Maternal vaccination with a type-III glycoconjugate protects mouse neonates against Group B Streptococcus intranasal infection

Group B Streptococcus (GBS) is generally an asymptomatic colonizer of human mucosa but it occasionally infects pregnant women and neonates through vertical transmission, causing disease during the first weeks of life with frequent and severe complications. Preclinical studies have shown that maternal vaccination with polysaccharide-based vaccines protects mothers and offspring from GBS mucosal colonization and consecutive infection. In these models, bacteria were inoculated in mouse either intravaginally in the last trimester of pregnancy or systemically in pups. Here, we investigated whether maternal vaccination with glycoconjugate vaccines may also prevent GBS-mediated colonization and disease in neonates using an infection route that more closely mimics inhalation or ingestion of bacteria during human delivery. To address this point, mice aged less than two days were intranasally challenged with epidemiologically relevant GBS strains. Bacteria were found to colonize nose and intestine, reaching in some cases lungs and blood during the first days of life. Bacteria were also found in vagina of a fraction of colonized female mice within the first month of life. GBS-specific IgG induced by maternal vaccination with a glycoconjugate vaccine formulation were found in blood and mucosal tissues of newborns. Finally, when intranasally challenged with GBS serotype III strains, pups delivered by vaccinated mothers were partially protected against mucosal colonization and deeper infection.

A small molecule produced by Lactobacillus species blocks Candida albicans filamentation by inhibiting a DYRK1-family kinase

The fungus Candida albicans is an opportunistic pathogen that can exploit imbalances in microbiome composition to invade its human host, causing pathologies ranging from vaginal candidiasis to fungal sepsis. Bacteria of the genus Lactobacillus are colonizers of human mucosa and can produce compounds with bioactivity against C. albicans. Here, we show that some Lactobacillus species produce a small molecule under laboratory conditions that blocks the C. albicans yeast-to-filament transition, an important virulence trait. It remains unexplored whether the compound is produced in the context of the human host. Bioassay-guided fractionation of Lactobacillus-conditioned medium linked this activity to 1-acetyl-β-carboline (1-ABC). We use genetic approaches to show that filamentation inhibition by 1-ABC requires Yak1, a DYRK1-family kinase. Additional biochemical characterization of structurally related 1-ethoxycarbonyl-β-carboline confirms that it inhibits Yak1 and blocks C. albicans biofilm formation. Thus, our findings reveal Lactobacillus-produced 1-ABC can prevent the yeast-to-filament transition in C. albicans through inhibition of Yak1.

Selective uptake into inflamed human intestinal tissue and immune cell targeting by wormlike polymer micelles

Over the 21st century, inflammatory bowel disease (IBD) has become a global disease with no causal therapeutic options. Selective targeting of inflamed areas in the gastrointestinal tract could be an effective treatment circumventing severe side effects for healthy tissue. Our study demonstrates that the shape of polymeric nanostructures represents so far rarely addressed key to required tissue selectivity in the intestine. Ex vivo experiments on human colonic biopsies revealed that crosslinked wormlike micelles featuring a dense poly(ethylene oxide) (PEO) shell exclusively enter the inflamed human mucosa without affecting healthy tissue. Similarly designed spherical micelles (∼25 nm) or vesicles (∼120 nm) penetrate both tissues or were barely uptaken at all, respectively. Moreover, it was found that the particles colocalize with immune cells in the lamina propria facilitating a specific targeting of the main pro-inflammatory cells within the diseased human mucosa. These findings demonstrate an untapped potential in particle design and enable new vistas for an effective treatment of IBD.

The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis

Sporadic colon cancer accounts for approximately 80% of colorectal cancer (CRC) with high incidence in Western societies strongly linked to long-term dietary patterns. A unique mouse model for sporadic CRC results from feeding a purified rodent Western-style diet (NWD1) recapitulating intake for the mouse of common nutrient risk factors each at its level consumed in higher risk Western populations. This causes sporadic large and small intestinal tumors in wild-type mice at an incidence and frequency similar to that in humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts and decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumor development. Here we establish that NWD1 transcriptionally reprograms Lgr5hi cells, and that nutrients are interactive in reprogramming. Furthermore, the DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, paralleled by reduced accumulation of relevant somatic mutations detected by single-cell exome sequencing. In compensation, NWD1 also reprograms Bmi1+ cells to function and persist as stem-like cells in mucosal homeostasis and tumor development. The data establish the key role of the nutrient environment in defining the contribution of two different stem cell populations to both mucosal homeostasis and tumorigenesis. This raises important questions regarding impact of variable human diets on which and how stem cell populations function in the human mucosa and give rise to tumors. Moreover, major differences reported in turnover of human and mouse crypt base stem cells may be linked to their very different nutrient exposures.

Binding of Candida albicans to Human CEACAM1 and CEACAM6 Modulates the Inflammatory Response of Intestinal Epithelial Cells

ABSTRACT Candida albicans colonizes human mucosa, including the gastrointestinal tract, as a commensal. In immunocompromised patients, C. albicans can breach the intestinal epithelial barrier and cause fatal invasive infections. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a), CEACAM5 (CEA), and CEACAM6 (CD66c) are immunomodulatory receptors expressed on human mucosa and are recruited by bacterial and viral pathogens. Here we show for the first time that a fungal pathogen (i.e., C. albicans) also binds directly to the extracellular domain of human CEACAM1, CEACAM3, CEACAM5, and CEACAM6. Binding was specific for human CEACAMs and mediated by the N-terminal IgV-like domain. In enterocytic C2BBe1 cells, C. albicans caused a transient tyrosine phosphorylation of CEACAM1 and induced higher expression of membrane-bound CEACAM1 and soluble CEACAM6. Lack of the CEACAM1 receptor after short hairpin RNA (shRNA) knockdown abolished CXCL8 (interleukin-8) secretion by C2BBe1 cells in response to C. albicans. In CEACAM1-competent cells, the addition of recombinant soluble CEACAM6 reduced the C. albicans-induced CXCL8 secretion. IMPORTANCE The present study demonstrates for the first time that fungal pathogens can be recognized by at least four members of the immunomodulatory CEACAM receptor family: CEACAM1, -3, -5, and -6. Three of the four receptors (i.e., CEACAM1, -5, and -6) are expressed in mucosal cells of the intestinal tract, where they are implicated in immunomodulation and control of tissue homeostasis. Importantly, the interaction of the major fungal pathogen in humans Candida albicans with CEACAM1 and CEACAM6 resulted in an altered epithelial immune response. With respect to the broad impact of CEACAM receptors on various aspects of the innate and the adaptive immune responses, in particular epithelial, neutrophil, and T cell behavior, understanding the role of CEACAMs in the host response to fungal pathogens might help to improve management of superficial and systemic fungal infections. The present study demonstrates for the first time that fungal pathogens can be recognized by at least four members of the immunomodulatory CEACAM receptor family: CEACAM1, -3, -5, and -6. Three of the four receptors (i.e., CEACAM1, -5, and -6) are expressed in mucosal cells of the intestinal tract, where they are implicated in immunomodulation and control of tissue homeostasis. Importantly, the interaction of the major fungal pathogen in humans Candida albicans with CEACAM1 and CEACAM6 resulted in an altered epithelial immune response. With respect to the broad impact of CEACAM receptors on various aspects of the innate and the adaptive immune responses, in particular epithelial, neutrophil, and T cell behavior, understanding the role of CEACAMs in the host response to fungal pathogens might help to improve management of superficial and systemic fungal infections.