Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice. SseI inhibits normal cell migration of primary macrophages and dendritic cells (DC) in vitro, and such inhibition requires the host factor IQ motif containing GTPase activating protein 1 (IQGAP1), an important regulator of cell migration. SseI binds directly to IQGAP1 and co-localizes with this factor at the cell periphery. The C-terminal domain of SseI is similar to PMT/ToxA, a bacterial toxin that contains a cysteine residue (C1165) that is critical for activity. Mutation of the corresponding residue in SseI (C178A) eliminates SseI function in vitro and in vivo, but not binding to IQGAP1. In addition, infection with wild-type (WT) S. typhimurium suppressed DC migration to the spleen in vivo in an SseI-dependent manner. Correspondingly, examination of spleens from mice infected with WT S. typhimurium revealed fewer DC and CD4+ T lymphocytes compared to mice infected with ΔsseI S. typhimurium. Taken together, our results demonstrate that SseI inhibits normal host cell migration, which ultimately counteracts the ability of the host to clear systemic bacteria.

IL-7 is a required factor for T-cell homeostasis. Because of low expression levels and poor reagent availability, the cellular sources of IL-7 have proven challenging to characterize. In this study, we describe a reporter mouse in which enhanced GFP is expressed from the endogenous Il7 locus. We show that IL-7 is produced by lymphatic endothelial cells (LECs) distributed throughout the systemic lymphatic vasculature as well as by fibroblastic reticular cells, and that phosphorylation of STAT5 in lymphocytes is higher in lymphatics than in blood. Furthermore, in nodes depleted of lymphocytes, Il7 transcription is increased in stromal but not in myeloid subsets. These data support recent findings that lymphocyte homeostasis is influenced by access to secondary lymphoid organs and point to LECs as an important in vivo source of IL-7, bathing trafficking immune cells under both resting and lymphopenic conditions.

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Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.

Transarterial radioembolization using yttrium-90 (Y-90) microspheres is an important therapy in the management of unresectable primary liver tumors or hepatic metastases. While radioembolization is generally well-tolerated, it is not free from adverse events, and familiarity with the prevention and treatment of radioembolization-specific complications is an important component of patient care. This article aims to review radioembolization-specific toxicities stratified by hepatic, extrahepatic, and systemic effects, with a focus on preventing and mitigating radioembolization-induced morbidity.

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Sixteen patients with cirrhosis (75% males, 87.5% Caucasians, with mean age of 50.3 þ 10 years) were included. Fifteen patients had decompensated cirrhosis (ascites:93%, VB: 26.7% and HE: 60.0%), while 1 patient had ascites due allograft dysfunction after orthotopic liver transplant (OLT). The mean PSG was reduced from 14.8 ± 5.0 mm Hg pre-TIPS to 5.3 ± 2.7 mm Hg post-TIPS. The mean Model for End-Stage Liver Disease (MELD) score increased from 13.6 ± 4.4 before TIPS to 15.7 ± 4.5 after TIPS. All sixteen patients had abdominal surgeries, one was emergent and 11 were hernia repair. Median time to surgery was 39 days. Median hospital stay was 4 days. The mean expected PO 30-day mortality risk was 27.3 ± 21.6%. Observed 30-day PO mortality rate was found to be 0%. Data was available on 12/16 patients at one year and the observed mortality was 8%. After TIPS, HE was reported in all 16 patients and ascites in 6 patients with 2 requiring revision of TIPS within 30 days after the procedure. One patient, with a PO 30-day mortality risk of 43.6%, died (78 days from the procedure) and 5 patients received liver transplant. Conclusions: Our retrospective review indicates that preoperative TIPS placement in patients with decompensated cirrhosis, especially ascites, can help reduce the PO mortality.