Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with Giardia muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after two weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including β-defensin 1 and resistin-like molecule β. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.

The sphingosine-1-phosphate receptor-1 (S1P1) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here we examine the cell subsets that express S1P1 in intestine using S1P1-eGFP mice, the regulation of S1P1 expression in lymphocytes after administration of DSS, after colitis induced by transfer of CD4+CD45RBhi cells and by crossing a mouse with TNF-driven ileitis with S1P1-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P1 expression. We found that not only T and B cells express S1P1, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P1 expression, while the enzymes that control tissue S1P levels in mice and humans with IBD were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T cell velocity and induced S1P1 degradation and retention of naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P1 expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.

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Background: To enable genomic care for all City of Hope (COH) patients, we implemented an enterprise-wide Precision Medicine program including 7 of our clinical network sites. Consented patients with and without cancer are eligible to opt into germline testing (155 gene cancer predisposition panel and ACMG 59 Actionable Disorders panel) and paired tumor-normal whole exome/RNA transcriptome sequencing. All assays are CAP-CLIA approved. Results are added to the electronic medical record (EMR). We describe the process of implementation through return of results (RoR). Methods: Potentially eligible patients are identified by their provider or through the EMR. Clinical Research Assistants (n=8, main campus) and Advance Practice Providers (APPs) (n=14 Genetic Counselors or n=1 Genetics Nurse Practitioner) and Licensed Vocational Nurses (n=5, clinical network) consent patients in-person and remotely. Clinical Research Nurses (n=5) or APPs order testing through the EMR, with treating providers copied on somatic results and GCs copied on germline results. All results are systematically reviewed by GCs and/or the weekly COH Precision Oncology Tumor Board (POTB). Results: From July 9, 2020 through August 26, 2022 12,105 patients have been offered participation, with 10,376 (85.7%) enrolling (7,892 original consents/ 2,484 reconsents), 735 (6.1%) declining, 984 (8.1%) deferring, and 10 (.1% ) with other consent statuses. 98.9% (10,259/10,376) opted for cancer predisposition germline testing and 98.5% (10,225/10,376) opted for ACMG Actionable Disorders testing 91.5% (9,497/10,376) patients agreed to future contact about additional research studies. 6,512 somatic tests have been reviewed (representing 6,295 patients) and presented through POTB. Somatic genomic results are uploaded to the EMR via PDF and returned by the treating physician. Germline results are returned through the EPIC genomics module. To scale RoR, patients with negative results, variants of unknown significance, and carriers for recessive conditions are sent letters. Patients with a cancer predisposition P/LP variant are disclosed via phone by a GC and referred to COH Cancer Genomics for counseling whereas patients with P/LP non-cancer ACMG variants are referred for outside genetic counseling through the testing laboratory. To improve efficiency, we do not notify patients of non-actionable variant reclassifications. Conclusion: We outline a new care model for the delivery of germline and somatic genetic testing at scale. High consent and opt-in rates for germline testing demonstrate patient interest and feasibility. Future work is planned to assess the impact of testing on clinical care and outcomes. Citation Format: Ilana Solomon, Heather Hampel, Kevin McDonnell, Kathleen Blazer, Alex Capasso, Anuja Chitre, Sandra Dreike, Hunaydah Elfarawi, Lauren Gima, Christine Hong, Gregory Idos, Elisabeth King, Rachelle Manookian, Bita Nehoray, Wai Park, Michael Restrepo, Susan Shehayeb, Elise Sobotka, Duveen Sturgeon, Elyssa Zukin, Stacy W. Gray, Stephen B. Gruber. The INSPIRE Study (Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation): scaling return of genomic results. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P051.