Introduction and Objectives Streptococcus pneumoniae is the commonest cause of pneumonia and associated with marked inflammatory responses that underpin its immunopathogenesis. Surprisingly little is known about the molecular determinants of host–pathogen interactions that mediate these responses. We have studied the role of the pneumococcal capsule and surface lipoproteins in innate immune responses by macrophages that comprise the first line of cellular immune defence within the lung.

Methods Human macrophage responses to wild type S pneumoniae (TIGR4) and isogenic mutant strains deficient in capsule (P1672) or surface lipoproteins (Δlgt) were investigated at the level of intracellular signalling, genome-wide transcriptional profiling and at protein level by cytokine ELISA.

Results Unencapsulated bacteria invoked greater activation of the classical NFkB pathway, suggesting that the capsule may serve to inhibit some innate immune host pathogen interactions. In contrast, the Δlgt strain showed attenuated activation of NFkB, suggesting that lipoproteins are important ligands for innate immune recognition of pneumococci. Transcriptional responses to both unencapsulated and Δlgt strains showed marked differences to wild type pneumococci. However, quantitatively, major gene expression changes were preserved in the mutant strains. Despite the divergent effects on NFkB activation, both unencapsulated and Δlgt strains showed attenuated responses amongst these genes, although some key responses such as upregulation of TNFα were equivalent in all strains. Transcription factor enrichment analysis was conducted for the list of genes up-regulated by each strain to obtain new insight into the different pathways by which pneumococci may activate inflammatory responses. As expected, genes up-regulated by the wild type strain were enriched only for the NFkB family. In keeping with the signalling data, the Δlgt strain was not enriched for NFkB but only the PPARγ-RXR transactivator, and the unencapsulated strain was highly enriched for NFkB and a raft of other transcription factors.

Conclusion Pneumococcal capsule and lipoproteins are important determinants of inflammatory responses to pneumococci. Our data suggest that the capsule inhibits multiple innate immune signalling pathways and that lipoproteins are critically important for activation of the canonical NFkB pathway. TNFα responses are independent of capsule and lipoproteins.