Immune Response to Influenza Infection

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

We study immune responses to Influenza infection and how the immune system contributes to damage and protection of the patient. Influenza, commonly called the Flu, and other infections of throat and lung are often harmless but sometimes lead to severe damage and even death. Different Flu viruses cause disease of different severity, indicating that viral factors influence disease outcome. Also, when different persons are infected by the same Flu virus, the clinical outcome can vary widely, showing that factors in the individuals body make a difference in the disease. The immune system is necessary to eliminate the virus but in the process contributes to lung damage. The rules in this battle between virus and immune system are not clear, and therefore, the outcome of infection cannot be predicted. Which factors can tip the balance between damage or death on one side and successful clearance of the virus on the other is not completely known. Our studies serve to understand better which characteristics of the virus and of the infected organism can change disease outcome. We attempt to identify factors that contribute to eliciting a strong immune response and to causing lung damage. Better knowledge of these factors will help design better medical intervention during Flu infection.

Technical Summary

We study early immune events in Influenza infection, specifically the interface between infected lung epithelium and innate immunity. The aim of our studies is to identify determinants of immunogenicity and pathogenicity in influenza virus infection and the immune response to it. Respiratory tract infections by bacteria and viruses are still one of the leading causes of death worldwide. Among these infections, seasonal influenza epidemics represent a constant burden to public health, and influenza pandemics caused by new strains pose a serious global threat. Despite this, it is largely unclear which mechanisms can tip the balance between self-limiting infection on one hand and morbidity and mortality due to lung pathology on the other hand. Influenza virus itself is cytopathic, and the immune response is necessary to eliminate the virus, but also involved in immune-mediated damage to lung tissue. It is still unclear how infected epithelial cells activate the immune system, how early events in the infection influence the induction of the immune response, and which viral and host factors are determinants for a protective or fatal outcome of infection. Work in this programme focuses on these early events and on the relationship between infected epithelial cells and immune cells. We have set up airway epithelial cell cultures from primary cells and now study how they activate innate immunity. In vitro work will be done both with wild-type and mutant murine cells and with human cells. These studies will be complemented by in vivo work using bone-marrow chimeras to assess the contribution of epithelial cells to the onset of anti-influenza immune responses. We will attempt to visualize viral infection by reporter gene strategies, to follow infection in vivo and perform functional tests on infected cells. We will assess the role of NK cells and neutrophils in the immune response to and immunopathology caused by influenza virus infection. Since co-infection by gram-positive bacteria is an important clinical complication of influenza infection, we will determine factors by which the viral infection sets the stage for subsequent bacterial attack. All these studies are instrumental to understand respiratory viral infections better, to predict their outcome and to identify modes of intervention that enhance protection and prevent damage.

Publications

10 25 50

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Cantisani R (2013) Toll-like receptor 9-independent responsiveness of human monocytes to microbial DNA. in Scandinavian journal of immunology

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Crotta S (2014) The transcription factor E4BP4 is not required for extramedullary pathways of NK cell development. in Journal of immunology (Baltimore, Md. : 1950)

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Davidson S (2015) Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. in Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

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Hartweger H (2014) Themis2 is not required for B cell development, activation, and antibody responses. in Journal of immunology (Baltimore, Md. : 1950)

 
Description CASE studentship
Amount £132,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 09/2017
 
Description CASE studentship
Amount £132,000 (GBP)
Funding ID BB/K501475/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description Collaboration with GSK
Amount £30,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 07/2013 
End 12/2013
 
Title Murine model of influenza and bacterial co-infection 
Description Disease model for the major type of lethality-associated infection in pandemic and seasonal influenza waves 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Allows the study of mechanism behind this common sequela of influenza infection associated with high morbidity and mortality 
 
Title Primary murine airway epithelial cell culture 
Description Lines generated from mouse trachea, can be generated from gene deficient mice 
Type Of Material Cell line 
Year Produced 2014 
Provided To Others? Yes  
Impact role in influenza infection of single genes can be tested in the primary target cell of the virus 
 
Description IFNAR1SA mice 
Organisation University of Pennsylvania
Department School of Veterinary Medicine (UPenn)
Country United States 
Sector Academic/University 
PI Contribution Analysed in-depth the genetically modified mouse provided to understand impact of prolonged interferon signalling on influenza severity.
Collaborator Contribution Provided genetically modified mouse for our studies.
Impact common publication in preparation
Start Year 2014
 
Description Interferon lambda 
Organisation Aarhus University
Country Denmark 
Sector Academic/University 
PI Contribution Used interferons provided for in vivo studies in infection models and in vitro on human cells.
Collaborator Contribution Provided bioactive purified human and mouse interferon lambda.
Impact Publication: http://embomolmed.embopress.org/content/8/9/1099.long
Start Year 2014
 
Description Mx mice 
Organisation Albert Ludwig University of Freiburg
Country Germany 
Sector Hospitals 
PI Contribution Used tissues and animals provided by the partner in several studies linked to influenza severity and therapy
Collaborator Contribution Provided tissues and animals from genetically modified mouse strains
Impact Publications: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003773 http://embomolmed.embopress.org/content/8/9/1099.long
Start Year 2013
 
Description Serpin E1 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution Analysed effect of Serpin e1 deficiency in influenza virus control in primary airway epithelia grown from gene-deleted mice.
Collaborator Contribution provided tissues for this analysis
Impact Publication: http://www.sciencedirect.com/science/article/pii/S009286741500118X
Start Year 2014
 
Description Streptococcus pneumoniae strains 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution Use S.p. strains to understand long-term changes in lung immunity.
Collaborator Contribution Provided range of S.p. strains.
Impact Publication in preparation
Start Year 2016
 
Title Interferon lambda as anti-influenza treatment option 
Description Based on our preclinical studies, we propose that interferon lambda may be a treatment option for severe influenza, as it has potent antiviral effect and does not show the pro-inflammatory side effects that type I interferons show. In vitro tests on human cells confirm the response patterns we have found in vivo in infection models. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Actively seeking support
Impact Based on our preclinical studies, we propose that interferon lambda may be a treatment option for severe influenza, as it has potent antiviral effect and does not show the pro-inflammatory side effects that type I interferons show. In vitro tests on human cells confirm the response patterns we have found in vivo in infection models. 
URL http://embomolmed.embopress.org/content/8/9/1099.long
 
Description Interview to German national newspaper Die Welt 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact German newspaper Die Welt interviewed me and other colleagues to understand better the new ways of collaboration at the Crick institute
Year(s) Of Engagement Activity 2017
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview by BBC 5 radio on our work identifying a molecular link between air pollution and respiratory disease
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b07rkgb2
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact German national radio station ARD came to find out about the vision of the Crick, how it is to work here as a German researcher and implications of Brexit.
Year(s) Of Engagement Activity 2017
 
Description School class visiting the institute 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 25 pupils were introduced to the research taking place at the NIMR, to raise interest in a career in academic research and the topics covered here.

Following the positive feed back by the class it was agreed to turn this into a regular annual event for subsequent years.
Year(s) Of Engagement Activity 2011,2012,2013,2014
 
Description School visit to institute 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Overview on influenza virus, epidemics and pandemics, and the research concerning influenza we perform here.

school reported high interest and satisfaction of the pupils who attended
Year(s) Of Engagement Activity 2013
 
Description Seminar to health professionals about influenza host susceptibility and novel treatment options 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Seminar and discussion at the London-wide Virology discussion group organised by professionals in the clinical sector with the aim of keeping up with recent academic progress. Lively discussion and much interest in the subject and the seminar content.
Year(s) Of Engagement Activity 2017
 
Description Television interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact German national television ARD interviewed about the new Crick institute, working conditions there and Brexit implications.
Year(s) Of Engagement Activity 2017