Immunity during inflammation

Professor Tracy Hussell - Head of Group

Though influenza causes significant mortality as a single infection, in combination with a secondary bacterial pneumonia it is far more severe. It is now apparent that 4 to 14 days after resolution of influenza induced symptoms a recurrence of fever, dyspnea, productive cough, and pulmonary consolidation arises due to a bacterial super infection, most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae. Amongst the 40-50 million deaths during the 1918-19 influenza pandemic a large proportion had co-existing bacterial pneumonia. Clinical and animal model evidence proves that combined infections are worse. Fatalities in the 1957 influenza pandemic were higher in those with a co-existing respiratory bacterium. Furthermore, if the titre of influenza is reduced by vaccination or anti-virals then respiratory bacterial infection is also reduced. Enhanced susceptibility to bacteria during influenza infection arises due to epithelial barrier disruption by this cytopathic virus, an increase in bacterial adhesion molecules, apoptosis of anti-bacterial immune cells and a decreases in alveolar macrophage phagocytosis.

Through prior MRC funding we have advanced our understanding of this complex outcome in two key ways:

1. In the Journal of Experimental Medicine we showed that influenza causes a long term blunting of alveolar macrophage responses to bacterial toll-like receptor ligands and
2. In Nature Immunology we show that influenza causes an overshoot in the expression of the negative regulatory receptor, CD200 receptor, on alveolar macrophages. Influenza therefore dampens key airway innate immune pathways and raises the threshold above which secondary bacteria are recognised.

On the basis of our recent evidence, we hypothesise that influenza infection pre-disposes to secondary bacterial pneumonia/sepsis by modulating specific pathways of innate immunity. These same pathways dictate the density of nasopharyngeal and lung bacterial and fungal commensals and also the repertoire of anti-bacterial peptides in the same sites. We hypothesise that influenza alters the repertoire and density of both commensals and anti-peptides, which in some precipitates life threatening bacterial pneumonia and sepsis.

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Key questions currently being addressed include:

1. Which immune potentiator and inhibitory pathways control bacterial colonisation in the lower respiratory tract during influenza infection?
   Collaborators: Johnathon McCullers (St Judes USA), John Brundage (Armed Forces Health Surveillance Centre, USA), Dennis Shank (Australian Army Malaria Institute, Australia) and Neil Barclay (Oxford, UK), Steve Cobbold (Oxford, UK).
2. What dictates the spectrum and load of nasopharyngeal commensal bacteria in mice and how does an alteration of these by influenza or immune modulation lead to lower respiratory tract and systemic complications?
   Collaborators: Bill Cookson (Imperial, UK), David Perlin (UNDMJ, USA).
3. How does influenza alter the airway and nasopharyngeal anti-bacterial peptide repertoire in mice and are these modified or restored by therapeutic manipulation?
   Collaborators: Dr Agranoff (Imperial, UK), Dr Robin Wait (Imperial, UK).
4. Can our innate imprinting hypothesis (see below) explain the unusual distribution of fatalities during the 1918-19 influenza pandemic?
   Collaborators: John Brundage (Armed Forces Health Surveillance Centre, USA), Dennis Shank (Australian Army Malaria Institute, Australia)
5. What is the role of infection on other subsequent or concurrent diseases; for example autoimmunity.
   Collaborator: Professor Marc Feldmann (The Kennedy Institute, London)
6. How is immune homeostasis maintained in the uninfected repiratory tract and what is required for inflammatory resolution.
7. Can immune potentiator pathways be harnessed or negative regulators blocked to improve vaccine efficacy to serious respiratory tract infections?
   Collaborators: Professor Douglas Young (NIMR, London) and Dr Barry Walker (NIBSC, London).
8. Can TH1 inflammatory disease be manipulated by IL-33/?
   Collaborators: Professor Eddy Liew (University of Glasgow, UK). 

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The innate immune rheostat

Due to the dynamics of the airways we tend to focus our concepts on macrophages as they form 95% of cells in the naïve and inflammation-resolved airway. Our prior research shows that the resting phenotype of airway macrophages depends on the balance between negative regulatory pathways and those that amplify immunity. Furthermore, this balancing act is adaptable by prior inflammatory events meaning that we all respond differently to the same inflammatory stimuli. One key negative regulator is CD200R that transmits a suppressive signal to myeloid cells (amongst others). CD200R critically regulates airway macrophages on which it is expressed at unusually high levels that is maintained by epithelial expression/secretion of IL-10 and TGFb. Its ligand, CD200, is expressed on the luminal aspect of the airway epithelium and limits alveolar macrophage activity (Figure 1a).

Receptors that amplify airway macrophages are also present; for example, Toll-like receptors (TLRs) that recognize conserved structures on microorganisms. In the absence of inflammation at homeostasis airway macrophages are poised to respond but held in check by negative regulators such as CD200R. The balance between negative regulators and amplifiers of innate immunity can be likened to the electrical rheostat found in a light dimmer switch, which is adjusted to dim or brighten the light. Similarly, negative and positive innate immune pathways form a variable "innate immune rheostat" which we show is adjusted by present and past infectious experiences. The position of this "innate immune rheostat" is thus dictated by the environment the innate immune cell resides in. Alveolar macrophages will respond differently to splenic or lymph node macrophages to the same stimuli. This site specific difference in reactivity is necessary to prevent responses to innocuous antigens or commensal microorganisms. During influenza infection the respiratory epithelium becomes damaged leading to a loss of IL-10, TGFb and CD200. Inflammation proceeds with vigor and at the same time other innate amplifiers are upregulated including OX40L. Incoming T cells expressing OX40 bind to OX40L and amplify innate inflammation further (Figure 1b).

Resolution of inflammation is via the same pathways that initially maintained homeostasis. However, in some cases CD200R and IL-10 overshoot their original homeostatic level (Figure 1c). Furthermore, we have published a long term de-sensitisation of alveolar macrophages to TLR agonists following influenza infection. In resolution airway macrophages are therefore more constrained than they were before. We believe the position of this adjustable innate immune rheostat dictates whether bacterial super-infections occur in the lower airways and that these arise between stages B and C in Figure one and for a long time after.

Figure 1:

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Selected publications

Snelgrove RJ; Jackson PL; Hardison MT; Noerager BD; Kinloch A; Gaggar A; Shastry S; Rowe SM; et al. (1 Oct 2010). A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 330:90-94.

Didierlaurent A; Goulding J; Patel S; Snelgrove R; Low L; Bebien M; Lawrence T; van Rijt LS; et al. (18 Feb 2008). Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J Exp Med. 205:323-329.

Snelgrove RJ; Goulding J; Didierlaurent AM; Lyonga D; Vekaria S; Edwards L; Gwyer E; Sedgwick JD; et al. (Sep 2008). A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. NAT IMMUNOL. 9:1074-1083.

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