Starvation induces changes in abundance and small RNA cargo of extracellular vesicles released from Plasmodium falciparum infected red blood cells.

The lethal malaria parasite Plasmodium falciparum needs to constantly respond and adapt to changes within the human host in order to survive and transmit. One such change is composed of nutritional limitation, which is augmented with increased parasite loads and intimately linked to severe disease development. Extracellular vesicles released from infected red blood cells have been proposed as important mediators of disease pathogenesis and intercellular communication but whether important for the parasite response to nutritional availability is unknown. Therefore, we investigated the abundance and small RNA cargo of extracellular vesicles released upon short-term nutritional starvation of P. falciparum in vitro cultures. We show that primarily ring-stage parasite cultures respond to glucose and amino acid deprivation with an increased release of extracellular vesicles. Small RNA sequencing of these extracellular vesicles further revealed human miRNAs and parasitic tRNA fragments as the main constituent biotypes. Short-term starvations led to alterations in the transcriptomic profile, most notably in terms of the over-represented biotypes. These data suggest a potential role for extracellular vesicles released from P. falciparum infected red blood cells in the response to nutritional perturbations, their potential as prognostic biomarkers and point towards an evolutionary conserved role among protozoan parasites.

Role of T cells during the cerebral infection with Trypanosoma brucei.

The infection by Trypanosoma brucei brucei (T.b.b.), a protozoan parasite, is characterized by an early-systemic stage followed by a late stage in which parasites invade the brain parenchyma in a T cell-dependent manner. Here we found that early after infection effector-memory T cells were predominant among brain T cells, whereas, during the encephalitic stage T cells acquired a tissue resident memory phenotype (TRM) and expressed PD1. Both CD4 and CD8 T cells were independently redundant for the penetration of T.b.b. and other leukocytes into the brain parenchyma. The role of lymphoid cells during the T.b.b. infection was studied by comparing T- and B-cell deficient rag1-/- and WT mice. Early after infection, parasites located in circumventricular organs, brain structures with increased vascular permeability, particularly in the median eminence (ME), paced closed to the sleep-wake regulatory arcuate nucleus of the hypothalamus (Arc). Whereas parasite levels in the ME were higher in rag1-/- than in WT mice, leukocytes were instead reduced. Rag1-/- infected mice showed increased levels of meca32 mRNA coding for a blood /hypothalamus endothelial molecule absent in the blood-brain-barrier (BBB). Both immune and metabolic transcripts were elevated in the ME/Arc of WT and rag1-/- mice early after infection, except for ifng mRNA, which levels were only increased in WT mice. Finally, using a non-invasive sleep-wake cycle assessment method we proposed a putative role of lymphocytes in mediating sleep alterations during the infection with T.b.b. Thus, the majority of T cells in the brain during the early stage of T.b.b. infection expressed an effector-memory phenotype while TRM cells developed in the late stage of infection. T cells and parasites invade the ME/Arc altering the metabolic and inflammatory responses during the early stage of infection and modulating sleep disturbances.

Colorectal cancer in Crohn's colitis is associated with advanced tumor invasion and a poorer survival compared with ulcerative colitis: a retrospective dual-center study.

PURPOSE: Colorectal cancer is a well-recognized complication of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's colitis (CC). In this study, we assess the clinico-pathological features and outcomes of patients with colorectal cancer from UC in comparison with CC. METHODS: Data of all patients with colitis-associated cancer (CAC) who underwent surgery at Erlangen or Würzburg University Clinic between 1995 and 2015 were selected. Clinical, histopathological, and survival data were analyzed retrospectively. RESULTS: Of all 88 patients with CAC, 20 patients had Crohn's colitis and 68 patients had ulcerative colitis. We observed a young median age at tumor diagnosis (49.5 years UC; 45.5 years CC, p = 0.208) in both diseases and a long median disease duration before CAC (19 years UC; 18 years CC; p = 0.840). Patients with CC suffered more often from rectal cancer (14 (70.0%) in CC; 23 (33.8%) in UC; p = 0.005) and advanced tumor stages (8 (47.0%) pT4 in CC; 14 (25.0%) pT4/ypT4 in UC; p = 0.008). Five-year overall survival rate was 39.3% for CC and 67.1% for UC (p = 0.009 for difference between the groups). Survival did not differ significantly between UC and CC in the multivariate analysis after correction for UICC tumor stage. CONCLUSION: CAC in CC showed advanced tumor stages associated with reduced survival compared with CAC in UC. This may be explained by less intense surveillance in patients with CC leading to delayed cancer diagnosis.