Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
INTRODUCTION
Even with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood.
RATIONALE
We reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection.
RESULTS
After nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient boost in mucosal markers of innate immune activation for several days after viral administration and no subsequent viral replication. In mice, chemokine-induced neutrophil recruitment to the airway before viral exposure transiently enhanced viral replication immediately after inoculation. As with human subjects, this was associated with decreased expression of some innate mediators in the respiratory tract, which was then followed by enhanced disease driven by CD8+ T cells.
CONCLUSION
Although reinfection with a respiratory virus can be partially explained by the waning of antibody titers and T cell numbers, neutrophilic inflammation in the airway at the time of pathogen exposure also predisposes individuals to symptomatic infection. After exposure, the response of the mucosa diverges: A mild and transient increase in nasal inflammatory mediators is accompanied by termination of viral infection, whereas failure to mount this response is followed by viral success.
The state of innate immune preparedness of the respiratory mucosa is thus a major determinant of susceptibility to viral challenge. Our results show the importance of understanding the mucosal microenvironment in studies of respiratory infection and highlight targets for local intervention, which may enhance protection against a range of respiratory pathogens.
Even with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood.
RATIONALE
We reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection.
RESULTS
After nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient boost in mucosal markers of innate immune activation for several days after viral administration and no subsequent viral replication. In mice, chemokine-induced neutrophil recruitment to the airway before viral exposure transiently enhanced viral replication immediately after inoculation. As with human subjects, this was associated with decreased expression of some innate mediators in the respiratory tract, which was then followed by enhanced disease driven by CD8+ T cells.
CONCLUSION
Although reinfection with a respiratory virus can be partially explained by the waning of antibody titers and T cell numbers, neutrophilic inflammation in the airway at the time of pathogen exposure also predisposes individuals to symptomatic infection. After exposure, the response of the mucosa diverges: A mild and transient increase in nasal inflammatory mediators is accompanied by termination of viral infection, whereas failure to mount this response is followed by viral success.
The state of innate immune preparedness of the respiratory mucosa is thus a major determinant of susceptibility to viral challenge. Our results show the importance of understanding the mucosal microenvironment in studies of respiratory infection and highlight targets for local intervention, which may enhance protection against a range of respiratory pathogens.
Date Issued
2020-10-09
Date Acceptance
2020-08-19
Citation
Science, 2020, 370 (6513), pp.1-15
ISSN
0036-8075
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
15
Journal / Book Title
Science
Volume
370
Issue
6513
Copyright Statement
© 2020, American Association for the Advancement of Science https://www.sciencemag.org/about/science-licenses-journal-article-reuse
This is an article distributed under the terms of the Science Journals Default License. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on Vol. 370, Issue 6513, DOI: 10.1126/science.aba9301
This is an article distributed under the terms of the Science Journals Default License. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on Vol. 370, Issue 6513, DOI: 10.1126/science.aba9301
Sponsor
Medical Research Council (MRC)
Wellcome Trust
Wellcome Trust
National Institute for Health Research
National Institute for Health Research
Wellcome Trust
Commission of the European Communities
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
GlaxoSmithKline Services Unlimited
Medical Research Council (MRC)
National Institute for Health Research
Wellcome Trust
Commission of the European Communities
Wellcome Trust
National Institute for Health Research
Wellcome Trust
Identifier
https://science.sciencemag.org/content/370/6513/eaba9301
Grant Number
G0902266
090382/Z/09/Z
090382/Z/09/Z
NF-SI-0513-10150
HPRU-2012-10064
105603/Z/14/Z
116019
MR/R502121/1
MR/R005982/1
MR/R005982/1
PO 4050681719
PO 3000941762
MR/T50256X/1
NIHR201385
071381/Z/03/Z
QLK2-CT-1999-01044
062177/Z/00/Z
NIHR200927
109058/Z/15/Z
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SYNCYTIAL VIRUS-INFECTION
DISEASE SEVERITY
T-CELLS
VIRAL LOAD
INFLUENZA
CYTOKINE
CHILDREN
IMMUNITY
INNATE
SECUKINUMAB
Adolescent
Adult
Animals
CD4 Lymphocyte Count
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Chemokine CXCL1
Humans
Inflammation
Interleukin-17
Mice
Mice, Inbred C57BL
Middle Aged
Nasal Mucosa
Neutrophil Activation
Neutrophils
Respiratory Syncytial Virus Infections
Respiratory Syncytial Viruses
Tumor Necrosis Factor-alpha
Young Adult
Nasal Mucosa
Neutrophils
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Animals
Mice, Inbred C57BL
Humans
Mice
Respiratory Syncytial Viruses
Respiratory Syncytial Virus Infections
Inflammation
Tumor Necrosis Factor-alpha
Interleukin-17
CD4 Lymphocyte Count
Neutrophil Activation
Adolescent
Adult
Middle Aged
Chemokine CXCL1
Young Adult
General Science & Technology
Publication Status
Published
Date Publish Online
2020-10-09