Innate Immunity and the Inter-exposure Interval Determine the Dynamics of Secondary Influenza Virus Infection and Explain Observed Viral Hierarchies.
Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus-innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
Pengxing
P
Cao
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
Ada W C
AW
Yan
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Modelling Infection and Immunity Lab, Centre for Disease Modelling, York Institute for Health Research, York University, Toronto, Ontario, Canada; Mathematics and Statistics, York University, Toronto, Ontario, Canada.
Jane M
JM
Heffernan
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
Stephen
S
Petrie
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
Robert G
RG
Moss
WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Louise A
LA
Carolan
WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Teagan A
TA
Guarnaccia
WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Anne
A
Kelso
WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Ian G
IG
Barr
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Modelling and Simulation, Infection and Immunity Theme, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
Jodie
J
McVernon
WHO Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Karen L
KL
Laurie
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Modelling and Simulation, Infection and Immunity Theme, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, Australia.
James M
JM
McCaw
D000818:Animals; D019295:Computational Biology; D004195:Disease Models, Animal; D005289:Ferrets; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D018448:Models, Immunological; D009975:Orthomyxoviridae / Q000276:immunology / Q000472:pathogenicity; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D019562:Viral Load