Outer membrane vesicles blebbing contributes to B. vulgatus mpk-mediated immune response silencing

Abstract

The Gram negative intestinal symbiont Bacteroides vulgatus mpk is able to prevent from induction of colonic inflammation in Rag1−/− mice and promotes immune balance in Il2−/− mice. These inflammation-silencing effects are associated with B. vulgatus mpk-mediated induction of semi-mature dendritic cells, especially in the colonic lamina propria (cLP). However the beneficial interaction of bacteria with host immune cells is limited due to the existence of a large mucus layer covering the intestinal epithelium. How can intestinal bacteria overcome this physical barrier and contact the host immune system?One mechanism is the production of outer membrane vesicles (OMVs) via ubiquitous blebbing of the outer membrane. These proteoliposomes have the ability to traverse the mucus layer. Hence, OMVs play an important role in immunomodulation and the maintenance of a balanced gut microbiota. Here we demonstrate that the stimulation of bone marrow derived dendritic cells (BMDCs) with isolated OMVs originated from B. vulgatus mpk leads to the induction of a tolerant semi-mature phenotype. Thereby, microbe- associated molecular patterns (MAMPs) delivered by OMVs are crucial for the interaction and the resulting maturation of immune cells. Additional to the binding to host TLR4, a yet unknown ligand to TLR2 is indispensable for the conversion of immature BMDCs into a semi-mature state. Thus, crossing the epithelial mucus layer and directly contact host cells, OMV mediate cross-tolerance via the transport of various Toll-like receptor antigens. These features make OMVs to a key attribute of B. vulgatus mpk for a vigorous acellular prevention and treatment of systemic diseases.

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

“…Nevertheless, the influence of the host commensal microbiota on the induction of this regulatory cell phenotype needs to be investigated in more detail. In earlier studies, we could demonstrate the effect of different immunogenic commensals on the differentiation and maturation of certain immune cells (e.g., CD11c + DCs), concluding that a potent TLR activation provided by strong immunogenic bacteria leads to enhanced immune responses, aggravating the course of disease (60,61,66,68,69,133,134). Thereby, our and other groups used genetically susceptible colitis mouse models (Rag1-, IL-2-, and IL-10-deficient) exhibiting a dysregulated immune system to mimic disease development in an immune suppressed host (60,61,135).…”

“…In order to show that B cells are activated and differentiated upon the MAMP recognition via TLRs and that the activation level is dependent on the immunogenicity of encountered microbes, B cells isolated from wild type (WT) and TLR2 −/− × TLR4 −/− (KO) mice were stimulated with two different immunogenic bacteria: B. vulgatus mpk and E. coli mpk (66)(67)(68)(69).…”

Galleria mellonella: A Novel Invertebrate Model to Distinguish Intestinal Symbionts From Pathobionts

“…In previous work, we conveyed that E. coli and B. vulgatus mpk are differentially recognized by TLR2- and TLR4-overexpressing human embryonic kidney (HEK) cells. E. coli leads to much stronger stimulation of both TLR2 and 4 than B. vulgatus ( 36 ).…”

Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment

“…Outer membrane vesicles (OMVs) are secreted by bacteria, range from 20 to 250 nm in diameter, and carry bacterial lipopolysaccharide (LPS), protease, membrane receptor, DNA, RNA and so forth (Bonnington & Kuehn, 2014;Guerrero-Mandujano, Hernandez-Cortez, Ibarra, & Castro-Escarpulli, 2017;Jan, 2017). Several studies suggested that OMVs play a vital role in the communication and regulation of the host (Maerz et al, 2018;Rosenthal et al, 2014;Sinha et al, 2015) and even indicated that OMVs are related to AD (Aguayo, Schuh, Vicente, & Aguayo, 2018;Olsen, Taubman, & Singhrao, 2016;Singhrao & Olsen, 2018).…”