SUMMARY
Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3 linked to α2,6 linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments.
Analysis of 179 new Ebola virus sequences from patient samples collected in Guinea between March 2014 and January 2015 shows how different lineages evolved and spread in West Africa.
Supplementary information
The online version of this article (doi:10.1038/nature14594) contains supplementary material, which is available to authorized users.
To end the largest known outbreak of Ebola virus disease (EVD) in West Africa and to prevent new transmissions, rapid epidemiological tracing of cases and contacts was required. The ability to quickly identify unknown sources and chains of transmission is key to ending the EVD epidemic and of even greater importance in the context of recent reports of Ebola virus (EBOV) persistence in survivors. Phylogenetic analysis of complete EBOV genomes can provide important information on the source of any new infection. A local deep sequencing facility was established at the Mateneh Ebola Treatment Centre in central Sierra Leone. The facility included all wetlab and computational resources to rapidly process EBOV diagnostic samples into full genome sequences. We produced 554 EBOV genomes from EVD cases across Sierra Leone. These genomes provided a detailed description of EBOV evolution and facilitated phylogenetic tracking of new EVD cases. Importantly, we show that linked genomic and epidemiological data can not only support contact tracing but also identify unconventional transmission chains involving body fluids, including semen. Rapid EBOV genome sequencing, when linked to epidemiological information and a comprehensive database of virus sequences across the outbreak, provided a powerful tool for public health epidemic control efforts.
Alterations in lipid metabolism have been reported in many types of cancer. Lipids have been implicated in the regulation of proliferation, differentiation, apoptosis, inflammation, autophagy, motility and membrane homeostasis. It is required that their biosynthesis is tightly regulated to ensure homeostasis and to prevent unnecessary energy expenditure. This review focuses on the emerging understanding of the role of lipids and lipogenic pathway regulation in breast cancer, including parallels drawn from the study of metabolic disease models, and suggestions on how these findings can potentially be exploited to promote gains in HER2/neu-positive breast cancer research.
Secretory IgA (SIgA), the predominant class of antibody in intestinal secretions, serves as the first line of defense against enteric infections. SIgA has also been proposed to function in immune surveillance, given that both SIgA and SIgA-antigen complexes are actively transported by Peyer’s patch M cells from the intestinal lumen to sub-epithelial dendritic cells (DCs). The goal of the present study was to identify the receptor(s) potentially utilized by mucosal DCs to recognize and internalize SIgA. We demonstrate that human colostral SIgA is recognized by purified recombinant human DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) in a solid phase binding assay, as well as by DC-SIGN ectopically expressed on the surface of Chinese hamster ovary (CHO-S) cells. The interaction between SIgA and DC-SIGN was specific, given that it was Ca2+-dependent and inhibited by mannan. Moreover, SIgA bound to, and was internalized by, endogenous DC-SIGN expressed on THP-1 cells following monocyte to macrophage-like cell differentiation by stimulation with phorbol ester and interleukin-4. These data identify DC-SIGN as a putative receptor for SIgA, and reveal a mechanism by which DCs could collaborate with M cells in immune surveillance at mucosal surfaces.
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