Pathogen recognition by nucleotide-binding oligomerization domain-like receptor (NLR) results in the formation of a macromolecular protein complex (inflammasome) that drives protective inflammatory responses in the host. It is thought that the number of inflammasome complexes forming in a cell is determined by the number of NLRs being activated, with each NLR initiating its own inflammasome assembly independent of one another; however, we show here that the important foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) simultaneously activates at least two NLRs, whereas only a single inflammasome complex is formed in a macrophage. Both nucleotide-binding domain and leucine-rich repeat caspase recruitment domain 4 and nucleotide-binding domain and leucine-rich repeat pyrin domain 3 are simultaneously present in the same inflammasome, where both NLRs are required to drive IL-1β processing within the Salmonella-infected cell and to regulate the bacterial burden in mice. Superresolution imaging of Salmonella-infected macrophages revealed a macromolecular complex with an outer ring of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain and an inner ring of NLRs, with active caspase effectors containing the pro-IL-1β substrate localized internal to the ring structure. Our data reveal the spatial localization of different components of the inflammasome and how different members of the NLR family cooperate to drive robust IL-1β processing during Salmonella infection.innate immunity | bacteria | caspase-1 | caspase-8 | ASC

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Staphylococci, in particular Staphylococcus aureus, are the predominant cause of bone infections worldwide. These infections are painful, debilitating and with the rise in antibiotic-resistant forms, increasingly difficult to treat. The growth in the number of prosthetic joint replacement procedures also provides new opportunities for these infections to take hold. Comprehending the mechanisms by which staphylococci interact with and damage bone is critical to the development of new approaches to meet this challenge. This review summarises current understanding of the mechanisms by which staphylococci infect and damage bone. We address the role of the inflammatory response to staphylococcal infection in disrupting the homeostatic balance of bone matrix deposition and resorption and thereby mediating bone destruction. A number of virulence factors that have been shown to contribute to bone infection and pathology are discussed, however no single factor has been defined as being specific to bone infections. Although traditionally considered an extracellular pathogen, there is increasing evidence that staphylococci are able to invade host cells, and that an intracellular lifestyle may facilitate long-term persistence in bone tissue, enabling evasion of antimicrobials and host immune responses. ‘Small colony variant’ strains, with mutations disabling the electron transport pathway appear particularly adept at invading and persisting within host cells, and exhibit enhanced antimicrobial resistance, and may represent a further complication in the treatment and management of staphylococcal bone disease.

Whole genome DNA microarrays were constructed and used to investigate genomic diversity in 18 Campylobacter jejuni strains from diverse sources. New algorithms were developed that dynamically determine the boundary between the conserved and variable genes. Seven hypervariable plasticity regions (PR) were identi¢ed in the genome (PR1 to PR7) containing 136 genes (50%) of the variable gene pool. When comparisons were made with the sequenced strain NCTC11168, the number of absent or divergent genes ranged from 2.6% (40 genes) to 10.2% (163) and in total 16.3% (269) of the genes were variable. PR1 contains genes important in the utilisation of alternative electron acceptors for respiration and may confer a selective advantage to strains in restricted oxygen environments. PR2, 3 and 7 contain many outer membrane and periplasmic proteins and hypothetical proteins of unknown function that might be linked to phenotypic variation and adaptation to di¡er-ent ecological niches. PR4, 5 and 6 contain genes involved in the production and modi¢cation of antigenic surface structures. ß