Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including: Staphylococcal abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast, S. aureus intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against S. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.
BackgroundIdentification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants.ResultsWith weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively. The more significant associations with phase led us to use a phase-based framework for the majority of our analyses. Phase transitions were characterized by rapid shifts in the microbiota, with transition out of P1 occurring nearly simultaneously with the change from meconium to normal stool. The rate of phase progression was positively associated with gestational age at birth, and delayed transition to a P3 microbiota was associated with growth failure. We found distinct bacterial metabolic functions in P1–3 and significant associations between nutrition, microbiota phase, and infant growth.ConclusionThe phase-dependent impact of nutrition on infant growth along with phase-specific metabolic functions suggests a pioneering potential for improving growth outcomes by tailoring nutrient intake to microbiota phase.Electronic supplementary materialThe online version of this article (10.1186/s40168-017-0377-0) contains supplementary material, which is available to authorized users.
Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8 − /CD4 − iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)α rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system.
Candida albicans is an opportunistic fungal organism frequently detected in the oral cavity of children with severe early childhood caries (S-ECC). Previous studies suggested the cariogenic potential of C. albicans, in vitro and in vivo, and further demonstrated its synergistic interactions with Streptococcus mutans. In combination, the 2 organisms are associated with higher caries severity in a rodent model. However, it remains unknown whether C. albicans influences the composition and diversity of the entire oral bacterial community to promote S-ECC onset. With 16s rRNA amplicon sequencing, this study analyzed the microbiota of saliva and supragingival plaque from 39 children (21 S-ECC and 18 caries-free [CF]) and 33 mothers (17 S-ECC and 16 CF). The results revealed that the presence of oral C. albicans is associated with a highly acidogenic and acid-tolerant bacterial community in S-ECC, with an increased abundance of plaque Streptococcus (particularly S. mutans) and certain Lactobacillus/Scardovia species and salivary/plaque Veillonella and Prevotella, as well as decreased levels of salivary/plaque Actinomyces. Concurrent with this microbial community assembly, the activity of glucosyltransferases (cariogenic virulence factors secreted by S. mutans) in plaque was significantly elevated when C. albicans was present. Moreover, the oral microbial community composition and diversity differed significantly by disease group (CF vs. S-ECC) and sample source (saliva vs. plaque). Children and mothers within the CF and S-ECC groups shared microbiota composition and diversity, suggesting a strong maternal influence on children's oral microbiota. Altogether, this study underscores the importance of C. albicans in association with the oral bacteriome in the context of S-ECC etiopathogenesis. Further longitudinal studies are warranted to examine how fungal-bacterial interactions modulate the onset and severity of S-ECC, potentially leading to novel anticaries treatments that address fungal contributions.
Staphylococcus aureus infection of bone is challenging to treat because it colonizes the osteocyte lacuno-canalicular network (OLCN) of cortical bone. To elucidate factors involved in OLCN invasion and identify novel drug targets, we completed a hypothesis-driven screen of 24 S. aureus transposon insertion mutant strains for their ability to propagate through 0.5 μm-sized pores in the Microfluidic Silicon Membrane Canalicular Arrays (μSiM-CA), developed to model S. aureus invasion of the OLCN. This screen identified the uncanonical S. aureus transpeptidase, penicillin binding protein 4 (PBP4), as a necessary gene for S. aureus deformation and propagation through nanopores. In vivo studies revealed that Δpbp4 infected tibiae treated with vancomycin showed a significant 12-fold reduction in bacterial load compared to WT infected tibiae treated with vancomycin (p<0.05). Additionally, Δpbp4 infected tibiae displayed a remarkable decrease in pathogenic bone-loss at the implant site with and without vancomycin therapy. Most importantly, Δpbp4 S. aureus failed to invade and colonize the OLCN despite high bacterial loads on the implant and in adjacent tissues. Together, these results demonstrate that PBP4 is required for S. aureus colonization of the OLCN and suggest that inhibitors may be synergistic with standard of care antibiotics ineffective against bacteria within the OLCN.
Cocolonization of human mucosal surfaces causes frequent encounters between various staphylococcal species, creating opportunities for the horizontal acquisition of mobile genetic elements. The majority of Staphylococcus aureus toxins and virulence factors are encoded on S. aureus pathogenicity islands (SaPIs). Horizontal movement of SaPIs between S. aureus strains plays a role in the evolution of virulent clinical isolates. Although there have been reports of the production of toxic shock syndrome toxin 1 (TSST-1), enterotoxin, and other superantigens by coagulase-negative staphylococci, no associated pathogenicity islands have been found in the genome of Staphylococcus epidermidis, a generally less virulent relative of S. aureus. We show here the first evidence of a composite S. epidermidis pathogenicity island (SePI), the product of multiple insertions in the genome of a clinical isolate. The taxonomic placement of S. epidermidis strain FRI909 was confirmed by a number of biochemical tests and multilocus sequence typing. The genome sequence of this strain was analyzed for other unique gene clusters and their locations. This pathogenicity island encodes and expresses staphylococcal enterotoxin C3 (SEC3) and staphylococcal enterotoxin-like toxin L (SElL), as confirmed by quantitative reverse transcription-PCR (qRT-PCR) and immunoblotting. We present here an initial characterization of this novel pathogenicity island, and we establish that it is stable, expresses enterotoxins, and is not obviously transmissible by phage transduction. We also describe the genome sequence, excision, replication, and packaging of a novel bacteriophage in S. epidermidis FRI909, as well as attempts to mobilize the SePI element by this phage.
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