Influenza A Virus Infection, Innate Immunity, and Childhood

Abstract

Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population.

Figure 1

Prevalence of Comorbid Conditions Among Patients Requiring Hospitalization for Influenza A Virus Infection During the 2012–2013 Influenza Season Children who were hospitalized with influenza were significantly less likely to have had a preexisting medical condition before their hospitalization compared with the adult population. Data are adapted from the Centers for Disease Control and Prevention FluView website.

Figure 2

How The Innate Immune Response to Influenza A Virus (IAV) Infection May Differ Between Children and Adults Viral RNA is recognized by Toll-like receptors located in the endosome, primarily TLR3 and TLR7, which activate the adaptor proteins Toll/interleukin (IL)–1 receptor domain–containing adapter-inducing interferon β (TRIF) and myeloid differentiation primary response gene 88 (MyD88), respectively. Activated TRIF and MyD88 act downstream on interferon regulatory factor 3 (IRF3), IRF7, and nuclear factor κB (NF-κB). Activated IRF3 and IRF7 translocate to the nucleus, where they stimulate transcription of the type I interferons (IFN-α/β). Nuclear factor κB serves as a transcription factor promoting production of proinflammatory cytokines and chemokines, including pro–interleukin-1β (pro–IL-1β), IL-6, IL-10, and IL-12. Alternatively, cytosolic viral RNA is recognized by retinoic acid–inducible gene I (RIG-I), which binds to its adaptor mitochondrial antiviral signaling protein (MAVS), stimulating IRF3 and NF-κB and their downstream transcription products IFN-α/β and proinflammatory cytokines. Nuclear factor κB activation, in addition to a second signal indicating cellular stress (changes in intracellular ionic concentrations, reactive oxygen species [ROS], potassium flux, etc), induces assembly of the multimeric nucleotide-binding oligomerization domain (NOD)–like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome protein complex. The NLRP3 inflammasome activates caspase 1, which cleaves the proinflammatory cytokines to release their mature forms. Upward and downward arrows indicate the relative cytokine response in the young pediatric population compared with adults. The overall consequence may move away from a helper T-cell subtype 1 (T_H1) response and toward a T_H2- and T_H17-predominant response that is more effective against extracellular pathogen clearance, leaving the young host at risk for the intracellular influenza pathogen. dsRNA indicates double-stranded RNA; ssRNA, single-stranded RNA. Illustration by Jacqueline Schaffer, MS, medical illustrator.