Person:

Mekalanos, John

This work demonstrates that it is possible to alter the prey target range of the antibacterial activity of the type 6 secretion system (T6SS). Being able to change the T6SS target specificity is the first step toward using the T6SS as an antipathogen or commensal therapeutic, prophylactic, or probiotic. This work also uncovers a cryptic secretion mechanism(s) for delivering protein substrates from the bacterial cytosol to the periplasm. This mechanism is exploited by some T6SS effectors as an alternative pathway for reaching periplasmic targets when they are by chance delivered into the cytosol of target cells.

Although maternal antibodies protect newborns from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice lacking the capacity to produce IgG are protected by maternal natural IgG antibodies to the enteric pathogen enterotoxigenic Escherichia coli (ETEC) when antibodies are delivered either trans-placentally or through milk. By challenging pups fostered on either maternal antibody¬–sufficient or –deficient dams, we found that milk-derived IgG was critical for protection against ETEC-induced disease. Pups utilize the neonatal Fc receptor (FcRn) to transfer IgG from milk into serum, and this IgG provides protection against systemic and mucosal E. coli infection. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by ETEC and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers ETEC protection in pups. The surprising role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defense mechanism against neonatal infection.

Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection1. Cholera toxin (CT) is required for V. cholerae to cause severe disease and is also thought to promote transmission of the organism in that victims can shed many liters of diarrheal fluid that typically contains in excess of 1011 organisms. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CT-mediated disease enhances pathogen growth and induces a distinct V. cholerae transcriptome signature that is indicative an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, a nutrient essential for growth2. The majority of iron in the mammalian host resides in a chelated form within the porphyrin structure of heme, and V. cholerae genetically encodes the ability to utilize heme as a source of iron3. We show that V. cholerae heme and vibriobactin utilization genes confer a growth advantage to the pathogen only when CT is produced. Furthermore, CT-induced capillary congestion pathology in the terminal ileum correlated with an increased bioavailability of luminal heme. CT-induced disease in the ileum also led to increased luminal concentrations of long-chain fatty acids (LCFAs) and L-lactate metabolites, as well as upregulation of V. cholerae iron-sulfur cluster-containing TCA cycle enzyme genes. Genetic analysis of V. cholerae suggested that heme and LCFA uptake-dependent growth of V. cholerae occurs during infection but only in a strain capable of producing CT in vivo. We conclude that CT-induced disease creates an iron-depleted metabolic niche in the gut that selectively promotes the explosive growth of this pathogen through acquisition of host-derived heme and fatty acids as nutrients.