Ellis, GT; (2014) The immune response in Influenza A-S. pneumoniae coinfection. Doctoral thesis , UCL (University College London).

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Abstract

Streptococcus pneumoniae coinfection is a major cause of influenza-associated mortality. In this thesis the underlying disease mechanisms and the role of the immune response are investigated in a mouse model. Coinfection with otherwise mild influenza and S. pneumoniae strains is shown to synergistically cause mortality and severe disease. Loss of bacterial but not viral control, and subsequent outgrowth, is identified as the main driver of mortality. Influenza-mediated immune impairment and lung damage have been proposed as mechanisms of coinfection. Here the aspects of the immune response profiled are not impaired; in contrast, coinfection induces a strong proinflammatory cytokine response and an influx of functional neutrophils. Depletion of neutrophils or TNF-α blockade exacerbates disease and bacterial outgrowth, showing these aspects of the immune response are protective. In addition to profiling the downstream response to bacterial outgrowth, the upstream causes of bacterial colonization are investigated. CCR2-/- mice are shown to be more resistant to coinfection. Influenza-infected CCR2-/- lungs lack inflammatory monocytes and exhibit reduced damage prior to coinfection. How inflammatory monocyte derived damage is mediated is investigated. Blockade of TRAIL - a cell-death inducing ligand - during the viral phase prior to coinfection ameliorates disease. Inflammatory monocytes are shown to comprise the majority of TRAIL-expressing cells during influenza infection, and TRAIL expression is largely absent in CCR2-/- mice. Therefore a mechanism is proposed for coinfection where influenza-induced TRAIL-expressing inflammatory monocytes cause lung damage, allowing bacterial colonization, while neutrophils and TNF-α counter subsequent bacterial outgrowth. Other aspects of coinfection, such as bacterial spread to the brain and other facets of the immune response, are also investigated.

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