This study was designed to investigate the distribution of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients, its clinical significance, and the expression profile of Th17 cell-associated cytokines. The percentage of Th17 cells detected by flow cytometry analysis (FACS) was significantly higher in 46 pancreatic tumor tissues (5.28 ± 1.65%) compared with corresponding adjacent normal tissues (2.57 ± 0.83%) (P = 0.031). In addition, the percentage of Th17 cells was significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.039). The percentage of Th17 cells in peripheral blood of 20 pancreatic cancer patients (3.99 ± 1.15%) was significantly higher than 15 healthy volunteers (1.98 ± 0.57%) (P = 0.027). Immunohistochemistry (IHC) was performed to detect IL-17⁺ cells in 46 pancreatic tumor tissues, as well as expression of CD34 in 24 tumor tissues. IL-17 was shown to mainly locate in cytoplasm, and the frequency of IL-17⁺ cells in tumor tissues (39/46) was higher than control (29/46). The presence of IL-17⁺ cells in tumor tissues was associated with tumor, node, and metastasis (TNM) stage, and lymph node metastasis (P = 0.012 and P = 0.009) but not with patient sex, age, tumor size, and histological grade (P > 0.05). Interestingly, distribution of Th17 cells in tumor tissues was positively correlated with microvessel density (MVD) (r = 0.86, P = 0.018). Furthermore, the median survival time of patients with high and low level of IL-17⁺ cells frequency was 14.5 and 18.5 months respectively (P = 0.023). The serum levels of Th17 cell-associated cytokines, IL-17 and IL-23 in 20 pancreatic patients detected by enzyme-linked immunosorbent assay (ELISA) were 69.2 ± 28.5 pg/mL and 266.5 ± 98.1 pg/mL, respectively, which were significantly higher than 15 healthy volunteers (P = 0.015 and P = 0.02). Moreover, levels of IL-17 and IL-23 were significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.04 and P = 0.036). This study suggests that increase in Th17 cells frequency and its related cytokines levels in pancreatic tumor tissues may indicate involvement in the invasion and metastasis of pancreatic cancer, which may thereby affect patient prognosis. Therefore, Th17 cells and related cytokines may be served as important immune indicators for predicting the prognosis of pancreatic cancer patients.

In response to the limited nutrients and stressful conditions of their habitats, many microorganisms including Salmonella form a biofilm by secreting a polymeric matrix to interweave individual cel...

Salmonellae are facultative intracellular pathogens that cause globally distributed diseases with massive morbidity and mortality in humans and animals. In the past decades, numerous studies were focused on host defenses against Salmonella infection. Autophagy has been demonstrated to be an important defense mechanism to clear intracellular pathogenic organisms, as well as a regulator of immune responses. Ubiquitin modification also has multiple effects on the host immune system against bacterial infection. It has been indicated that ubiquitination plays critical roles in recognition and clearance of some invading bacteria by autophagy. Additionally, the ubiquitination of autophagy proteins in autophagy flux and inflammation-related substance determines the outcomes of infection. However, many intracellular pathogens manipulate the ubiquitination system to counteract the host immunity. Salmonellae interfere with host responses via the delivery of ~30 effector proteins into cytosol to promote their survival and proliferation. Among them, some could link the ubiquitin-proteasome system with autophagy during infection and affect the host inflammatory responses. In this review, novel findings on the issue of ubiquitination and autophagy connection as the mechanisms of host defenses against Salmonella infection and the subverted processes are introduced.

Salmonella are common enteric bacterial pathogens that infect both humans and animals. Intestinal epithelial barrier, formed by a single layer of epithelial cells and apical junctional complex (AJC), plays a crucial role in host defense against enteric pathogens to prevent bacterial translocation. However, the underlying mechanisms of intestinal epithelial barrier dysfunction caused by Salmonella are poorly understood. It is found that a locus termed Salmonella plasmid virulence (spv) gene exists extensively in clinically important Salmonella serovars. SpvB is a key effector encoded within this locus, and closely related to Salmonella pathogenicity such as interfering with autophagy and iron homeostasis. To investigate the interaction between SpvB and intestinal epithelial barrier and elucidate the underlying molecular mechanism, we used the typical foodborne disease agent Salmonella enterica serovar Typhimurium (Salmonella typhimurium) carrying spvB or not to construct infection models in vivo and in vitro. C57BL/6 mice were orally challenged with S. typhimurium wild-type strain SL1344 or spvB-deficient mutant strain SL1344-ΔspvB. Caco-2 cell monolayer model, as a widely used model to mimic the human intestinal epithelium in vitro, was infected with SL1344, SL1344-ΔspvB, or spvB complementary strain SL1344-c-ΔspvB, respectively. The results showed that SpvB enhanced bacterial pathogenicity during S. typhimurium infection in vivo, and contributed to intestinal epithelial barrier dysfunction in both infection systems. This SpvB-mediated barrier dysfunction was attributed to the cellular redistribution of Claudin-1, Occludin, and E-cadherin junctional proteins. Moreover, by using pharmacological inhibitors, we found that F-actin rearrangement and suppression of protein kinase C (PKC) signaling pathway were involved in SpvB-mediated barrier dysfunction. In conclusion, the study reveals the contribution of Salmonella effector SpvB to the dysfunction of intestinal epithelial barrier integrity, which facilitates bacterial translocation via the paracellular route to promote Salmonella systemic dissemination. Our findings broaden the understanding of host–pathogen interactions in salmonellosis, and provide new strategies for the therapy in limiting bacterial dissemination during infection.

In Central China the declining incidence of Plasmodium vivax has been interrupted by epidemic expansions and imported cases. The impact of these changes on the local parasite population, and concurrent risks of future resurgence, was assessed. Plasmodium vivax isolates collected from Anhui and Jiangsu provinces, Central China between 2007 and 2010 were genotyped using capillary electrophoresis at seven polymorphic short tandem repeat markers. Spatial and temporal analyses of within-host and population diversity, population structure, and relatedness were conducted on these isolates. Polyclonal infections were infrequent in the 94 isolates from Anhui (4%) and 25 from Jiangsu (12%), with a trend for increasing frequency from 2008 to 2010 (2 to 19%) when combined. Population diversity was high in both provinces and across the years tested (H_E = 0.8 – 0.85). Differentiation between Anhui and Jiangsu was modest (F’ _ST = 0.1). Several clusters of isolates with identical multi-locus haplotypes were observed across both Anhui and Jiangsu. Linkage disequilibrium was strong in both populations and in each year tested (I_A^S = 0.2 – 0.4), but declined two- to four-fold when identical haplotypes were accounted for, indicative of occasional epidemic transmission dynamics. None of five imported isolates shared identical haplotypes to any of the central Chinese isolates. The population genetic structure of P. vivax in Central China highlights unstable transmission, with limited barriers to gene flow between the central provinces. Despite low endemicity, population diversity remained high, but the reservoirs sustaining this diversity remain unclear. The challenge of imported cases and risks of resurgence emphasize the need for continued surveillance to detect early warning signals. Although parasite genotyping has potential to inform the management of outbreaks, further studies are required to identify suitable marker panels for resolving local from imported P. vivax isolates.

SopF, a newly discovered effector secreted by Salmonella pathogenicity island-1 type III secretion system (T3SS1), was reported to target phosphoinositide on host cell membrane and aggravate systemic infection, while its functional relevance and underlying mechanisms have yet to be elucidated. PANoptosis (pyroptosis, apoptosis, and necroptosis) of intestinal epithelial cells (IECs) has been characterized as a pivotal host defense to limit the dissemination of foodborne pathogens, whereas the effect of SopF on IECs PANoptosis induced by Salmonella is rather limited. Here, we show that SopF can attenuate intestinal inflammation and suppress IECs expulsion to promote bacterial dissemination in mice infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). We revealed that SopF could activate phosphoinositide-dependent protein kinase-1 (PDK1) to phosphorylate p90 ribosomal S6 kinase (RSK) which down-regulated Caspase-8 activation. Caspase-8 inactivated by SopF resulted in inhibition of pyroptosis and apoptosis, but promotion of necroptosis. The administration of both AR-12 (PDK1 inhibitor) and BI-D1870 (RSK inhibitor) potentially overcame Caspase-8 blockade and subverted PANoptosis challenged by SopF. Collectively, these findings demonstrate that this virulence strategy elicited by SopF aggregates systemic infection via modulating IEC PANoptosis through PDK1-RSK signaling, which throws light on novel functions of bacterial effectors, as well as a mechanism employed by pathogens to counteract host immune defense.