Table 2.

Mechanisms and mediators of influenza–bacterial interactions

	Main infection vs bacterial co-infection	Effect during co-infection	Known phenotypic or disease effect	Mechanism or cytokine effect	Notes
Structural alterations or surface protein expression
Epithelial desquamation35,37–39,40	Increased	Increases bacterial adherence at sites of desquamation and tissue regeneration	Increases carriage density, duration, and sinusitis Primes for increased acquisition Increases pneumonia	Exposes basement membrane components, fibrinogen, hyaline, and other extracellular matrix proteins for bacterial binding	··
Platelet-activating factor receptor (PAFr)35,41–43	Upregulated on activated epithelial and endothelial cells	Increases bacterial adherence, replication, and invasion Helps excess macrophage or neutrophil recruitment Reduces bacterial lung titres Increases bloodstream invasion	Increases carriage density and duration Primes for increased acquisition Increases pneumonia Increases bacteraemia Reduces pneumonia Reduces mortality Increases bacteraemia	Binds phosphorylcholine embedded in bacterial cell walls (ie, ChoP) Enhances TNF-α, IL-6, and KC expression Reduces TNF-α, IL-1β, IL-6, KC, and MIP-1a Helps bacterial traversal of epithelial and endothelial layers to enter bloodstream	High viral doses Unencapsulated bacteria Infection 7 days after virus Low viral doses Encapsulated bacteria Infection 14 days after virus PAFr not needed for secondary pneumonia but possibly for bacteraemia
Polymeric immunoglobulin receptor (pIgR) 44,45,46	Upregulated on epithelial cells of mucosal surfaces	Increases bacterial adherence to epithelial cells Enables transcytosis of epithelial barriers	Synergistic increase in bacterial carriage density Increases pneumonia and bacteraemia Increased mortality	Influenza-mediated interferon γ production increases expression of pIgR pIgR binds choline binding proteins on bacterial surface (eg, PspA and cbpA) Binding increases adherence and facilitates epithelial transcytosis	pIgR facilitiates transcellular transport of IgA and IgM across the epithelial or mucosal layers. Bacteria exploit this function to move across the barriers of mucosal tissue
Ciliary beat frequency and coordination47,48	Reduced	Reduces bacterial clearance from respiratory tract	Increases bacterial carriage density Increases pneumonia Increased mortality	Viral haemagglutinin inhibits Caz+/Na+ channels via phospholipase C and proteinase kinase C activation	··
Innate immune cytokines, signalling, and systemic responses
Type I interferon (interferon α and interferon β)21,49,50–53	Synergistic increase	Reduces bacterial clearance mediated by monocytes, macrophages, and neutrophils from the nasopharynx and lungs	Increases bacterial carriage density and duration Enhances bacterial pneumonia and mortality Development of immunopathology	Excess type I interferon signalling through IFNAR inhibits: Nod2/CCl2 recruitment of monocytes/ macrophage to URT KC and MIP-2 in lungs, needed for neutrophil recruitment Th-17 polarisation and expression of IL-17, IL-22, IL-23, IL-1β, and MCP-1 needed for clearance mediated by Th-17 and macrophages γδT–cell production of IL-17 Induces granulocyte apoptosis in bone marrow	Excess type I interferon probably shuts down multiple antibacterial innate defences to prevent host-tissue injury Distinct URT and LRT effects show that there are clear anatomical differences in immune mechanisms
Type II interferon (interferon γ)34,54	Synergistic increase	Reduces alveolar macrophage phagocytosis Increases pIgR-mediated bacterial adherence (see pIgR above)	Enhances bacterial lung titres Increased pneumonia mortality Increases bacterial colonisation	Induced by excess IL-12 Blunts beneficial pro-inflammatory cytokine secretion from macrophages Increases levels of oxidative radicals in macrophages Reduces MARCO expression on surface of AMs required for proper bacterial detection and phagocytosis	Excess IL-12 mediated by interferon γ could be beneficial during primary bacterial infection55 Excess interferon γ might be downstream of increased type I interferon response (known to increase production of IL-12p70 from dendritic cells56)
IL-1254–56	Increased	Increases type II interferon	Increases bacterial lung titres Increased pneumonia mortality	Similar to effects with type II interferon	Similar to effects with type II interferon
IL-1057,58	Increased	Inhibits appropriate inflammatory response Inhibits neutrophil recruitment to lungs	Enhances bacterial lung titres Increased pneumonia mortality	Possible induction by excess indoleamine 2,3-dioxygenase Inhibition of neutrophil recruitment and activity, which prevents early neutrophil- mediated bacterial clearance	Could also increase interferon γ58 with similar effects as noted for type II interferon
TLR signalling59	Reduced	Prevents initiation of appropriate cytokine and cellular response pathways for bacterial clearance	Increased bacterial lung titres and mortality	Sustained desensitisation of TLR-2, TLR-4, and TLR-5 to bacterial ligands reduces monocyte and macrophage recruitment to lungs Blunts TLR activation of NF-κB in alveolar macrophages (required for expression of KC-mediated and MIP-2-mediated neutrophil recruitment to lungs) Possibly due to increased immunosuppressive activity of alternatively activated macrophages (see AAM below in this table)	Might last as long as 6 months after influenza infection TLR desensitisation might be crucial to reduce excess immunopathology60
Glucocorticoids61	Increased during systemic bacterial co-infection	Overall immune suppression Prevention of bacterial clearance	Increased systemic bacterial titres Reduce overall mortality from systemic bacterial infections	Generalised suppression of innate and adaptive immune mechanisms Reduce neutrophil, macrophage, and adaptive responses for bacterial clearance Reduce excess inflammation and prevent immunopathological reactions	Substantial immunopathological role as a main cause of death during post-influenza bacterial secondary infections
Cellular innate immunity
Alveolar macrophage	Reduced activity	Inefficient bacterial phagocytosis	Increased bacterial lung titres Increased pneumonia mortality	Excess interferon γ production reduces MARCO expression on AM macrophage cell surface that is needed for clearance of many lung pathogens	Similar effects to type II interferon, and alveolar macrophage apoptosis
Alternatively activated macrophage (AAM)62	Increased	Abrogates proper bacterial clearance by classic activated macrophages	Increases bacterial lung titres Increases pneumonia mortality	AAMs produce arginase-1, which competes with bactericidal effects of iNOS produced by classic-activated macrophages Might inhibit TLR-signalling or increase CD200-CD200R ligation	Excess AAM could last for weeks in the lungs after influenza infection, which is important for tissue remodelling, homoeostasis, and injury repair
Reduced neutrophils31,35,41,49,53,54,57,59,63,64	Reduced	Increased bacterial replication because of reduced neutrophil function	Increased bacterial lung titres Increased pneumonia mortality Excess immunopathological reactions	Excess type I interferon reduces KC and MIP-2 expression and neutrophil recruitment	When secondary infection occurs <4 days after viral infection
Increased neutrophils31,35,41,49,53,54,57,59,63,64	Increased	Excess neutrophils lead to inflammation and immunopathology	Increased bacterial lung titres Increased pneumonia mortality Excess immunopathology	Excess IL-10 expression reduces neutrophil bactericidal function (ROS generation) Retains immunopathological responses Excess KC and MIP-2 secretion recruit mixed pool of mature and immature neutrophils	When secondary infection occurs >4 days after viral infection
Neutrophil extracellular traps (NETs or NETosis)33,65	Increased	Reduced bacterial clearance and increased immunopathology	Increased bacterial acute otitis media Increased bacterial pneumonia	Bacterial Abs increase production of NETs Bacterial endonucleases degrade NETs NET degradation induce endothelial damage, sepsis, small vessel vasculitis, and alveolar capillary damage Excess immunopathological reactions	Direct injection of DNAse into middle ear to decrease NETosis reduced bacterial replication, which suggests therapeutic potential
Alveolar macrophage apoptosis66,67	Increased	Reduces alveolar macrophage-mediated clearance and increases immunopathological reactions	Increased bacterial pneumonia Increased immunopathological reactions	Increased AM FADD expression increases caspase-3 and caspase-8 >90% AM apoptosis Increases severe lung inflammation and damage	··
Systemic mechanisms
Tolerance to tissue damage68,69	Reduced	No effect on bacterial titres or infection	Increases severe disease and mortality	Substantial loss of epithelial tissue regeneration Reduced ability to cope with severe tissue damage during secondary infection	Particularly important for systemic bacterial infections 3–6 days after influenza infection
Hyperthermia and stress response70,71	Increased	Increases bacterial invasion and dissemination to lungs	Increases bacterial carriage density Increased acute otitis media Increased pneumonia Increased bacteraemia	Hyperthermia increases expression of bacterial virulence genes Increases bacterial dissemination from biofilms Stress response increases host glucose and ATP production (helps bacterial replication and invasion)	··

ChoP=phosphorylcholine. TNF-α=tumour necrosis factor-α. IL=interleukin. KC=keratinocyte chemoattractant CXCL1. MIP=macrophage inflammatory protein CXCL2. PspA=pneumococcal surface protein A. cbpA=choline-binding protein A. IFNAR=type I interferon receptor. Nod2=nucleotide-binding, oligomerisation domain-containing protein 2. CC=chemokine. URT=upper respiratory tract. AM=alveolar macrophage. Th=T helper. MCP-1=monocyte chemoattractant protein I. TLR=toll-like receptor. LRT=lower respiratory tract. MARCO=macrophage receptor with collagenous structure. iNOS=inducible nitric oxide synthase. Abs=antibodies. FADD=fas-associated protein with death domain. ROS=reactive oxygen species.