An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria.

The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients. However, it remains unclear to what extent Phe consumption by SYNB1618 in the gastrointestinal tract lowers plasma Phe levels in PKU patients. Here, we construct a mechanistic model that predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology. In addition, we extend a model of plasma Phe kinetics in PKU patients, in order to estimate plasma Phe lowering by SYNB1618. This approach provides a framework that can be used more broadly to define the therapeutic potential of synthetic biotics.

Air pollution particulate matter alters antimycobacterial respiratory epithelium innate immunity.

Inhalation exposure to indoor air pollutants and cigarette smoke increases the risk of developing tuberculosis (TB). Whether exposure to ambient air pollution particulate matter (PM) alters protective human host immune responses against Mycobacterium tuberculosis has been little studied. Here, we examined the effect of PM from Iztapalapa, a municipality of Mexico City, with aerodynamic diameters below 2.5 µm (PM2.5) and 10 µm (PM10) on innate antimycobacterial immune responses in human alveolar type II epithelial cells of the A549 cell line. Exposure to PM2.5 or PM10 deregulated the ability of the A549 cells to express the antimicrobial peptides human ß-defensin 2 (HBD-2) and HBD-3 upon infection with M. tuberculosis and increased intracellular M. tuberculosis growth (as measured by CFU count). The observed modulation of antibacterial responsiveness by PM exposure was associated with the induction of senescence in PM-exposed A549 cells and was unrelated to PM-mediated loss of cell viability. Thus, the induction of senescence and downregulation of HBD-2 and HBD-3 expression in respiratory PM-exposed epithelial cells leading to enhanced M. tuberculosis growth represent mechanisms by which exposure to air pollution PM may increase the risk of M. tuberculosis infection and the development of TB.

Seleniivibrio woodruffii gen. nov., sp. nov., a selenate- and arsenate-respiring bacterium in the Deferribacteraceae.

A Gram-type-negative, obligately anaerobic, selenate-respiring bacterium, strain S4(T), was isolated from activated sludge of a wastewater treatment plant in New Jersey after enrichment with 10 mM selenate as the sole electron acceptor. In addition to its selenate-respiring capability, strain S4(T) also respired arsenate with acetate as carbon source and electron donor. Fermentative growth was not observed. The optimum growth temperature was 37 °C and optimum pH was pH 7. Phylogenetic analysis of the 16S rRNA gene sequence revealed that strain S4(T) is a novel member of the family Deferribacteraceae, with the type strain of Denitrovibrio acetiphilus as its closest cultivated relative, with 91.5 % sequence similarity. The cellular fatty acid profile was composed predominantly of straight-chain fatty acids C14 : 0, C15 : 0, C16 : 0, C17 : 0 and C18 : 0, which distinguishes this organism from its closest relatives. The DNA G+C content was 47.7 mol%. Together, these findings support the conclusion that strain S4(T) represents a novel genus and species, for which the name Seleniivibrio woodruffii gen. nov., sp. nov. is proposed. The type strain of Seleniivibrio woodruffii is S4(T) ( = DSM 24984(T) = ATCC BAA-2290(T)).