Recent reports have shown that virus isolates from PML patients often have distinct changes within the major capsid protein. This paper shows that that these mutations result in abolished engagement of the carbohydrate receptor motif necessary for infection. Viruses with PML-associated mutations are not infectious in glial cells, suggesting that they may play an alternative role in PML. Interesting stuff, suggesting that interaction with cell surface receptors is an important determinant of tissue tropism and JC virus pathogenesis for PML, even though the best defence remains a healthy immune system.

Progressive Multifocal Leukoencephalopathy-Associated Mutations in the JC Polyomavirus Capsid Disrupt Lactoseries Tetrasaccharide c Binding. (2013) mBio 4(3): e00247-13 doi: 10.1128/mBio.00247-13
The human JC polyomavirus (JCPyV) is the causative agent of the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). The Mad-1 prototype strain of JCPyV uses the glycan lactoseries tetrasaccharide c (LSTc) and serotonin receptor 5-HT2A to attach to and enter into host cells, respectively. Specific residues in the viral capsid protein VP1 are responsible for direct interactions with the α2,6-linked sialic acid of LSTc. Viral isolates from individuals with PML often contain mutations in the sialic acid-binding pocket of VP1 that are hypothesized to arise from positive selection. We reconstituted these mutations in the Mad-1 strain of JCPyV and found that they were not capable of growth. The mutations were then introduced into recombinant VP1 and reconstituted as pentamers in order to conduct binding studies and structural analyses. VP1 pentamers carrying PML-associated mutations were not capable of binding to permissive cells. High-resolution structure determination revealed that these pentamers are well folded but no longer bind to LSTc due to steric clashes in the sialic acid-binding site. Reconstitution of the mutations into JCPyV pseudoviruses allowed us to directly quantify the infectivity of the mutants in several cell lines. The JCPyV pseudoviruses with PML-associated mutations were not infectious, nor were they able to engage sialic acid as measured by hemagglutination of human red blood cells. These results demonstrate that viruses from PML patients with single point mutations in VP1 disrupt binding to sialic acid motifs and render these viruses noninfectious.

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Multiple and complex layers of defense help plants to combat pathogens. A first line of defense relies on the detection, via dedicated host-encoded receptors, of signature molecules (so called pathogen-associated molecular patterns, PAMPs) produced by pathogens. In turn, this PAMP-triggered immunity (PTI) may be itself antagonized by adapted pathogens that have evolved virulence effectors to target key PTI components. Host plants react to PTI suppression by producing disease resistance (R) proteins that recognize virulence effectors and activate highly specific resistance called Effector Triggered Immunity (ETI). It has been noted that RNA silencing, a sequence-specific antiviral defense response based on the production of virus-derived 21–24 nt small RNAs on the one hand, and its suppression by virulence effectors, called viral suppressors of RNA silencing (VSRs) on the other, are conceptually similar to PTI. A new paper in PLOS Pathogens supports this hypothesis by showing that extreme resistance is indeed activated following detection, in specific host species, of the VSR activity of a viral virulence effector. The ensuing antiviral immunity displays many characteristics of ETI, suggesting that one or several R proteins must sense the integrity of the host silencing machinery.

Extreme Resistance as a Host Counter-counter Defense against Viral Suppression of RNA Silencing. (2013) PLoS Pathog 9(6): e1003435. doi:10.1371/journal.ppat.1003435
RNA silencing mediated by small RNAs (sRNAs) is a conserved regulatory process with key antiviral and antimicrobial roles in eukaryotes. A widespread counter-defensive strategy of viruses against RNA silencing is to deploy viral suppressors of RNA silencing (VSRs), epitomized by the P19 protein of tombusviruses, which sequesters sRNAs and compromises their downstream action. Here, we provide evidence that specific Nicotiana species are able to sense and, in turn, antagonize the effects of P19 by activating a highly potent immune response that protects tissues against Tomato bushy stunt virus infection. This immunity is salicylate- and ethylene-dependent, and occurs without microscopic cell death, providing an example of “extreme resistance” (ER). We show that the capacity of P19 to bind sRNA, which is mandatory for its VSR function, is also necessary to induce ER, and that effects downstream of P19-sRNA complex formation are the likely determinants of the induced resistance. Accordingly, VSRs unrelated to P19 that also bind sRNA compromise the onset of P19-elicited defense, but do not alter a resistance phenotype conferred by a viral protein without VSR activity. These results show that plants have evolved specific responses against the damages incurred by VSRs to the cellular silencing machinery, a likely necessary step in the never-ending molecular arms race opposing pathogens to their hosts.

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Virions at the Gates: Receptors and the Host–Virus Arms Race. (2013) PLoS Biol 11(5): e1001574. doi:10.1371/journal.pbio.1001574
All viruses need to bind to specific receptor molecules on the surface of target cells to initiate infection. Virus–receptor binding is highly specific, and this specificity determines both the species and the cell type that can be infected by a given virus. In some well-studied cases, the virus-binding region on the receptor has been found to be unrelated to the receptor’s normal cellular function. Resistance to virus infection can thus evolve by selection of mutations that alter amino acids in the binding region with minimal effect on normal function. This sort of positive selection can be used to infer the history of the host–virus “arms race” during their coevolution. In a new study, Demogines et al. use a combination of phylogenetic, structural, and virological analysis to infer the history and significance of positive selection on the transferrin receptor TfR1, a housekeeping protein required for iron uptake and the cell surface receptor for at least three different types of virus. The authors show that only two parts of the rodent TfR1 molecule have been subject to positive selection and that these correspond to the binding sites for two of these viruses—the mouse mammary tumor virus (a retrovirus) and Machupo virus (an arenavirus). They confirmed this result by introducing the inferred binding site mutations into the wild-type protein and testing for receptor function. Related arenaviruses are beginning to spread in human populations in South America as the cause of often fatal hemorrhagic fevers, and, although Demogines et al. could find no evidence of TfR1 mutations in this region that might have been selected as a consequence of human infection, the authors identified one such mutation in Asian populations that affects infection with these viruses.

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Novel Quorum-Sensing Peptides Mediating Interspecies Bacterial Cell Death. (2013) mBio 4(3): e00314-13 doi: 10.1128/mBio.00314-13
Escherichia coli mazEF is a toxin-antitoxin stress-induced module mediating cell death. It requires the quorum-sensing signal (QS) “extracellular death factor” (EDF), the penta-peptide NNWNN (EcEDF), enhancing the endoribonucleolytic activity of E. coli toxin MazF. Here we discovered that E. coli mazEF-mediated cell death could be triggered by QS peptides from the supernatants (SN) of the Gram-positive bacterium Bacillus subtilis and the Gram-negative bacterium Pseudomonas aeruginosa. In the SN of B. subtilis, we found one EDF, the hexapeptide RGQQNE, called BsEDF. In the SN of P. aeruginosa, we found three EDFs: the nonapeptide INEQTVVTK, called PaEDF-1, and two hexadecapeptides, VEVSDDGSGGNTSLSQ, called PaEDF-2, and APKLSDGAAAGYVTKA, called PaEDF-3. When added to a diluted E. coli cultures, each of these peptides acted as an interspecies EDF that triggered mazEF-mediated death. Furthermore, though their sequences are very different, each of these EDFs amplified the endoribonucleolytic activity of E. coli MazF, probably by interacting with different sites on E. coli MazF. Finally, we suggest that EDFs may become the basis for a new class of antibiotics that trigger death from outside the bacterial cells.

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The modulation of apoptosis by oncogenic viruses. (2013) Virology Journal, 10: 182 doi:10.1186/1743-422X-10-182
Transforming viruses can change a normal cell into a cancer cell during their normal life cycle. Persistent infections with these viruses have been recognized to cause some types of cancer. These viruses have been implicated in the modulation of various biological processes, such as proliferation, differentiation and apoptosis. The study of infections caused by oncogenic viruses had helped in our understanding of several mechanisms that regulate cell growth, as well as the molecular alterations leading to cancer. Therefore, transforming viruses provide models of study that have enabled the advances in cancer research. Viruses with transforming abilities, include different members of the Human Papillomavirus (HPV) family, Hepatitis C virus (HCV), Human T-cell Leukemia virus (HTLV-1), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV).Apoptosis, or programmed cell death, is a tightly regulated process that plays an important role in development and homeostasis. Additionally, it functions as an antiviral defense mechanism. The deregulation of apoptosis has been implicated in the etiology of diverse diseases, including cancer. Oncogenic viruses employ different mechanisms to inhibit the apoptotic process, allowing the propagation of infected and damaged cells. During this process, some viral proteins are able to evade the immune system, while others can directly interact with the caspases involved in apoptotic signaling. In some instances, viral proteins can also promote apoptosis, which may be necessary for an accurate regulation of the initial stages of infection.

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• What Is Asthma?
• Why Do Fungi Make Spores? And a Guide to Terminology
• Do Fungal Spores Cause Asthma?
• Which Species Are Associated with Asthma?
• If Identification to Species Matters, Will New Tools Provide Needed Data?

Asthma and the Diversity of Fungal Spores in Air. (2013) PLoS Pathog 9(6): e1003371. doi:10.1371/journal.ppat.1003371
The diversity of fungal spores in air is vast, but research on asthma focuses on a handful of easily identified, culturable species. Ecologists are developing new tools to probe communities and identify the full complement of fungi in habitats. These tools may enable identification of novel asthma triggers, but scientists involved in public health or medicine rarely interact with mycologists focused on ecology. With this primer, my aim is to facilitate communication by providing doctors with a basic, modern guide to spores, by teaching mycologists the essential facts of asthma, and by providing patients with a succinct summary of what is known about spores and asthma. By highlighting the use of emerging metagenomics technologies in ecology, I intend to illustrate how these tools might be used to more thoroughly understand the potential diversity of fungi involved in asthma.

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Microbiology Today: Getting the message out

The Society for General Microbiology (SGM) leads the way on antimicrobial resistance.

http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm

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See: 10 things you should know about novel coronavirus (nCoV)

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Microbiology Today: Antimicrobial-resistant gonorrhoea

The control of bacterial STIs for public health is dependent on delivery of prevention messages to raise awareness, use of appropriate diagnostic tests to reduce the burden of infection and provision of effective antimicrobial therapy to break transmission. In the absence of an apparent protective immune response, and hence no effective vaccine, antimicrobial therapy is an essential component of control but is often compromised by resistance resulting in therapeutic failure.

http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm

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