Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a non-canonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Treg) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in ‘sensing’ protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.

Abstract. Conidiobolomycosis is reported in the state of Piauí, in the semiarid region of northeastern Brazil. Affected sheep had depression, weight loss, serous or mucohemorrhagic nasal discharge, and cranium-facial asymmetry from exophthalmos of 1 eye, generally with increased volume of the eyeball, keratitis, and corneal ulceration. At necropsy of 60 sheep, friable masses were observed in the posterior region of the nasal cavity, often destroying the ethmoturbinate bones. Frequently, the lesions invaded the nasal sinuses, cribiform plate, orbit, and brain. The masses were irregular, granular with moist surfaces, and soft and friable with white, yellow, or tan coloration. Dissemination of the lesion to lungs was observed in 27 sheep, to the brain in 26, to lymph nodes in 3, to the kidney in 2, and to the gallbladder and heart in 1. The microscopic examination showed granulomatous inflammation composed of central necrosis surrounded by lymphocytes, epithelioid and giant cells, and fibrous tissue. In all lesions, negatively stained structures representing hyphae were surrounded by Splendore-Hoeppli material. Coagulative necrosis, thrombosis, and vasculitis were also observed. Grocott methenamine silver stain showed 8-30-mm-thick hyphae, rarely septate or ramified, irregular in shape, and with black contoured wall, sometimes with bulbous dilatation in the extremities. On electron microscopy, the hyphae had a thick double wall surrounded by cellular remnants and an inflammatory exudate. Conidiobolus coronatus was isolated from the lesions of 6 sheep. Conidiobolomycosis is an important disease of sheep in the state of Piauí, and other regions of northeastern Brazil.

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

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Type I interferons (IFNs) are cytokines that orchestrate diverse immune responses to viral and bacterial infections. Although typically considered to be most important molecules in response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. In this study, we addressed the role of type I IFN signaling during Brucella abortus infection, a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Herein, we have shown that B. abortus induced IFN-β in macrophages and splenocytes. Further, IFN-β induction by Brucella was mediated by IRF3 signaling pathway and activates IFN-stimulated genes via STAT1 phosphorylation. In addition, IFN-β expression induced by Brucella is independent of TLRs and TRIF signaling but MyD88-dependent, a pathway not yet described for Gram-negative bacteria. Furthermore, we have identified Brucella DNA as the major bacterial component to induce IFN-β and our study revealed that this molecule operates through a mechanism dependent on RNA polymerase III to be sensed probably by an unknown receptor via the adaptor molecule STING. Finally, we have demonstrated that IFN-αβR KO mice are more resistant to infection suggesting that type I IFN signaling is detrimental to host control of Brucella. This resistance phenotype is accompanied by increased IFN-γ and NO production by IFN-αβR KO spleen cells and reduced apoptosis.