The innate host response system is composed of various mechanisms designed to detect and facilitate host responses to microbial components, such as lipopolysaccharides (LPS). To enable this to occur, innate systems contain multiple pattern recognition receptors (i.e., LBP, CD14, and TLRs), which identify certain features within bacterial LPS that are foreign to the host, as well as essential and uniquely specific for bacteria. Innate host identification of unique bacterial components or patterns, therefore, relies on the inability of bacteria to alter these essential or critical components dramatically. Historically, LPS have been viewed as essential outer-membrane molecules containing both a highly variable outer region (O-segment) as well as a relatively conserved inner region (lipid A). However, over the last decade, new evidence has emerged, revealing that increased natural diversity or heterogeneity within specific components of LPS, such as lipid A-resulting in minor to moderate changes in lipid A structure-can produce dramatic host responses. Therefore, examples of natural lipid A heterogeneity, and the mechanisms that control it, represent a novel approach in which bacteria modulate host responses and may thereby confer specific advantages to certain bacterial species under changing environmental host conditions.

SummaryPorphyromonas gingivalis is a Gram-negative bacterium strongly associated with periodontitis, a chronic inflammatory disease of the tissue surrounding the tooth root surface. Lipopolysaccharide (LPS) obtained from P. gingivalis is unusual in that it has been shown to display an unusual amount of lipid A heterogeneity containing both tetra-and penta-acylated lipid A structures. In this report, it is shown that penta-acylated lipid A structures facilitate E-selectin expression whereas tetra-acylated lipid A structures do not. Furthermore, it is shown that tetra-acylated lipid A structures are potent antagonists for E-selectin expression. Both tetra-and penta-acylated lipid A structures interact with TLR4 although experiments utilizing human, mouse and human/mouse chimeric TLR4 proteins demonstrated that they interact differentially with the TLR4 signalling complexes. The presence of two different structural types of lipid A in P. gingivalis LPS, with opposing effects on the Eselectin response suggests that this organism is able to modulate innate host responses by alterations in the relative amount of these lipid A structures.

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Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain1,2. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment3,4. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (Treg) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1+ Treg cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1− Treg cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.