The Landscape of IFN/ISG Signaling in HIV-1-Infected Macrophages and Its Possible Role in the HIV-1 Latency.

A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation. Macrophages play a protagonist role in this context since they are persistently infected while being a major effector of the innate immune response through the generation of type-I interferons (type I IFN) and IFN-stimulated genes (ISGs). The balance in the IFN signaling and the ISG induction is critical to promote a successful HIV-1 infection. Classically, the IFNs response is fine-tuned by opposing promotive and suppressive signals. In this context, it was described that HIV-1-infected macrophages can also synthesize some antiviral effector ISGs and, positive and negative regulators of the IFN/ISG signaling. Recently, epitranscriptomic regulatory mechanisms were described, being the N6-methylation (m6A) modification on mRNAs one of the most relevant. The epitranscriptomic regulation can affect not only IFN/ISG signaling, but also type I IFN expression, and viral fitness through modifications to HIV-1 RNA. Thus, the establishment of replication-competent latent HIV-1 infected macrophages may be due to non-classical mechanisms of type I IFN that modulate the activation of the IFN/ISG signaling network.

CD4+Foxp3+T Regulatory Cells Promote Transplantation Tolerance by Modulating Effector CD4+ T Cells in a Neuropilin-1-Dependent Manner.

Several mechanisms of immune suppression have been attributed to Foxp3+ T regulatory cells (Treg) including modulation of target cells via inhibition of cell proliferation, alteration of cytokine secretion, and modification of cell phenotype, among others. Neuropilin-1 (Nrp1), a co-receptor protein highly expressed on Treg cells has been involved in tolerance-mediated responses, driving tumor growth and transplant acceptance. Here, we extend our previous findings showing that, despite expressing Foxp3, Nrp1KO Treg cells have deficient suppressive function in vitro in a contact-independent manner. In vivo, the presence of Nrp1 on Treg cells is required for driving long-term transplant tolerance. Interestingly, Nrp1 expression on Treg cells was also necessary for conventional CD4+ T cells (convT) to become Nrp1+Eos+ T cells in vivo. Furthermore, adoptive transfer experiments showed that the disruption of Nrp1 expression on Treg cells not only reduced IL-10 production on Treg cells, but also increased the frequency of IFNγ+ Treg cells. Similarly, the presence of Nrp1KO Treg cells facilitated the occurrence of IFNγ+CD4+ T cells. Interestingly, we proved that Nrp1KO Treg cells are also defective in IL-10 production, which correlates with deficient Nrp1 upregulation by convT cells. Altogether, these findings demonstrate the direct role of Nrp1 on Treg cells during the induction of transplantation tolerance, impacting indirectly the phenotype and function of conventional CD4+ T cells.

Effect of environmental disturbance on the population of sandflies and leishmania transmission in an endemic area of Venezuela.

The exploitation of new wilderness areas with crops is increasing and traditional crop substitution has been modified by new more productive crops. The results show the anthropogenic disturbance effect on the sandflies population and Leishmania transmission in endemic areas of Venezuela. Three agroecosystems with variable degrees of ecological disturbance, forest (conserved), cacao (fragmented), and orangery (disturbed), were selected. Four methods to sandfly capture were used; the specimens were identified and infected with Leishmania. Diversity, population structure, ANOVA, Tukey test, and simple correlation analysis were carried out. Shannon traps were able to capture 94.7% of the total sandflies, while CDC light traps, Sticky traps, and direct suction just captured 2.2%, 1.2%, and 0.9%, respectively. The results showed the effect of ecological disturbance degree on the composition of sandflies and population structure, revealing a dominance level increased but decreased on the diversity and richness of sandflies species in the greatest ecological disturbance area in relation to areas with less organic disturbance. Environments more disturbed cause adaptability of certain species such as Lutzomyia gomezi and Lutzomyia walkeri. These changes on the composition of sandflies population and structure emerging species could cause increasing of leishmaniasis transmission.

Programmed hepatocytes cell death associated with FLIP downregulation in response to extracellular preS1/2.

Chronic hepatitis B virus (HBV) infection involves liver damage resulting in continuous cell injury and death. During HBV infection, hepatocytes exhibit changes in death receptor expression and in their susceptibility to death. These changes are observed not only in infected cells but also in bystander cells. Because excess viral surface protein (HBsAg) is secreted in large amounts as soluble particles containing preS proteins, the role of soluble preS1/2 in hepatocyte (HepG2) death modulation is an important issue to be explored. An increase of cell death induced by preS1/2 was observed. Also, cell death was associated with the down-regulation of FLIP and activation of caspase 8, caspase 9, and BID. Additionally, hepatocytes exhibited a sensitization to death mediated by the Fas receptor. These results, may contribute to understanding the role of envelope proteins (preS1/2) in the pathogenesis of HBV infection.

Characteristics of plasminogen binding to Trypanosoma cruzi epimastigotes.

The binding constants of the interaction between plasminogen and Trypanosoma cruzi epimastigotes were determined. An indirect method in which the bound plasminogen is detached from the cell by epsilon-aminocaproic acid and a direct method through biotinylated plasminogen were used. The analyses revealed a dissociation constant (Kd) from 0.4 to 1.2microM, these values being compatible with recognition in vivo. Moreover, epimastigotes from the gut of Rhodnius prolixus were able to bind plasminogen from the blood meal. Fragments derived from elastase digestion of plasminogen were tested for their ability to bind T. cruzi cells. The fragment with highest ability to interact with the parasite was miniplasminogen that bound in a concentration-dependent and saturable manner with a Kd similar to that for plasminogen. This binding was inhibited by epsilon-aminocaproic acid indicating that the lysine-binding site of kringle 5 may be responsible for the interaction of plasminogen with T. cruzi.