Project description:Drug discovery for novel anti-infectives is essential to meet the global health threat of antibiotic resistant bacterial infections, including those caused by Staphylococcus aureus1,2. Because ~90% of S. aureus infections involve skin and soft tissues (SSTIs)3,4, we hypothesized that developing anti-virulence therapeutics5,6 for SSTIs could minimize pressure on resistance development while sparing conventional antibiotics for control of systemic infections. We identified a small molecule inhibitor that disrupted signaling by a quorum sensing operon, agr, associated with human SSTIs7,8 without affecting agr-independent growth.
Project description:Streptococcus pyogenes (Group A Streptococcus: GAS) is a major human pathogen that causes streptococcal pharyngitis, skin and soft-tissue infections, and life-threatening conditions such as streptococcal toxic shock syndrome (STSS). A large number of virulence-related genes are encoded on GAS genomes, which are involved in host-pathogen interaction, colonization, immune invasion, and long-term survival within hosts, causing the diverse symptoms. Here, we investigated the interaction between GAS-derived extracellular vesicles and host cells in order to reveal pathogenicity mechanisms induced by GAS infection.
Project description:CS Baby Biome randomized control trial aims to investigate if the timing of intrapartum antibiotics given to mother influences the infant gut microbiome composition. The study was performed in women delivering via elective CS, who received antibiotics prior to skin incision, or after umbilical cord clamping.
Project description:Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation. C57BL6 mice were divided into low-dose penicillin or control groups. Given antibiotics via drinking water after weaning. Sacrificed and liver sections collected for RNA extraction.
Project description:Staphylococcus aureus is a major pathogen of healthcare settings with a high rate of morbidity and mortality. S. aureus has also emerged as a serious threat in healthy individuals in the community. Increasingly, antibiotic resistant S. aureus strains, particularly methicillin resistant S. aureus (MRSA), are causing these community-acquired infections (CA-MRSA). Because of the rising incidence of antibiotic resistance, including resistance to “last resort” antibiotics, development of prophylactic vaccines for S. aureus is considered a high priority. A complete, accurate characterization of the transcriptome of the host during different types of infection would expedite S. aureus vaccine development by identifying antigens that would be optimal vaccine targets. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to comprehensively and systematically define the transcriptome (the complete set of transcribed regions in a genome) of an organism in a manner that is significantly more sensitive than microarray hybridization approaches. We propose a comprehensive characterization of the host transcriptome in two different murine models of infection (systemic infection and skin and soft tissue infection (SSTI)). We believe that this research will provide insight into potential vaccine targets that are expressed at high levels in both types of infection. We also wish to determine what mouse genes are up- or down-regulated during the course of these infections in order to better characterize the host-pathogen interaction. This description of the in vivo transcriptome will give novel insight into how the host senses and responds to infection with S. aureus in different infection types, and how the host tissue responds to bacterial invasion.
Project description:Wound infections are traditionally thought to occur when microbial burden exceeds the innate clearance capacity of host immune system. Here we introduce the idea that the wound environment itself plays a significant contributory role to wound infection. We developed a clinically relevant murine model of soft tissue infection to explore the role of activation of microbial virulence in response to tissue factors as a mechanism by which pathogenic bacteria cause wound infections. Mice underwent abdominal skin incision and light muscle injury with a crushing forceps versus skin incision alone followed by topical inoculation of Pseudomonas aeruginosa. Pseudomonas aeruginosa whole genome transcriptional profiling demonstrated that fascia induced the activation of multiple genes responsible for the synthesis of the iron scavenging protein pyochelin.
Project description:Wound infections are traditionally thought to occur when microbial burden exceeds the innate clearance capacity of host immune system. Here we introduce the idea that the wound environment itself plays a significant contributory role to wound infection. We developed a clinically relevant murine model of soft tissue infection to explore the role of activation of microbial virulence in response to tissue factors as a mechanism by which pathogenic bacteria cause wound infections. Mice underwent abdominal skin incision and light muscle injury with a crushing forceps versus skin incision alone followed by topical inoculation of Pseudomonas aeruginosa. Pseudomonas aeruginosa whole genome transcriptional profiling demonstrated that fascia induced the activation of multiple genes responsible for the synthesis of the iron scavenging protein pyochelin. Ex-vivo murine fascia homogenates were prepared and Pseudomonas aeruginosa MPAO1 was incubated with an inoculum of the fascia homogenate solution. Pseudomonas aeruginosa MPAO1 incubated under the same condtions without the homogenate was used as the control group. Three biological replicates in each group was used.