In a study published in the prestigious Immunity journal on February 21, 2017, researchers from the Institut Pasteur in Paris and in Shanghai, Bicêtre Hospital (AP-HP), Paris-Sud University and the CNRS (French National Center for Scientific Research) reported on the discovery of a new group of B lymphocytes, which are only present in infants and are the preferential target of the virus responsible for bronchiolitis. This shows why this infection of the lower respiratory tract mainly affects newborns so severely, in contrast to older children. This publication paves the way for new diagnostic and therapeutic possibilities for treating acute bronchiolitis.
Bronchiolitis — the leading cause of consultations and hospital treatment in pediatric departments and pediatric intensive care units during the winter months — is an infection caused by the respiratory syncytial virus (RSV), which affects the lower respiratory tract. Its severity is specific to the age of the patient. While the infection remains asymptomatic in adults, young infants are very susceptible to the virus. In particular, newborns under three months old are the most prone to developing very severe bronchiolitis, which requires respiratory assistance in intensive care. There is no vaccine or treatment for this infection. Severe RSV infection represents 2-6% of all admissions to pediatric intensive care units in developed countries. It is estimated that each hospitalization in pediatric intensive care for severe RSV infection costs between 28,000 and 92,000 US dollars.
In this context, Richard Lo-Man’s group at the Institut Pasteur (Human Histopathology Unit) together with Prof. Pierre Tissières’s team at Bicêtre Hospital (AP-HP NICU) and Paris-Sud University, and the Institut Pasteur of Shanghai, newly identified a B lymphocyte population only found in very young children (under 1 year old) which is preferentially infected by the RSV virus.
B lymphocytes are immune system cells producing antibodies capable of neutralizing pathogens that protect against infectious diseases. However, the B lymphocytes discovered by the scientists have regulatory properties, which tend to reduce the inflammation and immune response to the virus. By infecting these specific B lymphocytes — named nBreg (for neonatal regulatory B lymphocytes) — in infants, RSV activates nBregs that decrease viral clearance and thus contribute to the disease severity.
More specifically, the researchers have described a mechanism whereby the RSV virus infects the nBreg lymphocytes. This mechanism draws on a dual recognition system between the virus and the immune cell. The initial recognition occurs through contact between a protein on the surface of the virus (F protein) and a specific antibody on the surface of the nBreg cell. Lymphocyte activation and expression of CX3CR1 which in turn recognizes the viral G protein leads to viral infection. By infecting this cell, the virus can then inhibit the antiviral immune response, by expressing the anti-inflammatory response genes. Thanks to this mechanism, the RSV virus therefore uses the infant immune system to persist in its host.
"Our research sheds light on the unclear reasons as to why infants are susceptible to RSV bronchiolitis", explains Richard Lo-Man. By identifying these new nBreg lymphocytes as prognostic biomarkers for the severity of the disease, the research will enable risk factors to be defined at birth, and help develop more effective treatment".
Image: Mathilde Boissole
 AP-HP, Institute for Integrative Biology of the Cell (CNRS/CEA/Paris-Sud University)
Respiratory syncytial virus infects regulatory B cells in human neonates via chemokine receptor CX3CR1 and promotes lung disease severity, Immunity, 21 février 2017.
Dania Zhivaki1,2, Sébastien Lemoine3,4, Annick Lim5, Ahsen Morva1, Pierre-Olivier Vidalain6, Liliane Schandene7, Nicoletta Casartelli8,9, Marie-Anne Rameix-Welti10,11, Pierre-Louis Hervé12, Edith Dériaud3,4, Benoit Beitz13, Maryline Ripaux-Lefevre13, Jordi Miatello14,15,16, Brigitte Lemercier5, Valerie Lorin17,18, Delphyne Descamps12, Jenna Fix12, Jean-François Eléouët12, Sabine Riffault12, Olivier Schwartz8,9, Fabrice Porcheray13, Françoise Mascart7,19, Hugo Mouquet17,18, Xiaoming Zhang20, Pierre Tissières14,15,16 and Richard Lo-Man1, 22
(1) Neonatal Immunity group, Human histopathology and animal models, Institut Pasteur, Paris, France
(2) Paris 7 Diderot University, Paris, France
(3) Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France
(4) Inserm U1041, France
(5) Departement d’Immunologie, Institut Pasteur, Paris, France
(6) Unité de Génomique virale et vaccination, Institut Pasteur, France
(7) Immunobiology Clinic, Hopital Erasme, Brussels, Belgium
(8) Virus et Immunité, Institut Pasteur, Paris, France
(9) UMR CNRS 3568, France
(10) Inserm U1173, Versailles-Saint-Quentin University, Saint-Quentin en Yvelines, France ;
(11) AP-HP, Laboratoire de Microbiologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France
(12) Unité de Virologie et Immunologie Moléculaires, INRA, Université Paris-Saclay, Jouy-en-Josas, France
(13) Bioaster Microbiology Technology Institute, Paris, France
(14) APHP, Pediatric ICU and Neonatal Medicine, Paris South University Hospitals, Le Kremlin-Bicêtre, France
(15) School of Medicine, Paris South University, Le Kremlin-Bicêtre, France
(16) Institute of Integrative Biology of the Cell - UMR 9196, Paris Saclay University, Gif-sur-Yvette, France
(17) Laboratory of Humoral Response to Pathogens, Department of Immunology, Institut Pasteur, Paris, France
(18) Inserm U1222, Paris, France.
(19) Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium
(20) Unit of Innate Defense and Immune Modulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
(21) Corresponding author
About the AP-HP (Paris Public Hospital Network): The AP-HP is a globally-recognized European-scale university teaching hospital network. Every year, its 39 hospitals treat eight million patients during appointments, as emergencies, or as part of scheduled hospital stays or home care. It ensures a 24/7 public health care service for all, which is both a duty and a source of pride. The AP-HP is the leading employer in the Greater Paris area: 100,000 people – doctors, researchers, paramedics, administrative staff and workers – are on its staff. http://www.aphp.fr
About Paris-Sud University Hospitals: This Hospital Group, which is made up of three hospitals (Antoine-Béclère in Hauts-de-Seine, and Bicêtre and Paul-Brousse in Val-de-Marne), offers a full range of health care services that stand out for their highly complementary nature in terms of treatment for children and adults. These health care services are built around nine teaching hospital centers that offer outreach activities, referral and expertise. Teams from the Hospital Group do their utmost to adapt health care services to patients’ changing health care needs, for instance by developing early diagnosis tools, outpatient care or therapeutic education. http://hopitaux-paris-sud.aphp.fr
About the Institut Pasteur: The Institut Pasteur, a private foundation with officially recognized charitable status set up by Louis Pasteur in 1887, is today an internationally renowned center for biomedical research with a network of 33 institutes worldwide. In the pursuit of its mission to prevent and fight against diseases in France and throughout the world, the Institut Pasteur operates in four main areas: scientific and medical research, public health and health monitoring, education, and business development and technology transfer. www.pasteur.fr
About the CNRS: The French National Center for Scientific Research is the main public research body in France and Europe. It produces knowledge for the benefit of society. With close to 32,000 employees, a 2015 budget of €3.3 bn (including €769 m of self-generated resources) and a presence throughout France, the CNRS is active in all fields of knowledge and is supported by over 1,100 laboratories. The CNRS has a long-standing tradition of excellence with 21 Nobel Prize winners and 12 Fields Medals. www.cnrs.fr