Association of MICA and MICB alleles with symptomatic dengue infection

Dengue viruses (DV) are one of the most important arthropod-borne viral diseases in the developing world. DV can cause syndromes that are either self-limiting or severe. Allelic variants of human leukocyte antigen (HLA) genes have been demonstrated to be associated with disease susceptibility. Here we report the association of nonclassical HLA class I MICA–MICB genes with disease outcome during DV infection. A sequencing-based typing method and genotyping of MICA and MICB in a well-characterized group of Cuban individuals with dengue hemorrhagic fever (DHF), dengue fever (DF), or asymptomatic dengue infection (ADI) was performed. Statistical analysis revealed a tendency for MICA*008 and MICB*008 to associate with susceptibility to illness when symptomatic versus asymptomatic cases (odds ratio [OR] = 2.1, p_v = 0.03, and OR = 10.4, p = 0.0096, respectively) were compared. Surprisingly, a stronger association of both allelic forms was observed for the DF patients compared with the ADI group (MICA*008, OR = 5.2, p = 0.0001; and MICB*008, OR = 13.2, p = 0.0025) rather than the severe cases. Major histocompatibility class I-related gene-related natural killer cells and/or γδ and αβ T-cell activation might regulate the development of symptomatic DF and DHF.     

Experimental severe Pseudomonas aeruginosa pneumonia and antibiotic therapy in piglets receiving mechanical ventilation

BACKGROUND: Little is known about the general and local consequences of severe pneumonia under mechanical ventilation (SPMV) and how these are resolved with antibiotic therapy (ABT). OBJECTIVES: To investigate the physiologic, biological, microbiological, and pathologic changes produced by experimental SPMV in a porcine model, and to evaluate the effect of ABT. METHODS: Pseudomonas aeruginosa was inoculated in 12 large white-Landrace piglets receiving mechanical that were killed after 72 h if death did not occur before. Vital signs, serum and BAL cytokines, serum C-reactive protein (CRP), and graded postmortem lung pathology and cultures (blood and quantitative BAL and lung) were evaluated. Six piglets received inappropriate ABT (no ABT or ceftriaxone), and six piglets received appropriate ABT (ciprofloxacin). Measurements and main results: Pathologic and microbiological evidence of infection were present in all the animals in both groups. SPMV produced significant oxygenation and lung compliance worsening, increased serum CRP, and reduced BAL fluid tumor necrosis factor (TNF)-alpha. Arterial thrombosis in lung pathology was associated with higher temperature, hypoxemia and low lung compliance, higher initial serum CRP and TNF-alpha concentrations, and increased serum interleukin (IL)-6 and BAL IL-6 and TNF-alpha. Reduced ABT reduced body temperature and culture positivity. CONCLUSIONS: This model resembles VAP and has been used for studying pulmonary infection and inflammation related to mechanical ventilation. ABT reduced fever and bacterial burden in SPMV but had no effect on cytokine or CRP concentrations, oxygenation, or lung mechanics. Pulmonary artery thrombosis was associated with worse response to infection.     

Preclinical modeling of cytosine arabinoside response in Mll-Enl translocator mouse leukemias

Mouse models of human cancer are a potential preclinical setting for drug testing and for development of methods for delivery of macromolecular drugs to tumors. We have assessed a mouse model of leukemia caused by Mll-Enl protein fusion as a preclinical situation in which myeloid-lineage leukemia results from de novo occurrence of chromosomal translocations between Mll and Enl genes. Here, we show that the mouse leukemias respond to cytosine arabinoside, a frontline treatment for human leukemia. The observations show that the myeloid cells are susceptible to the drug and the mice undergo a remission that comprises a reduction of the myeloid population of cells and recovery of the lymphoid population. This translocator model should therefore prove useful for future drug assessments against the recurrent mixed-lineage leukemia-associated translocations.     

Host Cell Factors as Antiviral Targets in Arenavirus Infection

Among the members of the Arenaviridae family, Lassa virus and Junin virus generate periodic annual outbreaks of severe human hemorrhagic fever (HF) in endemic areas of West Africa and Argentina, respectively. Given the human health threat that arenaviruses represent and the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. Since diverse host cell pathways and enzymes are used by RNA viruses to fulfill their replicative cycle, the targeting of a host process has turned an attractive antiviral approach in the last years for many unrelated virus types. This strategy has the additional benefit to reduce the serious challenge for therapy of RNA viruses to escape from drug effects through selection of resistant variants triggered by their high mutation rate. This article focuses on novel strategies to identify inhibitors for arenavirus therapy, analyzing the potential for antiviral developments of diverse host factors essential for virus infection.