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1 December 2006

Volume 194, Number 11
The Journal of Infectious Diseases 2006;194:1580–1588
© 2006 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2006/19411-0016$15.00
DOI: 10.1086/508747
MAJOR ARTICLE

Lactobacilli Expressing Variable Domain of Llama Heavy‐Chain Antibody Fragments (Lactobodies) Confer Protection against Rotavirus‐Induced Diarrhea

Neha Pant,1,a

Anna Hultberg,1,a

Yaofeng Zhao,1

Lennart Svensson,2

Qiang Pan‐Hammarström,1

Kari Johansen,3

Peter H. Pouwels,5

Franco M. Ruggeri,8

Pim Hermans,6

Leon Frenken,7

Thomas Borén,4

Harold Marcotte,1 and

Lennart Hammarström1

1Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska Huddinge, Stockholm, 2Division of Molecular Virology, University of Linköping, Linköping, 3Department of Virology, Swedish Institute for Infectious Disease Control, Karolinska Institutet, Solna, and 4Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; 5TNO, Prevention and Health, Division of Immunology and Infectious Disease, Leiden, 6BAC BV, Naarden, and 7Unilever Foods and Health Research Institute, Vlaardingen, The Netherlands; 8Laboratorio di Ultrastrutture, Instituto Superiore di Sanitá, Rome, Italy

Background.Rotavirus‐induced diarrhea poses a worldwide medical problem in causing substantial morbidity and mortality among children in developing countries. We therefore developed a system for passive immunotherapy in which recombinant lactobacilli constitutively express neutralizing variable domain of llama heavy‐chain (VHH) antibody fragments against rotavirus.

Methods.VHH were expressed in Lactobacillus paracasei, in both secreted and cell surface–anchored forms. Electron microscopy was used to investigate the binding efficacy of VHH‐expressing lactobacilli. To investigate the in vivo function of VHH‐expressing lactobacilli, a mouse pup model of rotavirus infection was used.

Results.Efficient binding of the VHH antibody fragments to rotavirus was shown by enzyme‐linked immunosorbent assay and scanning electron microscopy. VHH fragments expressed by lactobacilli conferred a significant reduction in infection in cell cultures. When administered orally, lactobacilli‐producing surface‐expressed VHH markedly shortened disease duration, severity, and viral load in a mouse model of rotavirus‐induced diarrhea when administered both fresh and in a freeze‐dried form.

Conclusions.Transformed lactobacilli may form the basis of a novel form of prophylactic treatment against rotavirus infections and other diarrheal diseases.

Received 10 February 2006; accepted 10 June 2006; electronically published 23 October 2006.

Reprints or correspondence: Prof. Lennart Hammarström, Div. of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, SE‐141 86, Stockholm, Sweden ().

Cited by

Ghislaine Behar, Patrick Chames, Isabelle Teulon, Amélie Cornillon, Faisal Alshoukr, Françoise Roquet, Martine Pugnière, Jean-Luc Teillaud, Anne Gruaz-Guyon, André Pèlegrin, Daniel Baty. (2009) Llama single-domain antibodies directed against nonconventional epitopes of tumor-associated carcinoembryonic antigen absent from nonspecific cross-reacting antigen. FEBS Journal 276:14, 3881-3893
Online publication date: 1-Aug-2009.
CrossRef
Janusz Wesolowski, Vanina Alzogaray, Jan Reyelt, Mandy Unger, Karla Juarez, Mariela Urrutia, Ana Cauerhff, Welbeck Danquah, Björn Rissiek, Felix Scheuplein, Nicole Schwarz, Sahil Adriouch, Olivier Boyer, Michel Seman, Alexei Licea, David V. Serreze, Fernando A. Goldbaum, Friedrich Haag, Friedrich Koch-Nolte. (2009) Single domain antibodies: promising experimental and therapeutic tools in infection and immunity. Medical Microbiology and Immunology
Online publication date: 16-Jul-2009.
CrossRef
Harold Marcotte, Neha Pant, Lennart Hammarström. (2008) Engineered lactobody-producing lactobacilli: a novel form of therapy against rotavirus infection. Future Virology 3:4, 327-341
Online publication date: 1-Aug-2008.
CrossRef
M. M. Harmsen, H. J. Haard. (2007) Properties, production, and applications of camelid single-domain antibody fragments. Applied Microbiology and Biotechnology 77:1, 13-22
Online publication date: 9-Nov-2007.
CrossRef
Ulrich Desselberger. (2007) Second European Rotavirus Biology Meeting. Future Virology 2:5, 429-435
Online publication date: 1-Oct-2007.
CrossRef

  • Potential conflict of interest: Unilever has applied for a patent on the use of VHH for the mitigation of rotavirus‐induced diarrhea.

    Financial support: Swedish International Development Agency; Swedish Research Council; European Union ADRI (project QLK2‐CT‐2001‐01216); Swedish Agency for Research in Developing Countries.

  • N.P. and A.H. contributed equally to the work.

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