., Lisnić, B., Smith, L.M., and Jung, J.U.

Abstract

The cloning of herpesviruses as bacterial artificial chromosomes (BACs) has revolutionized the study of herpesvirus biology, allowing rapid and precise manipulation of viral genomes. Several clinical strains of human cytomegalovirus (HCMV) have been cloned as BACs; however, no low-passage strains of murine CMV (MCMV), which provide a model mimicking these isolates, have been cloned. Here, the low-passage G4 strain of was BAC cloned. G4 carries an m157 gene that does not ligate the natural killer (NK) cell-activating receptor, Ly49H, meaning that unlike laboratory strains of MCMV, this virus replicates well in C57BL/6 mice. This BAC clone exhibited normal replication during acute infection in the spleen and liver but was attenuated for salivary gland tropism. Next-generation sequencing revealed a C-to-A mutation at nucleotide position 188422, located in the 3′ untranslated region of sgg1, a spliced gene critical for salivary gland tropism. Repair of this mutation restored tropism for the salivary glands. Transcriptional analysis revealed a novel spliced gene within the sgg1 locus. This small open reading frame (ORF), sgg1.1, starts at the 3′ end of the first exon of sgg1 and extends exon 2 of sgg1. This shorter spliced gene is prematurely terminated by the nonsense mutation at nt 188422. Sequence analysis of tissue culture-passaged virus demonstrated that sgg1.1 was stable, although other mutational hot spots were identified. The G4 BAC will allow in vivo studies in a broader range of mice, avoiding the strong NK cell responses seen in B6 mice with other MCMV BAC-derived MCMVs.

Published
2020

7. Analysis of Virus and Host Proteomes During Productive HSV-1 and VZV Infection in Human Epithelial Cells

Author

Ouwendijk, W.J.D. (Werner), Dekker, L.J.M. (Lennard), Ham, H.J. van den, Lenac Rovis, T. (Tihana), Haefner, E.S. (Erik S.), Jonjic, S. (Stipan), Haas, J. (Jürgen), Luider, T.M. (Theo), Verjans, G.M.G.M. (George), Ouwendijk, W.J.D. (Werner), Dekker, L.J.M. (Lennard), Ham, H.J. van den, Lenac Rovis, T. (Tihana), Haefner, E.S. (Erik S.), Jonjic, S. (Stipan), Haas, J. (Jürgen), Luider, T.M. (Theo), and Verjans, G.M.G.M. (George)

Abstract

Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) are two closely related human alphaherpesviruses that persistently infect most adults worldwide and cause a variety of clinically important diseases. Herpesviruses are extremely well adapted to their hosts and interact broadly with cellular proteins to regulate virus replication and spread. However, it is incompletely understood how HSV-1 and VZV interact with the host proteome during productive infection. This study determined the temporal changes in virus and host protein expression during productive HSV-1 and VZV infection in the same cell type. Results demonstrated the temporally coordinated expression of HSV-1 and VZV proteins in infected cells. Analysis of the host proteomes showed that both viruses affected extracellular matrix composition, transcription, RNA processing and cell division. Moreover, the prominent role of epidermal growth factor receptor (EGFR) signa

Published
2020
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12. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author

Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, Zychlinsky, A, Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, and Zychlinsky, A

Abstract

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Published
2019

13. Molecular Analysis of the Protective Immune Response to Murine Cytomegalovirus

Author

Koszinowski, U. H., Reddehase, M. J., del Val, M., Münch, K., Messerle, M., Volkmer, H., Jonjić, S., Melchers, Fritz, editor, Albert, E. D., editor, von Boehmer, H., editor, Dierich, M. P., editor, Du Pasquier, L., editor, Eichmann, K., editor, Gemsa, D., editor, Götze, O., editor, Kalden, J. R., editor, Kaufmann, S. H. E., editor, Kirchner, H., editor, Resch, K., editor, Riethmüller, G., editor, Schimpl, A., editor, Sorg, C., editor, Steinmetz, M., editor, Wagner, H., editor, and Zachau, H. G., editor

Published
1989
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15. Guidelines for the use of flow cytometry and cell sorting in immunological studies

Author

Cossarizza, A. (Andrea), Chang, H.-D. (Hyun-Dong), Radbruch, A. (Andreas), Andrä, I. (Immanuel), Annunziato, F. (Francesco), Bacher, P. (Petra), Barnaba, V. (Vincenzo), Battistini, L. (Luca), Bauer, W.M. (Wolfgang M.), Baumgart, S. (Sabine), Becher, B. (Burkhard), Beisker, W. (Wolfgang), Berek, C. (Claudia), Blanco, A. (Alfonso), Borsellino, G. (Giovanna), Boulais, P.E. (Philip E.), Brinkman, R.R. (Ryan R.), Büscher, M. (Martin), Busch, D.H. (Dirk), Bushnell, T.P. (Timothy P.), Cao, X. (Xuetao), Cavani, A. (Andrea), Chattopadhyay, P.K. (Pratip K.), Cheng, Q. (Qingyu), Chow, S. (Sue), Clerici, M. (Mario), Cooke, A. (Anne), Cosma, A. (Antonio), Cosmi, L. (Lorenzo), Cumano, A. (Ana), Dang, V.D. (Van Duc), Davies, D. (Derek), De Biasi, S. (Sara), Del Zotto, G. (Genny), Della Bella, S. (Silvia), Dellabona, P. (Paolo), Deniz, G. (Gunnur), Dessing, M. (Mark), Diefenbach, A. (Andreas), Santo, J.P. (James) di, Dieli, F. (Francesco), Dolf, A. (Andreas), Donnenberg, V.S. (Vera S.), Dörner, A. (Andrea), Ehrhardt, G.R.A. (Götz R. A.), Endl, E. (Elmar), Engel, P. (Pablo), Engelhardt, B. (Britta), Esser, C. (Charlotte), Everts, B. (Bart), Falk, C.S. (Christine S.), Fehniger, T.A. (Todd A.), Filby, A. (Andrew), Fillatreau, S. (Simon), Follo, M. (Marie), Förster, I. (Irmgard), Foster, J. (John), Foulds, G.A. (Gemma A.), Frenette, P.S. (Paul S.), Galbraith, D. (David), Garbi, N. (Natalio), García-Godoy, M.D. (Maria Dolores), Ghoreschi, K. (Kamran), Gibellini, L. (Lara), Goettlinger, C. (Christoph), Goodyear, C.S. (Carl), Gori, A. (Andrea), Grogan, J.L. (Jane), Gross, M. (Mor), Grützkau, A. (Andreas), Grummitt, D. (Daryl), Hahn, J. (Jonas), Hammer, Q. (Quirin), Hauser, A.E. (Anja E.), Haviland, D.L. (David L.), Hedley, D. (David), Herrera, G. (Guadalupe), Herrmann, M. (Martin), Hiepe, F. (Falk), Holland, T. (Tristan), Hombrink, P. (Pleun), Houston, J.P. (Jessica P.), Hoyer, B.F. (Bimba F.), Huang, B. (Bo), Hunter, C.A. (Christopher A.), Iannone, A. (Anna), Jäck, H.-M. (Hans-Martin), Jávega, B. (Beatriz), Jonjic, S. (Stipan), Juelke, K. (Kerstin), Jung, S. (Steffen), Kaiser, T. (Toralf), Kalina, T. (Tomas), Keller, B. (Baerbel), Khan, S. (Srijit), Kienhöfer, D. (Deborah), Kroneis, T. (Thomas), Kunkel, D. (Désirée), Kurts, C. (Christian), Kvistborg, P. (Pia), Lannigan, J. (Joanne), Lantz, O. (Olivier), Larbi, A. (Anis), LeibundGut-Landmann, S. (Salome), Leipold, M.D. (Michael D.), Levings, M.K., Litwin, V. (Virginia), Liu, Y. (Yanling), Lohoff, M. (Michael), Lombardi, G. (Giovanna), Lopez, L. (Lilly), Lovett-Racke, A. (Amy), Lubberts, E.W. (Erik), Ludewig, B. (Burkhard), Lugli, E. (Enrico), Maecker, H.T. (Holden T.), Martrus, G. (Glòria), Matarese, G. (Giuseppe), Maueröder, C. (Christian), McGrath, M. (Mairi), McInnes, I.B. (Iain), Mei, H.E. (Henrik E.), Melchers, F. (Fritz), Melzer, S. (Susanne), Mielenz, D. (Dirk), Mills, K. (Kingston), Mjösberg, J.M. (Jenny), Moore, J. (Jonni), Moran, B. (Barry), Moretta, A. (Alessandro), Moretta, L. (Lorenzo), Mosmann, T.R. (Tim R.), Müller, S. (Susann), Müller, W. (Werner), Münz, C. (Christian), Multhoff, G. (Gabriele), Munoz, L.E. (Luis Enrique), Murphy, K.M. (Kenneth M.), Nakayama, T. (Toshinori), Nasi, M. (Milena), Neudörfl, C. (Christine), Nolan, J. (John), Nourshargh, S. (Sussan), O'Connor, J.-E. (José-Enrique), Ouyang, W. (Wenjun), Oxenius, A. (Annette), Palankar, R. (Raghav), Panse, I. (Isabel), Peterson, P. (Pärt), Peth, C. (Christian), Petriz, J. (Jordi), Philips, D. (Daisy), Pickl, W. (Winfried), Piconese, S. (Silvia), Pinti, M. (Marcello), Pockley, A.G. (A. Graham), Podolska, M.J. (Malgorzata Justyna), Pucillo, C. (Carlo), Quataert, S.A. (Sally A.), Radstake, T.R.D.J. (Timothy R. D. J.), Rajwa, B. (Bartek), Rebhahn, J.A. (Jonathan A.), Recktenwald, D. (Diether), Remmerswaal, D. (Daniëlle), Rezvani, K. (Katy), Rico, L.G. (Laura G.), Robinson, J.P. (J. Paul), Romagnani, C. (Chiara), Rubartelli, A. (Anna), Ruland, J. (Jürgen), Sakaguchi, S. (Shimon), Sala-de-Oyanguren, F. (Francisco), Samstag, Y. (Yvonne), Sanderson, S. (Sharon), Sawitzki, B. (Birgit), Scheffold, A. (Alexander), Schiemann, M. (Matthias), Schildberg, F. (Frank), Schimisky, E. (Esther), Schmid, S.A. (Stephan A), Schmitt, S. (Steffen), Schober, K. (Kilian), Schüler, T. (Thomas), Schulz, A.R. (Axel Ronald), Schumacher, T.N. (Ton), Scotta, C. (Cristiano), Shankey, T.V. (T. Vincent), Shemer, A. (Anat), Simon, A.-K. (Anna-Katharina), Spidlen, J. (Josef), Stall, A.M. (Alan M.), Stark, R. (Regina), Stehle, C. (Christina), Stein, M. (Merle), Steinmetz, T. (Tobit), Stockinger, H. (Hannes), Takahama, Y. (Yousuke), Tarnok, A. (Attila), Tian, Z. (ZhiGang), Toldi, G. (Gergely), Tornack, J. (Julia), Traggiai, E. (Elisabetta), Trotter, J. (Joe), Ulrich, H. (Henning), van der Braber, M. (Marlous), Van Lier, R.A.W. (Rene A. W.), Veldhoen, M. (Marcello), Vento-Asturias, S. (Salvador), Vieira, P. (Paulo), Voehringer, D. (David), Volk, H.D. (Hans), von Volkmann, K. (Konrad), Waisman, A. (Ari), Walker, R. (Rachael), Ward, M.D. (Michael D.), Warnatz, K. (Klaus), Warth, S. (Sarah), Watson, J.V. (James V.), Watzl, C. (Carsten), Wegener, L. (Leonie), Wiedemann, A. (Annika), Wienands, J. (Jürgen), Willimsky, G. (Gerald), Wing, J. (James), Wurst, P. (Peter), Yu, L. (Liping), Yue, A. (Alice), Zhang, Q. (Qianjun), Zhao, Y. (Yi), Ziegler, S. (Susanne), Zimmermann, J. (Jakob), Cossarizza, A. (Andrea), Chang, H.-D. (Hyun-Dong), Radbruch, A. (Andreas), Andrä, I. (Immanuel), Annunziato, F. (Francesco), Bacher, P. (Petra), Barnaba, V. (Vincenzo), Battistini, L. (Luca), Bauer, W.M. (Wolfgang M.), Baumgart, S. (Sabine), Becher, B. (Burkhard), Beisker, W. (Wolfgang), Berek, C. (Claudia), Blanco, A. (Alfonso), Borsellino, G. (Giovanna), Boulais, P.E. (Philip E.), Brinkman, R.R. (Ryan R.), Büscher, M. (Martin), Busch, D.H. (Dirk), Bushnell, T.P. (Timothy P.), Cao, X. (Xuetao), Cavani, A. (Andrea), Chattopadhyay, P.K. (Pratip K.), Cheng, Q. (Qingyu), Chow, S. (Sue), Clerici, M. (Mario), Cooke, A. (Anne), Cosma, A. (Antonio), Cosmi, L. (Lorenzo), Cumano, A. (Ana), Dang, V.D. (Van Duc), Davies, D. (Derek), De Biasi, S. (Sara), Del Zotto, G. (Genny), Della Bella, S. (Silvia), Dellabona, P. (Paolo), Deniz, G. (Gunnur), Dessing, M. (Mark), Diefenbach, A. (Andreas), Santo, J.P. (James) di, Dieli, F. (Francesco), Dolf, A. (Andreas), Donnenberg, V.S. (Vera S.), Dörner, A. (Andrea), Ehrhardt, G.R.A. (Götz R. A.), Endl, E. (Elmar), Engel, P. (Pablo), Engelhardt, B. (Britta), Esser, C. (Charlotte), Everts, B. (Bart), Falk, C.S. (Christine S.), Fehniger, T.A. (Todd A.), Filby, A. (Andrew), Fillatreau, S. (Simon), Follo, M. (Marie), Förster, I. (Irmgard), Foster, J. (John), Foulds, G.A. (Gemma A.), Frenette, P.S. (Paul S.), Galbraith, D. (David), Garbi, N. (Natalio), García-Godoy, M.D. (Maria Dolores), Ghoreschi, K. (Kamran), Gibellini, L. (Lara), Goettlinger, C. (Christoph), Goodyear, C.S. (Carl), Gori, A. (Andrea), Grogan, J.L. (Jane), Gross, M. (Mor), Grützkau, A. (Andreas), Grummitt, D. (Daryl), Hahn, J. (Jonas), Hammer, Q. (Quirin), Hauser, A.E. (Anja E.), Haviland, D.L. (David L.), Hedley, D. (David), Herrera, G. (Guadalupe), Herrmann, M. (Martin), Hiepe, F. (Falk), Holland, T. (Tristan), Hombrink, P. (Pleun), Houston, J.P. (Jessica P.), Hoyer, B.F. (Bimba F.), Huang, B. (Bo), Hunter, C.A. (Christopher A.), Iannone, A. (Anna), Jäck, H.-M. (Hans-Martin), Jávega, B. (Beatriz), Jonjic, S. (Stipan), Juelke, K. (Kerstin), Jung, S. (Steffen), Kaiser, T. (Toralf), Kalina, T. (Tomas), Keller, B. (Baerbel), Khan, S. (Srijit), Kienhöfer, D. (Deborah), Kroneis, T. (Thomas), Kunkel, D. (Désirée), Kurts, C. (Christian), Kvistborg, P. (Pia), Lannigan, J. (Joanne), Lantz, O. (Olivier), Larbi, A. (Anis), LeibundGut-Landmann, S. (Salome), Leipold, M.D. (Michael D.), Levings, M.K., Litwin, V. (Virginia), Liu, Y. (Yanling), Lohoff, M. (Michael), Lombardi, G. (Giovanna), Lopez, L. (Lilly), Lovett-Racke, A. (Amy), Lubberts, E.W. (Erik), Ludewig, B. (Burkhard), Lugli, E. (Enrico), Maecker, H.T. (Holden T.), Martrus, G. (Glòria), Matarese, G. (Giuseppe), Maueröder, C. (Christian), McGrath, M. (Mairi), McInnes, I.B. (Iain), Mei, H.E. (Henrik E.), Melchers, F. (Fritz), Melzer, S. (Susanne), Mielenz, D. (Dirk), Mills, K. (Kingston), Mjösberg, J.M. (Jenny), Moore, J. (Jonni), Moran, B. (Barry), Moretta, A. (Alessandro), Moretta, L. (Lorenzo), Mosmann, T.R. (Tim R.), Müller, S. (Susann), Müller, W. (Werner), Münz, C. (Christian), Multhoff, G. (Gabriele), Munoz, L.E. (Luis Enrique), Murphy, K.M. (Kenneth M.), Nakayama, T. (Toshinori), Nasi, M. (Milena), Neudörfl, C. (Christine), Nolan, J. (John), Nourshargh, S. (Sussan), O'Connor, J.-E. (José-Enrique), Ouyang, W. (Wenjun), Oxenius, A. (Annette), Palankar, R. (Raghav), Panse, I. (Isabel), Peterson, P. (Pärt), Peth, C. (Christian), Petriz, J. (Jordi), Philips, D. (Daisy), Pickl, W. (Winfried), Piconese, S. (Silvia), Pinti, M. (Marcello), Pockley, A.G. (A. Graham), Podolska, M.J. (Malgorzata Justyna), Pucillo, C. (Carlo), Quataert, S.A. (Sally A.), Radstake, T.R.D.J. (Timothy R. D. J.), Rajwa, B. (Bartek), Rebhahn, J.A. (Jonathan A.), Recktenwald, D. (Diether), Remmerswaal, D. (Daniëlle), Rezvani, K. (Katy), Rico, L.G. (Laura G.), Robinson, J.P. (J. Paul), Romagnani, C. (Chiara), Rubartelli, A. (Anna), Ruland, J. (Jürgen), Sakaguchi, S. (Shimon), Sala-de-Oyanguren, F. (Francisco), Samstag, Y. (Yvonne), Sanderson, S. (Sharon), Sawitzki, B. (Birgit), Scheffold, A. (Alexander), Schiemann, M. (Matthias), Schildberg, F. (Frank), Schimisky, E. (Esther), Schmid, S.A. (Stephan A), Schmitt, S. (Steffen), Schober, K. (Kilian), Schüler, T. (Thomas), Schulz, A.R. (Axel Ronald), Schumacher, T.N. (Ton), Scotta, C. (Cristiano), Shankey, T.V. (T. Vincent), Shemer, A. (Anat), Simon, A.-K. (Anna-Katharina), Spidlen, J. (Josef), Stall, A.M. (Alan M.), Stark, R. (Regina), Stehle, C. (Christina), Stein, M. (Merle), Steinmetz, T. (Tobit), Stockinger, H. (Hannes), Takahama, Y. (Yousuke), Tarnok, A. (Attila), Tian, Z. (ZhiGang), Toldi, G. (Gergely), Tornack, J. (Julia), Traggiai, E. (Elisabetta), Trotter, J. (Joe), Ulrich, H. (Henning), van der Braber, M. (Marlous), Van Lier, R.A.W. (Rene A. W.), Veldhoen, M. (Marcello), Vento-Asturias, S. (Salvador), Vieira, P. (Paulo), Voehringer, D. (David), Volk, H.D. (Hans), von Volkmann, K. (Konrad), Waisman, A. (Ari), Walker, R. (Rachael), Ward, M.D. (Michael D.), Warnatz, K. (Klaus), Warth, S. (Sarah), Watson, J.V. (James V.), Watzl, C. (Carsten), Wegener, L. (Leonie), Wiedemann, A. (Annika), Wienands, J. (Jürgen), Willimsky, G. (Gerald), Wing, J. (James), Wurst, P. (Peter), Yu, L. (Liping), Yue, A. (Alice), Zhang, Q. (Qianjun), Zhao, Y. (Yi), Ziegler, S. (Susanne), and Zimmermann, J. (Jakob)

Published
2017
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16. Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration

Author

Gonzalez-Motos, V, Jurgens, C, Ritter, B, Kropp, KA, Duran, V, Larsen, O, Binz, A, Ouwendijk, Werner, Rovis, TL, Jonjic, S, Verjans, Georges, Sodeik, B, Krey, T, Bauerfeind, R, Schulz, TF, Kaufer, BB, Kalinke, U, Proudfoot, AEI, Rosenkilde, MM, Viejo-Borbolla, A, Gonzalez-Motos, V, Jurgens, C, Ritter, B, Kropp, KA, Duran, V, Larsen, O, Binz, A, Ouwendijk, Werner, Rovis, TL, Jonjic, S, Verjans, Georges, Sodeik, B, Krey, T, Bauerfeind, R, Schulz, TF, Kaufer, BB, Kalinke, U, Proudfoot, AEI, Rosenkilde, MM, and Viejo-Borbolla, A

Published
2017

28. CMV regulation of mouse PVR

Author

Lenac Rovis T, Stanietsky N, Jordan S, Juranic Lisnic V, Tomic A, Babic M, Krmpotic A, Tsukerman P, Mandelboim O, and Jonjic S

Published
2013

33. Female Sex Hormones Modulate the Course of MCMV Infection

Author

Tomac, J., Vilajtovic, J., Jurica Arapovic, Cekinovic, D., Pugel, Pernjak E., Jonjic, S., and Reinhold E. Schmidt

Subjects
sex hormone, MCMV modulation
Abstract

Objective: Sex steroid hormones influence the components of both innate and adaptive immunity, resulting in differences of immune responses between genders. Moreover, hormonal changes associated with pregnancy modify the severity of some infections and diseases. Progesteron has been proved as an inhibitor of antiviral immunity in both human and animal studies. Cytomegalovirus (CMV), a hepesvirus, is a ubiquitous pathogen and can be isolated from all body fluids of patients undergoing primary infection. CMV infection in gonads is predominantly described in immunocompromised patients and its role in gonadal insufficiency is still not completely elucidated. The aim of this study was to test whether sex hormones change the course and immunosurveillance of murine CMV (MCMV) infection in BALB/c mice. Methods: Female mice were treated with PMSG and hCG to trigger ovulation and luteinization. Virgin animals as well as pregnant ones were intravenously infected with MCMV and sacrificed daily from 1st to 10th day post infection. Viral titers in various organs were analyzed using a standard plaque forming assay. Virus spread was examined using immunohistochemistry. Progesterone levels in plasma were measured using Progesterone EIA kit. Results: MCMV successfully infected ovarian tissue in immunocompetent mice. Numerous infected cells were detected predominantly in corpora lutea, while follicles were free from infection. Our results showed higher susceptibility of pregnant mice to MCMV infection in various organs examined, while ovaries of pregnant mice showed delay in clearance of productive infection as compared to non-pregnant animals. The infection induced a strong innate immune response in corpora lutea which was predominantly comprised of infiltrating macrophages, while CD4+ and CD8+ T cells seemed to play a minor role. Increased plasma progesterone levels were observed in infected mice as compared to controls. Conclusions: Our study provides a new insight into the pathogenesis of MCMV infection in female reproductive tissue as well as its dependence on sex steroid environment. An elevated progesterone level underpins virus replication. These findings could bring evidence for the role of CMV infection in the pathogenesis of gonadal dysfunction.

Published
2009

35. Cmv4, a New Locus Linked to the NK Cell Gene Complex, Controls Innate Resistance to Cytomegalovirus in Wild-Derived Mice

Author

Adam, Sg, Caraux, A., Fodil-Cornu, N., Loredo-Osti, Jc, Lesjean-Pottier, S., Jaubert, J., Bubic, I., Jonjic, S., Guenet, Jl, Vidal, Sm, and Francesco Colucci

Subjects
Cmv4, cytomegalovirus
Abstract

CMV can cause life-threatening disease in immunodeficient hosts. Experimental infection in mice has revealed that the genetically determined natural resistance to murine CMV (MCMV) may be mediated either by direct recognition between the NK receptor Ly49H and the pathogen-encoded glycoprotein m157 or by epistatic interaction between Ly49P and the host MHC H-2Dk. Using stocks of wild-derived inbred mice as a source of genetic diversity, we found that PWK/Pas (PWK) mice were naturally resistant to MCMV. Depletion of NK cells subverted the resistance. Analysis of backcrosses to susceptible BALB/c mice revealed that the phenotype was controlled by a major dominant locus effect linked to the NK gene complex. Haplotype analysis of 41 polymorphic markers in the Ly49h region suggested that PWK mice may share a common ancestral origin with C57BL/6 mice ; in the latter, MCMV resistance is dependent on Ly49H-m157 interactions. Nevertheless, PWK mice retained viral resistance against m157- defective mutant MCMV. These results demonstrate the presence of yet another NK cell-dependent viral resistance mechanism, named Cmv4, which most likely encodes for a new NK activating receptor. Identification of Cmv4 will expand our understanding of the specificity of the innate recognition of infection by NK cells.

Published
2006

36. Comprehensive analysis of varicella-zoster virus proteins using a new monoclonal antibody collection

Author

Roviš, T.L. (Tihana Lenac), Bailer, S.M. (Susanne), Pothineni, V.R. (Venkata R), Ouwendijk, W.J.D. (Werner), Šimić, H. (Hrvoje), Babić, M. (Marina), Miklić, K. (Karmela), Malić, S. (Suzana), Verweij, M.C., Baiker, M. (Martin), Gonzalez, O. (Orland), Brunn, A. (Albrecht von), Zimmer, R., Früh, K. (Klaus), Verjans, G.M.G.M. (George), Jonjic, S. (Stipan), Haasb, J. (Jürgeni), Roviš, T.L. (Tihana Lenac), Bailer, S.M. (Susanne), Pothineni, V.R. (Venkata R), Ouwendijk, W.J.D. (Werner), Šimić, H. (Hrvoje), Babić, M. (Marina), Miklić, K. (Karmela), Malić, S. (Suzana), Verweij, M.C., Baiker, M. (Martin), Gonzalez, O. (Orland), Brunn, A. (Albrecht von), Zimmer, R., Früh, K. (Klaus), Verjans, G.M.G.M. (George), Jonjic, S. (Stipan), and Haasb, J. (Jürgeni)

Abstract

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles. Due to the virus's restricted host and cell typetropism and the lack of tools for VZV proteomics, it is one of the least-characterized human herpesviruses. We generated 251monoclonal antibodies (MAbs) against 59 of the 71 (83%) currently known unique VZV proteins to characterize VZV proteinexpression in vitro and in situ. Using this new set of MAbs, 44 viral proteins were detected by Western blotting (WB) and indirectimmunofluorescence (IF); 13 were detected by WB only, and 2 were detected by IF only. A large proportion of viral proteinswas analyzed for the first time in the context of virus infection. Our study revealed the subcellular localization of 46 proteins, 14of which were analyzed in detail by confocal microscopy. Seven viral proteins were analyzed in time course experiments andshowed a cascade-like temporal gene expression pattern similar to those of other herpesviruses. Furthermore, selected MAbstested positive on human skin lesions by using immunohistochemistry, demonstrating the wide applicability of the MAb collection.Finally, a significant portion of the VZV-specific antibodies reacted with orthologs of simian varicella virus (SVV), thusenabling the systematic analysis of varicella in a nonhuman primate model system. In summary, this study provides insight intothe potential function of numerous VZV proteins and novel tools to systematically study VZV and SVV pathogenesis.

Published
2013
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37. IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence

Author

Mandaric, S, Walton, SM, Rulicke, T, Richter, K, Girard Madoux, Mathilde, Clausen, Björn, Zurunic, A, Kamanaka, M, Flavell, RA, Jonjic, S, Oxenius, A, Mandaric, S, Walton, SM, Rulicke, T, Richter, K, Girard Madoux, Mathilde, Clausen, Björn, Zurunic, A, Kamanaka, M, Flavell, RA, Jonjic, S, and Oxenius, A

Abstract

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the proinflammatory cytokines IL-12, IFN-gamma and TNF-alpha as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10(-/-) mice led to faster control of lytic viral replication, but this came at the expense of TNF-alpha mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.

Published
2012

44. Restoration of cytomegalovirus antigen presentation by gamma interferon combats viral escape

Author

Hengel, H, Lucin, P, Jonjic, S, Ruppert, T, and Koszinowski, U H

Abstract

An immediate-early protein of murine cytomegalovirus (MCMV), pp89, elicits an immunodominant and protective major histocompatibility complex (MHC) class I Ld-restricted CD8+ T-lymphocyte response. Remarkably, presentation of the naturally processed peptide of pp89, the nonapeptide YPHFMPTNL, is abolished during permissive MCMV infection in vitro. This defect in pp89 presentation is due to the expression of MCMV early gene functions that specifically block the transport of peptide-charged MHC class I complexes to the cell surface (M. Del Val, H. Hengel, H. Häcker, U. Hartlaub, T. Ruppert, P. Lucin, and U. H. Koszinowski, J. Exp. Med. 176:729-738, 1992). Here, we demonstrate that MCMV-specific CD8+ T lymphocytes can reconstitute pp89 presentation in a parakrine fashion. The lymphocytes mediate the restoration of antigen presentation by MCMV-infected cells by releasing gamma interferon (IFN-gamma). IFN-gamma has no effect on synthesis and stability of the viral antigen pp89 nor does it interfere with the expression of viral early genes and their inhibitory effect on MHC class I molecular maturation. IFN-gamma results in a 25-fold increase in the synthesis of MHC class I molecules and a similar increase in the abundance of pp89-derived peptide. Many of the MHC molecules remain retained by the viral effect, but a surplus of MHC molecules escapes the effect and provides the effective surface presentation of the peptide. Adoptive cell transfer studies demonstrate the IFN-gamma dependence of CD8+ T-lymphocyte function in vivo. Altogether, these data reconcile the paradoxical findings of an impaired pp89 presentation in vitro in parallel with pp89-specific CD8+ T-cell protection in vivo. The results also imply a role of IFN-gamma in the T-lymphocyte-mediated control of cytomegalovirus infection. The known propensity of cytomegalovirus to cause serious disease in the immunocompromised host is discussed in the light of these findings.

Published
1994
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45. Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes

Author

Jonjic, S, Pavic, I, Lucin, P, Rukavina, D, and Koszinowski, U H

Abstract

Although the relative contribution of different immune effector functions to clearing tissues of cytomegalovirus is controversial, the contribution of CD8+ T lymphocytes has generally been accepted as essential. In this report, we show that under certain conditions the CD8+ T-lymphocyte subset can be dispensable for clearance of cytomegalovirus. Mice depleted of the CD8+ T-lymphocyte subset eliminated infectious virus with a clearance kinetics similar to that of normal mice. Adoptive transfer studies revealed that the limitation of virus spread required the cooperation between the CD4+ subset and other cells. Comparison between protective functions generated in fully immunocompetent and in CD8- mice demonstrated that elimination of the CD8+ subset before infection altered the quality of the antiviral immune response. The compensatory protective activity gained by CD4+ cells in CD8- mice was absent in normal mice recovering from virus infection.

Published
1990
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46. Adoptive immunotherapy of murine cytomegalovirus adrenalitis in the immunocompromised host: CD4-helper-independent antiviral function of CD8-positive memory T lymphocytes derived from latently infected donors

Author

Reddehase, M J, Jonjic, S, Weiland, F, Mutter, W, and Koszinowski, U H

Abstract

The ability of memory T lymphocytes derived from latently infected mice to control murine cytomegalovirus disease in the immunocompromised host was studied by adoptive transfer experiments. At a stage of pathogenesis when virus had already colonized target tissues, a therapeutic antiviral function could be ascribed to the CD8+ subset. This in vivo function was not restricted to sites in which intravenously infused lymphocytes usually are trapped or home in, such as the lungs or the spleen, respectively, but was also evident in the adrenal glands, a site to which antiviral effector cells have to specifically migrate. Specific infiltration of adrenal gland cortical tissue by donor-derived CD8+ memory T lymphocytes was demonstrated. CD4+ memory T lymphocytes had no antiviral effect by themselves and also were not required for the function of the CD8+ effector cells in this short-term immunotherapy model. These findings should help settle the debate about which subset of T lymphocytes comprises the effector cells that can directly control cytomegalovirus infection in the murine model system.

Published
1988
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47. Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands

Author

Lucin, P, Pavic, I, Polic, B, Jonjic, S, and Koszinowski, U H

Abstract

Cytomegalovirus (CMV), similar to other members of the Herpesviridae family, can establish both persistent and latent infections. Each of the CMVs that are found in many animal species replicates in the salivary gland, and oral secretion represents a source of horizontal transmission. Locally restricted replication characterizes the immunocompetent individual, whereas in the immunocompromised host, protean disease manifestations occur due to virus dissemination. The virus is cleared by immune surveillance, and CD8+ T lymphocytes play a major role. Remarkably, certain cell types of salivary gland tissues are exempt from CD8+ T-lymphocyte control of murine CMV infection and require the activity of CD4+ T lymphocytes. The results presented here suggest that this activity is a function of Th1 cells. Neutralization of endogenous gamma interferon abrogated the antiviral activity of Th1 cells but not that of CD8+ T lymphocytes in other tissues. Neutralization of endogenous gamma interferon did not interfere with the induction of the cellular and humoral immune response but acted during the effector phase. Recombinant gamma interferon could not replace the function of Th1 cells in vivo and had limited direct antiviral activity in vitro. The results therefore suggest that gamma interferon represents one, but not the only, essential factor involved in salivary gland clearance, establishment of CMV latency, and, eventually, the control of horizontal transmission.

Published
1992
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48. Molecular basis for cytolytic T-lymphocyte recognition of the murine cytomegalovirus immediate-early protein pp89

Author

Del Val, M, Volkmer, H, Rothbard, J B, Jonjic, S, Messerle, M, Schickedanz, J, Reddehase, M J, and Koszinowski, U H

Abstract

The murine cytomegalovirus protein pp89, which is encoded by gene ieI, is a nonstructural regulatory protein expressed in the immediate-early phase of the viral replication cycle and located mainly in the nucleus of infected cells. Protection of BALB/c (H-2d) mice against a lethal murine cytomegalovirus challenge infection is achieved by vaccination with a recombinant vaccinia virus, MCMV-ieI-VAC, expressing pp89 as the only murine cytomegalovirus gene product. The protection is entirely mediated by T lymphocytes of the CD8+ subset. In the present report, we analyzed the molecular basis of the recognition of pp89 by BALB/c CD8+ cytolytic T lymphocytes. A series of internal and terminal deletion mutants of gene ieI was constructed and cloned in vaccinia virus, and the antigenicity and immunogenicity of the fragments of pp89 expressed by the recombinants were studied. A region of only one-sixth of the protein, from amino acids 154 to 249 and encoded by the fourth exon of gene ieI, was sufficient for both the recognition in vitro of the protein by pp89-specific cytotoxic T lymphocytes and the induction in vivo of pp89-specific cytotoxic T lymphocytes. By using synthetic peptides, the sequence between residues 161 and 179, which is located within the defined domain, was identified as an epitope presented to BALB/C cytotoxic T lymphocytes by the class I major histocompatibility antigen Ld.

Published
1988
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49. A nonstructural viral protein expressed by a recombinant vaccinia virus protects against lethal cytomegalovirus infection

Author

Jonjic, S, del Val, M, Keil, G M, Reddehase, M J, and Koszinowski, U H

Abstract

The nonstructural immediate-early protein pp89 of murine cytomegalovirus (MCMV) is the first viral protein synthesized after infection and has a regulatory function in viral gene expression. Despite its localization in the nucleus of infected cells, pp89 is also the dominant antigen recognized by MCMV-specific cytolytic T lymphocytes. The recombinant vaccinia virus MCMV-ieI-VAC, which expresses pp89, was used to study the capacity of this protein to induce protective immunity in BALB/c mice. Vaccination with MCMV-ieI-VAC induced a long-lasting immunity that protected mice against challenge with a lethal dose of MCMV but did not prevent infection and morbidity. In vivo depletion of CD8+ T lymphocytes before challenge completely abrogated the protective immunity. CD8+ T lymphocytes derived from MCMV-ieI-VAC-primed donors and adoptively transferred into sublethally irradiated and MCMV-infected recipients were found to limit viral replication in host tissues, whereas CD4+ T lymphocytes and pp89-specific antiserum had no protective effect. The data demonstrate for the first time that a single nonstructural viral protein can confer protection against a lethal cytolytic infection and that this immunity is entirely mediated by the CD8+ subpopulation of T lymphocytes.

Published
1988
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50. Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs

Author

Reddehase, M J, Weiland, F, Münch, K, Jonjic, S, Lüske, A, and Koszinowski, U H

Abstract

Interstitial pneumonia associated with viral replication in lung tissue was observed after cytomegalovirus infection of total-body gamma-irradiated mice, whereas in noncompromised hosts the lungs were not affected and virus multiplication was restricted to the salivary glands. The radiation damage could either predispose normally nonpermissive cell types for productive infection or abrogate an immune control of the tissue manifestation of infection by elimination of lymphocytes. Adoptive transfer of lymphoid cells into irradiated, infected recipients supported the second alternative. Even when infection was established in the lungs, as manifested by the presence of infected lung tissue cells in the alveolar septa, an antiviral effect could be assigned to the Lyt-2+, L3T4- subset of T lymphocytes specifically sensitized in the immunocompetent donor. These cells did not require in vitro propagation to perform effector cell functions in vivo and were operative under physiological conditions in comparatively low numbers. Hence, there is reason to assume that T lymphocytes are responsible for the tissue distribution of cytomegalovirus replication during infection.

Published
1985
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