Refugial isolation and range expansions drive the genetic structure of \u3cem\u3eOxyria sinensis\u3c/em\u3e (Polygonaceae) in the Himalaya-Hengduan Mountains

The formation of the Mekong-Salween Divide and climatic oscillations in Pleistocene were the main drivers for the contemporary diversity and genetic structure of plants in the Himalaya-Hengduan Mountains (HHM). To identify the relative roles of the two historical events in shaping population history of plants in HHM, we investigated the phylogeographic pattern of Oxyria sinensis, a perennial plant endemic to the HHM. Sixteen chloroplast haplotypes were identified and were clustered into three phylogenetic clades. The age of the major clades was estimated to be in the Pleistocene, falling into several Pleistocene glacial stages and postdating the formation of the Mekong-Salween Divide. Range expansions occurred at least twice in the early and middle Pleistocene, but the spatial genetic distribution rarely changed since the Last Glacial Maximum. Our results suggest that temporary mountain glaciers may act as barriers in promoting the lineage divergence in O. sinensis and that subsequential range expansions and secondary contacts might reshape the genetic distribution in geography and blur the boundary of population differentiation created in the earlier glacial stages. This study demonstrates that Pleistocene climatic change and mountain glaciers, rather than the Mekong-Salween Divide, play the primary role in shaping the spatial genetic structure of O. sinensis

Activated NK cells kill hepatic stellate cells via p38/PI3K signaling in a TRAIL-involved degranulation manner

NK cells are important in regulating hepatic fibrosis via their cytotoxic killing of hepatic stellate cells (HSCs). NK cells are activated by both cytokines such as IL-12 and IL-18, and innate immune stimuli such as ligation of TLRs. The secretion of IL-18 depends upon activation of the inflammasome, whereas TLRs are stimulated by microbial products. In the case of NK cells, IL-18 acts synergistically with stimulation of TLR3 to cause cell activation and cytotoxic function. In the present study, we activated NK cells to kill HSCs via IL-18 and TLR3 ligand stimulation, and dissected the signaling pathways or molecules critical for such activation or killing. We find that such activation depends on signaling via the p38/PI3K/AKT pathway, and that the activatedNK cells mediate HSC death in a TRAIL-involved mechanism. As liver fibrosis is a major global health problem with no good solution, these results emphasize that the p38/PI3K/AKT pathway in NK cells may be a novel drug target to promote fibrosis regression

Endophytic Beauveria bassiana promotes plant biomass growth and suppresses pathogen damage by directional recruitment

IntroductionEntomopathogenic fungi (EPF) can colonize and establish symbiotic relationships with plants as endophytes. Recently, EPF have been reported to suppress plant pathogens and induce plant resistance to diseases. However, the potential mechanisms via which EPF as endophytes control major plant diseases in situ remain largely unknown.MethodsPot and field experiments were conducted to investigate the mechanisms via which an EPF, Beauveria bassiana, colonizes tomato, under Botrytis cinerea infection stress. B. bassiana blastospores were inoculated into tomato plants by root irrigation. Tomato resistance to tomato gray mold caused by B. cinerea was evaluated by artificial inoculation, and B. bassiana colonization in plants and rhizosphere soil under B. cinerea infection stress was evaluated by colony counting and quantitative PCR. Furthermore, the expression levels of three disease resistance-related genes (OXO, CHI, and atpA) in tomato leaves were determined to explore the effect of B. bassiana colonization on plant disease resistance performance in pot experiments.ResultsB. bassiana colonization could improve resistance of tomato plants to gray mold caused by B. cinerea. The incidence rate, lesion diameter, and disease index of gray mold decreased in both the pot and field experiments following B. bassiana colonization. B. bassiana was more likely to accumulate in the pathogen infected leaves, while decreasing in the rhizosphere soil, and induced the expression of plant resistance genes, which were up-regulated in leaves.DiscussionThe results indicated that plants could “recruit” B. bassiana from rhizosphere soil to diseased plants as directional effects, which then enhanced plant growth and resistance against pathogens, consequently inhibiting pathogen infection and multiplication in plants. Our findings provide novel insights that enhance our understanding of the roles of EPF during pathogen challenge

HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway

Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection

Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection

Background and aims HBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells. Methods Monocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining. Results In chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-β, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-β expression via the MyD88/NFκ B signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation. Conclusions Our findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition

Hepatitis B virus–induced imbalance of inflammatory and antiviral signaling by differential phosphorylation of STAT1 in human monocytes

It is not clear how hepatitis B virus (HBV) modulates host immunity during chronic infection. In addition to the key mediators of inflammatory response in viral infection, monocytes also express a high-level IFN-stimulated gene, CH25H, upon response to IFN-a exerting an antiviral effect. In this study, the mechanism by which HBV manipulates IFN signaling in human monocytes was investigated. We observed that monocytes from chronic hepatitis B patients express lower levels of IFN signaling/stimulated genes and higher levels of inflammatory cytokines compared with healthy donors. HBV induces monocyte production of inflammatory cytokines via TLR2/MyD88/NF-kB signaling and STAT1-Ser727 phosphorylation and inhibits IFN-a–induced stat1, stat2, and ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10–dependent, partially autocrine manner. Further, we found that enhancement of STAT1 activity with a small molecule (2-NP) rescued HBV-mediated inhibition of IFN signaling and counteracted the induction of inflammatory cytokines. In conclusion, HBV contributes to the monocyte inflammatory response but inhibits their IFN-a/b responsiveness to impair antiviral innate immunity. These effects are mediated via differential phosphorylation of Tyr701 and Ser727 of STAT1

Brucella Dysregulates Monocytes and Inhibits Macrophage Polarization through LC3-Dependent Autophagy

Brucellosis is caused by infection with Brucella species and exhibits diverse clinical manifestations in infected humans. Monocytes and macrophages are not only the first line of defense against Brucella infection but also a main reservoir for Brucella. In the present study, we examined the effects of Brucella infection on human peripheral monocytes and monocyte-derived polarized macrophages. We showed that Brucella infection led to an increase in the proportion of CD14++CD16− monocytes and the expression of the autophagy-related protein LC3B, and the effects of Brucella-induced monocytes are inhibited after 6 weeks of antibiotic treatment. Additionally, the production of IL-1β, IL-6, IL-10, and TNF-α from monocytes in patients with brucellosis was suppressed through the LC3-dependent autophagy pathway during Brucella infection. Moreover, Brucella infection inhibited macrophage polarization. Consistently, the addition of 3-MA, an inhibitor of LC3-related autophagy, partially restored macrophage polarization. Intriguingly, we also found that the upregulation of LC3B expression by rapamycin and heat-killed Brucella in vitro inhibits M2 macrophage polarization, which can be reversed partially by 3-MA. Taken together, these findings reveal that Brucella dysregulates monocyte and macrophage polarization through LC3-dependent autophagy. Thus, targeting this pathway may lead to the development of new therapeutics against Brucellosis