title: Modeling Influenza Virus Infection: A Roadmap for Influenza Research.
abstract: Influenza A virus (IAV) infection represents a global threat causing seasonal outbreaks and pandemics. Additionally, secondary bacterial infections, caused mainly by Streptococcus pneumoniae, are one of the main complications and responsible for the enhanced morbidity and mortality associated with IAV infections. In spite of the significant advances in our knowledge of IAV infections, holistic comprehension of the interplay between IAV and the host immune response (IR) remains largely fragmented. During the last decade, mathematical modeling has been instrumental to explain and quantify IAV dynamics. In this paper, we review not only the state of the art of mathematical models of IAV infection but also the methodologies exploited for parameter estimation. We focus on the adaptive IR control of IAV infection and the possible mechanisms that could promote a secondary bacterial coinfection. To exemplify IAV dynamics and identifiability issues, a mathematical model to explain the interactions between adaptive IR and IAV infection is considered. Furthermore, in this paper we propose a roadmap for future influenza research. The development of a mathematical modeling framework with a secondary bacterial coinfection, immunosenescence, host genetic factors and responsiveness to vaccination will be pivotal to advance IAV infection understanding and treatment optimization.
authors.affiliation: Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Alessandro.Boianelli@helmholtz-hzi.de.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boianelli
authors.affiliation: Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. nguyenkinh@ytecongcong.com.
authors.forename: Van Kinh
authors.initials: VK
authors.lastname: Nguyen
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Thomas.Ebensen@helmholtz-hzi.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Kai.Schulze@helmholtz-hzi.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Schulze
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Esther.Wilk@helmholtz-hzi.de.
authors.forename: Esther
authors.initials: E
authors.lastname: Wilk
authors.affiliation: Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Niharika.Sharma@helmholtz-hzi.de.
authors.forename: Niharika
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Sabine.Stegemann-Koniszewski@helmholtz-hzi.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Stegemann-Koniszewski
authors.affiliation: Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Dunja.Bruder@helmholtz-hzi.de.|Infection Immunology, Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke-University, Magdeburg 39106, Germany. Dunja.Bruder@helmholtz-hzi.de.
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ftoapanta@medicine.umaryland.edu.
authors.forename: Franklin R
authors.initials: FR
authors.lastname: Toapanta
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. CarlosAlberto.Guzman@helmholtz-hzi.de.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.affiliation: Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. mmh@theoretical-biology.de.|Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig 38106, Germany. mmh@theoretical-biology.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer-Hermann
authors.affiliation: Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany. Esteban.Vargas@helmholtz-hzi.de.
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Hernandez-Vargas
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D060085:Coinfection / Q000382:microbiology* / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D007251:Influenza, Human / Q000150:complications* / Q000473:pathology / Q000821:virology*; D008962:Models, Theoretical; D009975:Orthomyxoviridae / Q000254:growth & development* / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000382:microbiology* / Q000473:pathology
keywords: aging; coinfection; host genetic factors; influenza; mathematical models; parameters estimation; vaccinology