Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson disease (PD), Crohn’s disease and leprosy. Because all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions

Bacterial Activation of Invariant Natural Killer T (iNKT) Cells

Invariant natural killer T (iNKT) cells are a set of innate T lymphocytes, whose T-cell receptor is highly conserved between humans and mice. Following activation with lipid antigens, iNKT cells can respond with a diverse array of cytokines and chemokines to direct the immune response. To this end, iNKT cells have been studied in a number of immune diseases, including bacterial infection, asthma, and cancer. iNKT cell activation can occur through different pathways, which include antigen-dependent and cytokine-dependent mechanisms. The goal of this thesis was to examine iNKT cell activation following bacterial infection and elucidate how this is modulated by tissue location and the cytosolic pattern recognition receptors NOD1 and NOD2. I investigated the role of NOD1 and NOD2, members of the NOD-like receptor (NLR) family, in iNKT cell activation using gene-knockout mice and NOD specific ligands. We demonstrated that NOD1 and NOD2 enhanced the iNKT cell IFNγ response during Toll-like receptor (TLR) stimulation, and following S. typhimurium and L. monocytogenes challenge, which are infections that can engage both the TLR and NLR innate immune receptors. This full activation was dependent on NOD1 and NOD2 synergy with TLR4 within antigen-presenting cells (APCs), which led to increased IL-12 secretion. This synergy was important in systemic tissues, but not in mucosal tissues such as the intestines.Beginning at birth the bacterial community forms a life long interaction with the human body, on our skin, and mucosal surfaces; this interaction influences our health and susceptibility to disease. The immune system mediates the host interaction with bacteria using different protective mechanisms. We further studied iNKT cells at the level of the intestine using bacterial (S. typhimurium) or chemical challenges (dextran sodium sulfate or DSS) that disrupt the intestinal environment. We demonstrated that an observed colitis susceptibility of iNKT cell-deficient mice was independent of iNKT cells and instead was mediated by altered microbiota. Taken together, this work contributes to our understanding iNKT cell function in different contexts of disease and host responses to bacterial challenge.Ph.D.2016-06-16 00:00:0

Nod1 and Nod2 Regulation of Inflammation in the Salmonella Colitis Model▿ †

The pattern recognition molecules Nod1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin-treated mouse model of Salmonella colitis, we found that mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. Nod1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, Nod1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS

Role of Nod1 in Mucosal Dendritic Cells during Salmonella Pathogenicity Island 1-Independent Salmonella enterica Serovar Typhimurium Infection ▿

Recent advances in immunology have highlighted the critical function of pattern-recognition molecules (PRMs) in generating the innate immune response to effectively target pathogens. Nod1 and Nod2 are intracellular PRMs that detect peptidoglycan motifs from the cell walls of bacteria once they gain access to the cytosol. Salmonella enterica serovar Typhimurium is an enteric intracellular pathogen that causes a severe disease in the mouse model. This pathogen resides within vacuoles inside the cell, but the question of whether cytosolic PRMs such as Nod1 and Nod2 could have an impact on the course of S. Typhimurium infection in vivo has not been addressed. Here, we show that deficiency in the PRM Nod1, but not Nod2, resulted in increased susceptibility toward a mutant strain of S. Typhimurium that targets directly lamina propria dendritic cells (DCs) for its entry into the host. Using this bacterium and bone marrow chimeras, we uncovered a surprising role for Nod1 in myeloid cells controlling bacterial infection at the level of the intestinal lamina propria. Indeed, DCs deficient for Nod1 exhibited impaired clearance of the bacteria, both in vitro and in vivo, leading to increased organ colonization and decreased host survival after oral infection. Taken together, these findings demonstrate a key role for Nod1 in the host response to an enteric bacterial pathogen through the modulation of intestinal lamina propria DCs