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.

Influenza A virus (IAV) is a highly contagious RNA virus that causes respiratory tract infections in humans and animals. Seasonal IAV is responsible for considerable disease worldwide, with the World Health Organization estimating 3 to 5 million severe cases of IAV each year and approximately 250 000 to 500 000 deaths.¹Pandemics threaten to affect significantly more people. During the 1918 pandemic, it is estimated that IAV was responsible for 50 to 100 million deaths.² The burden of IAV infection is highest in children, the elderly, and persons with chronic medical conditions. Each year, IAV infection affects up to 40% of children younger than 5 years in the United States and 90 million worldwide.³ Approximately 20 million of these children develop lower respiratory tract infections, and 1 million may experience severe, life-threatening disease.⁴ Although underlying medical conditions place certain children at increased risk of severe IAV infection, a considerable amount of morbidity and mortality occurs in healthy children. In the United States, the number of deaths each year in previously healthy children is almost equal to the number of deaths in children with chronic conditions, including asthma and prematurity. In contrast, adults who develop severe lower respiratory tract disease with IAV infection almost always have predisposing conditions that place them at increased risk of death (Figure 1).⁵ In mouse models of IAV pneumonia, increased mortality and pulmonary injury are seen in juvenile mice compared with adults despite neither having previous exposure to the virus.^6,7 This discrepancy suggests that there may be age-related differences in the pathogenesis of IAV infection that leave children at particularly high risk of severe disease.

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.⁵

Mild IAV infection is characterized by fever, headache, sore throat, and coryza. Progression to lower respiratory tract disease can lead to cough, wheezing, impairment in gas exchange, and ultimately respiratory failure. Children may be particularly susceptible to severe IAV infection for various reasons. Small pediatric airways are prone to obstruction by the secretions produced during IAV infection, which can result in substantial respiratory distress.⁸ Infants also have a more cartilaginous (and therefore more compliant) chest wall, leaving the lungs more susceptible to collapse during infection and difficult to reinflate.⁸ The combination of these anatomic factors may increase the severity of symptoms once infection is established. However, why IAV is able to establish lower respiratory tract infection so effectively in otherwise healthy children is yet to be fully explained.

In addition to anatomic factors, the quality and quantity of the immune response appear to change with age. Young children with naive adaptive immune systems are dependent on their innate immunity toward off threats as adaptive immunity develops.⁹ This circumstance likely contributes to the vulnerability of young children to infection. However, immature adaptive immunity does not adequately explain the different inflammatory responses to infection seen in children and adults. Various viral infections have different outcomes depending on the age at which they are acquired,⁹ and vaccine responses vary depending on age.¹⁰ The mechanisms underlying these age-related differences in immune signaling are incompletely understood. Therefore, a better understanding of innate immune responses in children is crucial for developing targeted therapeutic strategies and improved vaccine design to support this population.

Pathogenesis of IAV Infection

Influenza A virus is a single-stranded, enveloped RNA virus with 8 RNA segments that encode 12 proteins. Type A influenza is classified into subtypes depending on which versions of 2 different proteins are present on the surface of the virus: hemagglutinin (HA) and neuraminidase (NA). There are 17 versions of HA and 10 versions of NA. Therefore, a virus with version 1 of the HA protein and version 2 of the NA protein is classified as influenza A subtype H1N2 (H1N2). The influenza A subtypes are further classified into strains, and the names of the virus strains include the place where the strain was first found and the year of discovery. Therefore, an H1N1 strain isolated in California in 2009 is referred to as A/California/7/2009 (H1N1). There are approximately 170 different combinations of the HA and NA proteins possible, but, in practice, only a few circulate through the human population at any given time. A recent analysis of patients infected with H1N1 virus from 2009 to 2014 revealed that the H1N1 virus has drifted from the prototype A/California/7/2009 virus by approximately 1.3%.¹¹ Subtypes H1N1 and H3N2 are in general circulation worldwide. Other combinations circulate in animals (eg, the H5N1 virus found in birds). The subtypes that exist within a population change over time. For example, the H2N2 subtype, which infected people between 1957 and 1968, is no longer found in humans.

Accumulation of mutations over time allows IAV to evade recognition by the adaptive immune system, necessitating yearly modification of anti-influenza vaccines and annual immunization. This phenomenon is known as antigenic drift and is responsible for seasonal influenza epidemics. Alternatively, antigenic shift occurs when there is exchange of RNA between human and nonhuman IAV strains, which results in a virus previously unseen by the human population and therefore capable of causing pandemics.¹² Influenza B viruses (IBVs) are capable of causing the same spectrum of disease as IAV, but their limited host range is thought to prevent frequent reassortment and thus emergence of widely varying strains capable of causing pandemics. Although IBV can be an important pathogen in young children, research on its pathogenesis in children is limited, so IAV will be the focus of this review.

The initial target of IAV infection is the respiratory epithelium. Influenza A virus binds to sialic acid residues through its HA protein, which triggers endocytosis of the virus.¹³ Once internalized, acidification of the endosome leads to dissociation of the viral ribonucleoprotein complex, which is transported to the nucleus, where viral replication occurs.¹⁴ Following replication, new virions are assembled at the cell surface and released through cleavage of HA–sialic acid linkages by the viral NA.¹⁵ Influenza A virus may be detected at multiple points along the pathway of viral internalization, replication, and release. Detection of IAV leads to a coordinated response by the innate immune system to produce proinflammatory cytokines and induce antiviral signaling.¹² Proinflammatory cytokines recruit effector cells for viral clearance and cells of the adaptive immune system to develop antigen-specific responses and immune memory. Antiviral signaling combats intracellular infection through type I interferons (IFNs) and transcription of hundreds of IFN-regulated genes.¹⁶

Innate Immune Mechanisms Against IAV

Detection of IAV first occurs within the infected respiratory epithelial cell through recognition of the virus by germline-encoded receptors of the innate immune system known as pattern recognition receptors (PRRs).¹⁷ There are 3 main classes of PRRs involved in IAV detection, including the Toll-like receptors (TLRs), the retinoic acid–inducible gene (RIG)–like receptors, and the nucleotide-binding oligomerization domain (NOD)–like receptors.^12,16 The first class probes the extracellular and endosomal compartments, whereas the latter 2 classes scan the cytosol. Activation of these PRRs leads to cytokine production that initiates antimicrobial programming and recruits effector immune cells. The fact that the germline encodes PRRs has led many researchers to conclude that the innate immune system is present at birth and does not change throughout life. However, there is increasing evidence that the downstream signaling events after identification of microbes by PRRs are not equal across age groups.^18–21

The TLRs are the first family of PRRs to recognize infection of the respiratory epithelium by IAV.¹² Eleven TLRs have been described in humans, and at least 2 are involved in IAV infection. As IAV replicates within the epithelial cell, it creates double-stranded RNA recognizablebyTLR3.²² As the infection spreads from epithelial cells to alveolar macrophages and dendritic cells (DCs), TLR7 can identify single-stranded IAV RNA.²³ Signaling through TLR3 and TLR7 culminates in production of proinflammatory cytokines and chemokines, in particular interleukin6(IL-6), IL-12,andtumornecrosis factor (TNF),²⁴ as well as antiviral IFNs (Figure 2).

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.

As IAV replicates in alveolar macrophages and epithelial cells, it can also be identified by RIG-I, a member of the RIG-like helicase receptor family. Retinoic acid–inducible gene I has been shown to detect single-stranded IAV RNA bearing the 5′-triphosphate moiety that is generated during viral replication.²⁵ Once activated, RIG-I binds to its adaptor mitochondrial antiviral signaling protein to initiate nuclear factor κB (NF-κB) and IFN regulatory factor 3 signaling to result in proinflammatory cytokine production and type I IFN production, respectively. RIG-I activation is key to efficient IFN production and therefore control of IAV replication.²⁵ Mice deficient in RIG-I are highly susceptible to IAV-induced lung injury.^26,27

Respiratory epithelial cells, macrophages, and DCs also contain NOD-like receptors (NLRs) for detection of microbial invasion and cellular injury. Activation of certain NLRs leads to inflammasome assembly. Inflammasomes are multimeric protein complexes that assemble to activate caspase 1, which is required for the proteolytic maturation and release of the proinflammatory cytokines IL-1β and IL-18. The NLR family, pyrin domain–containing 3 (NLRP3) inflammasome comprises a PRR (NLRP3), the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and an effector protein (caspase 1). The NLRP3 inflammasome assembly has recently been shown to require the intermediate filament vimentin, which may act as a scaffold on which inflammasome components can converge.²⁸ Two signals are required for inflammasome activation, including a priming signal that induces production of the precursor cytokines pro–IL-1β and pro– IL-18 via the transcription factor NF-κB and a second signal that leads to inflammasome assembly and cleavage of these precursors to their mature forms. In the case of IAV infection, the first signal is thought to occur through TLR3 or TLR7 recognition of the virus, leading to NF-κB activation and production of pro–IL-1β and pro–IL-18. The second signal appears to result from changes in the intracellular ionic concentrations detected by NLRP3, although other indicators of cellular stress have been implicated in inflammasome assembly, including reactive oxygen species, potassium flux, and lysosomal rupture.²⁹ The influenza virus proton channel, M2, has been shown to be sufficient and necessary to induce inflammasome activation and release of mature IL-1β and IL-18.³⁰ Recently, the IAV protein polymerase B1-F2 (which was a key virulence factor during the 1918 pandemic) was also shown to activate the NLRP3 inflammasome.³¹

The NLRP3 inflammasome is necessary for survival in lethal mouse models of IAV infection.^32–34 Loss of NLRP3, ASC, or caspase 1 in mice leads to decreased IL-1β and IL-18 secretion and increases mortality from IAV. In sublethal models, NLRP3 may be dispensable for survival.³² Absence of the IL-1 receptor significantly decreases survival after IAV infection.³⁵ Alternatively, excessive inflammasome activation may also contribute to immunopathologic changes seen in lethal IAV infection.³¹ Therefore, inflammasome signaling must be tightly controlled to promote eradication of the virus while limiting collateral damage to the host.

Developmental Dependent Changes in PRR Signaling

Of the PRR families, the TLRs are the best studied, and their maturation throughout the first years of life are the best characterized. Many investigators have shown equal amounts of TLR expression in children and adults as well as an ability in children to upregulate TLRs in response to infection.^36–39 However, the downstream effects of TLR activation appear to differ by age (Table).⁴⁰ Possibly important for IAV infection are the observations that young children may produce large amounts of IL-6²¹ and IL-10^18,40 in response to TLR stimulation and decreased amounts of IL-12,²¹ type I IFNs,⁴¹ and IFN-γ.²¹ How these differences in cytokine production may influence IAV pathogenesis in children is discussed below in the Age-Dependent Differences in Susceptibility to IAV subsection.

Table.

Relative Cytokine Response to Pattern Recognition Receptor (PRR) Activation in Children Compared With Adults^a

PRR Agonist	Age, mo	IL-6	IL-10	IL-12 (p70)	IL-23	IL-1β	IFN-γ	IFN-α	Source
TLR3
Poly I:C	0		↑	↓					Belderbos et al,18 2009
	1		↑	=
	0						↓↓		Burl et al,19 2011
	0	=	=	↓↓↓		=	↓↓↓	↓	Corbett et al,21 2010
	12	=	=	↓↓↓		=	↓↓↓	↓↓
	24	=	=	↓↓		=	↓↓↓	↓↓↓
	0	↑	↑	↓			↓		Kollman et al,20 2009
TLR7
Loxoribine	0		=					↓↓	Belderbos et al,18 2009
	1		↑					=
Guardiquimod	0	=	=			↓↓	↓↓		Burl et al,19 2011
	1	↑	↑↑				↓
	12	↑↑	↑				↓
TLR 7/8
3M-003	0	=	↑↑↑	↓↓↓	↑↑↑	=	↓↓	↓	Corbett et al,21 2010
	12	↓↓	↑↑	↓↓↓	↑	↓↓↓	↓↓↓	↑
	24	↓↓↓	=	↓↓↓	=	↓↓↓	↓↓↓	=
	0	↑	↑	↓	↑	↑	↓	↓	Kollman et al,20 2009

Abbreviations: IFN, interferon; IL, interleukin; Poly I:C, polyinosinic-polycytidylic acid; TLR, Toll-like receptor.

^aArrows indicate cytokine levels after PRR activation. ↓ Indicates decreased; ↓↓, moderately decreased; ↓↓↓, greatly decreased; ↑, increased; ↑↑, moderately increased; ↑↑↑, greatly increased; and =, similar levels between children and adults. Empty cells indicate no testing.

Little is known about the ontogeny of the NLR response and even less about changes in RIG-like receptor (RLR) signaling over time. A study⁴² of NLRP3 inflammasome stimulation in whole blood from children in Papua New Guinea showed that IL-1β production was highest in infants younger than 3 months and steadily decreased until 10 months of age. Interleukin 1β has been shown to be elevated in pediatric patients with severe influenza, but so has its antagonist.^43,44 In addition, IL-1 receptor antagonist polymorphisms have been associated with severe community-acquired pneumonia in children.⁴⁵ How inflammasome activation and RLR signaling differ between children and adults is unknown and represents an important area of future investigation.

Age-Dependent Differences in Susceptibility to IAV

A few studies have attempted to investigate the apparent vulnerability of young children to IAV infection. Increased mortality has been replicated in juvenile mice,^6,7 but the mechanism of this age-dependent susceptibility is unclear. A major outstanding question is whether such pathologic conditions seen in young animals and children are secondary to enhanced viral replication, impaired viral clearance, excessive inflammation, or increased susceptibility to secondary bacterial infections.

Viral Replication and Clearance

Alterations in the kinetics of viral replication and clearance have been shown in animal models of juvenile IAV infection. Compared with primary airway epithelial cells from adult rhesus monkeys, those from infant animals demonstrated increased viral replication and decreased secretion of IFN-α, a type I IFN important for host defense against viruses because of its ability to interrupt the viral replication cycle.⁴⁶ In addition, IFN-α was absent from bronchoalveolar lavage fluid (BALF) of IAV-infected infant monkeys. Although BALF was not collected from IAV-infected adult animals for comparison, these results led the authors to speculate that impaired IFN-α production in the infants permitted increased viral replication and contributed to excess IAV-induced morbidity in this age group. Consistent with this hypothesis, increased viral titers have been recovered from the lungs of IAV-infected juvenile mice compared with adult mice, which correlated with increased lung injury in the younger animals.⁶

The cytokine IL-12 may be important for controlling IAV replication, and limited production has been documented in children after PRR stimulation.^18,20,21 Neutralizing IL-12 in IAV-infected adult mice results in increased viral titers. In contrast, administration of IL-12 early in infection improves outcomes.⁴⁷ It remains unknown whether early IL-12 production is impaired in IAV-infected infants and whether decreased IL-12 alters the course of infection in children.

Another key signaling molecule involved in viral containment and clearance is IFN-γ. It is primarily secreted by natural killer (NK) cells and T cells but can also be produced by macrophages and DCs.^48,49 It has direct antiviral activity and promotes the cytotoxic activity of macrophages and T cells.⁵⁰ Neonatal mice infected with IAV produced less IFN-γcomparedwith adults, which correlated with fewer CD8⁺ cytotoxic T cells in neonatal lungs.⁵¹ This finding may be an example of how the unique characteristics of the pediatric innate immune response early in IAV infection may modify the adaptive immune response. Consistent with these findings in mice, an autopsy study⁵² of lung tissues from human infants with fatal IAV infection found diffuse staining for viral antigen but near absence of cytotoxic T cells, suggesting that impairment in viral clearance contributed to mortality. Additional evidence correlating IFN-γ production with viral illnesses in young children is from a study⁵³ of ex vivo umbilical cord blood (UCB) mononuclear cell function. Decreased IFN-γ production by UCB mononuclear cells in response to phytohemagluttin stimulation was associated with increased severity of viral infections throughout the first year of life. Vigorous IFN-γ secretion correlated with fewer viral infections for the same period.

In addition, NK cells are important for limiting viral replication and promoting viral clearance through lysis of infected cells. Equal activation of UCB NK cells by IAV has been demonstrated, but decreased perforin expression and increased apoptosis were seen.⁵⁴ The authors speculated that the resulting decrease in functional NK cells increases the susceptibility of newborns to IAV. In another study,⁵⁵ birth weight influenced cytokine production by UCB NK cells. The UCB NK cells from smaller infants produced less IFN-γ and TNF. In addition, UCB DCs have been infected with IAV.⁵⁶ Although decreased upregulation of DC activation markers in response to IAV was seen, UCB DCs were not more susceptible to apoptosis than adult DCs and produced equal amounts of proinflammatory cytokines; however, they produced less IFN-α. Because DCs are an important source of antiviral IFNs during IAV infection, if this deficit also occurs in naturally occurring IAV infection in newborns, it could lead to increased virus burden and contribute to the susceptibility of young infants to IAV.

An alternative explanation for increased viral replication in these animal and ex vivo models of pediatric IAV infection could be successful viral evasion of the immune response. To replicate successfully and establish widespread infection, IAV has developed multiple strategies to combat recognition by the innate and adaptive immune systems.¹² To our knowledge, the effectiveness of viral evasion strategies is not known to differ between children and adults, but it has not been carefully explored and may deserve further investigation.

Excessive Inflammation

There is now contrasting evidence challenging the conclusions that children have a deficient inflammatory response, an impaired type I IFN response, and an inability to limit IAV replication. Instead, evidence is emerging regarding a pathologic role for an excessive inflammatory response to IAV in children. Multiple studies^44,57,58 have correlated elevations in the proinflammatory cytokine IL-6 with the severity of symptoms in pediatric patients, and the IL-6 antagonist tociluzimab was incidentally seen to decrease the duration of symptoms during IAV infection.⁵⁹ Increased IL-6 was associated with more severe lung injury and death in a ferret model of IAV infection.⁶⁰ However, complete absence of IL-6 may be harmful, with IL-6 knockout mice having increased viral titers and less likelihood of survival following IAV infection.^61,62

A recent prospective study⁵⁸ of natural IAV infection also challenges the hypothesis that an impaired innate immune response to IAV is responsible for increased severity of illness in children. In that study, viral load was equal between children and adults and did not correlate with clinical outcomes. In addition, the presence of neutralizing antibodies was not predicted by age nor did it correlate with cytokine secretion. Infants and young children had significantly higher levels of inflammatory nasal cytokines and type I IFNs than adults. These findings are consistent with a recent study⁶³ that correlated excessive type I IFN production with immunopathologic changes during IAV infection in mice. Disease severity in children was predicted by the presence of a mix of inflammatory and anti-inflammatory proteins (elevated IFN-α 2, monocyte chemotactic protein 3, and IL-10).⁵⁸ Based on their findings, the authors concluded that children have an immunologic predisposition to enhanced inflammation during IAV infection and not an inability to control viral replication. They proposed that this inflammation is responsible for the morbidity seen in this population.

Relative Immunosuppression and Secondary Bacterial Infection

The elevated level of nasal IL-10 seen in natural IAV infection in children is consistent with a body of literature exploring PRR responses in young children that demonstrates robust IL-10 production by peripheral blood mononuclear cells in response to PRR stimulation (Table). Classically, IL-10 is regarded as a regulatory cytokine, with a role in immune tolerance and limiting infection-associated immunopathologic conditions. Evidence suggests that the IL-10–mediated downregulation of inflammation may have deleterious effects in early IAV infection by lessening the efficacy of the helper T-cell subtype 1 (T_H1) immune response needed to combat infection.⁶⁴ In a mouse model, IL-10 deficiency was associated with increased influenza-specific antibody titers in BALF, improved viral clearance, and longer survival compared with wild-type mice.⁶⁵ The authors proposed that IL-10 diminishes the CD4⁺ T-cell response that is crucial for production of virus-specific antibodies, thus inhibiting viral clearance. There was no appreciable difference in the extent of pulmonary inflammation on histologic examination after IAV infection between the 2 groups, suggesting that a lack of IL-10 does not significantly increase lung inflammation. Compatible with these findings, the addition of supplemental IL-10 to wild-typemice in early influenza resulted in increased mortality.⁶⁶ This evidence suggests that infants with a dominant primary IL-10 response may be at risk for worse outcomes after IAV infection.

In addition to preventing an effective T_H1 response to IAV, elevated IL-10 may contribute to immunoparalysis after IAV infection and increase the susceptibility to secondary bacterial infections. Children who did not survive influenza A (H1N1) virus infection had increases in the inflammatory proteins IL-6, IL-8, IFN-inducible protein 10, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1α.⁴⁴ However, there were also increases in the anti-inflammatory proteins IL-1 receptor antagonistandIL-10 in these non-survivors, but this trend did not reach significance. In addition, ex vivo TNF secretion from macrophages was significantly depressed. The authors speculated that this relative immunosuppression left children susceptible to secondary bacterial infection and contributed to mortality in their cohort. Data are limited on the incidence of bacterial pneumonia in pediatric IAV infection, but bacterial coinfection has been reported in 43% to 75% of fatal cases^44,67 and is likely an important contributor to IAV-induced morbidity and mortality.

Conclusions

Healthy children develop severe IAV infection at a rate that is out of proportion to that of their adult counterparts. This epidemiologic observation may be related to age-dependent changes in the innate immune response to pathogen detection. The consequence of developmental differences in PRR signaling during IAV infection may manifest as impaired viral clearance, excessive inflammation, increased susceptibility to secondary infection, or a combination of these factors. The most consistent finding in the literature to date is that young children produce decreased amounts of the cytokines IL-12 and IFN-γ, increased amounts of IL-6 and IL-1β,andgreater amounts of the anti-inflammatory cytokine IL-10 (Figure 2).⁴¹ Data are contradictory regarding the role of type I IFNs in pediatric susceptibility to severe IAV infection. Although animal models have suggested impaired viral clearance in the young host, emerging data in humans suggest that a pathologic role of the host inflammatory response, and not unchecked viral replication, may be responsible for the severity of disease in children. In addition, a subsequent anti-inflammatory response may predispose the young host to secondary bacterial infection and contribute to mortality. Defining the relative contributions of (1) a child’s ability to control IAV replication, (2) the tendency to produce excessive inflammation, and (3) a predisposition to a state of relative immunosuppression will be important in developing innovative therapies to support children with severe IAV infection. Because infections are the primary cause of death in children worldwide, elucidation of the details of innate immune system development will aid in establishing strategies to protect this vulnerable population and tailor therapeutics.

At a Glance.

• Influenza A virus can cause life-threatening disease in otherwise healthy children.

• The innate immune response to infection changes throughout childhood and may predispose children to severe influenza infection.

• Excessive inflammation, and not unchecked viral replication, likely contributes to severe influenza infection in children.

• A compensatory anti-inflammatory response may then predispose to secondary bacterial infections.

• Because children and adults appear to respond to influenza infection differently, the development of therapies specific for children is necessary.

• Better understanding of the susceptibility of young children to influenza will be essential to developing targeted therapies to protect this vulnerable population.