This week, Tues 25th November, we will be looking at this paper 

Shed GP of Ebola Virus Triggers Immune Activation and Increased Vascular Permeability

Beatriz Escudero-Pérez, Valentina A. Volchkova, Olga Dolnik, Philip Lawrence, Viktor E. Volchkov mail

 

Discussion points

  1. Is the paper well written?
  2. Do the results support the conclusions?
  3. What work would you like to see done in the future?

 

Hope to see you there on Tuesday

 

Zoo

This week on Microbiology Twitter Journal Club, we’ll be discussing  a brand new broad spectrum antiviral Favipiravir, and it’s efficacy compared to Ribavirin against Mouse Norovirus.

Abstract

Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this study, we show that the broad-range antiviral nucleoside favipiravir reduces viral load in vivo by exerting antiviral mutagenesis in a mouse model for norovirus infection. Increased mutation frequencies were observed in samples from treated mice and were accompanied with lower or in some cases undetectable levels of infectious virus in faeces and tissues. Viral RNA isolated from treated animals showed reduced infectivity, a feature of populations approaching extinction during antiviral mutagenesis. These results suggest that favipiravir can induce norovirus mutagenesis in vivo, which in some cases leads to virus extinction, providing a proof-of-principle for the use of favipiravir derivatives or mutagenic nucleosides in the clinical treatment of noroviruses.

Discussion points:

  • Is Favipiravir better than Ribavirin, and does the paper provide enough evidence for that ?
  • Was the data presented clearly ?
  • Do those stars above the graphs mean Christmas is coming, or something more foreboding ?
  • What would you have done differently?

Join the discussion at 8pm GMT tomorrow with #MicroTwJC.

Our next Journal club will be on the 28th of October 2014 at 8 pm on this paper here:

Regulation of the AbrA1/A2 Two-Component System in Streptomyces coelicolor and the Potential of Its Deletion Strain as a Heterologous Host for Antibiotic Production by Sergio Rico, Ana Yepes, Héctor Rodríguez, Jorge Santamaría, Sergio Antoraz, Eva M. Krause, Margarita Díaz, Ramón I. Santamaría, published on October 10, 2014 DOI:10.1371/journal.pone.0109844

Link: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0109844

Background
Streptomyces is a genus of actinobacteria, a group of Gram-positive soil bacteria with an unusual life cycle, involving substrate mycelium, formation of aerial hyphae and spore formation. They are prolific producers of bioactive metabolites, such as clavulinic acid or FK-506 and thus are of great interest for industry. The onset for the production of these metabolites usually happens when nutrients are limited and come along with the developmental stages. The regulation of antibiotic production has been extensively studied mainly in S.coelicolor which is one of the model organisms and many genetic tools are available. For more details see this review here: http://mmbr.asm.org/content/77/1/112.short
Regulation of the AbrA1/A2 Two-Component System in Streptomyces coelicolor and the Potential of Its Deletion Strain as a Heterologous Host for Antibiotic Production
By Sergio Rico, Ana Yepes, Héctor Rodríguez, Jorge Santamaría, Sergio Antoraz, Eva M. Krause, Margarita Díaz, Ramón I. Santamaría
Published on October 10, 2014DOI: 10.1371/journal.pone.0109844
Abstract
The Two-Component System (TCS) AbrA1/A2 from Streptomyces coelicolor M145 is a negative regulator of antibiotic production and morphological differentiation. In this work we show that it is able to auto-regulate its expression, exerting a positive induction of its own operon promoter, and that its activation is dependent on the presence of iron. The overexpression of the abrA2 response regulator (RR) gene in the mutant ΔabrA1/A2 results in a toxic phenotype. The reason is an excess of phosphorylated AbrA2, as shown by phosphoablative and phosphomimetic AbrA2 mutants. Therefore, non-cognate histidine kinases (HKs) or small phospho-donors may be responsible for AbrA2 phosphorylation in vivo. The results suggest that in the parent strain S. coelicolor M145 the correct amount of phosphorylated AbrA2 is adjusted through the phosphorylation-dephosphorylation activity rate of the HK AbrA1. Furthermore, the ABC transporter system, which is part of the four-gene operon comprising AbrA1/A2, is necessary to de-repress antibiotic production in the TCS null mutant. Finally, in order to test the possible biotechnological applications of the ΔabrA1/A2strain, we demonstrate that the production of the antitumoral antibiotic oviedomycin is duplicated in this strain as compared with the production obtained in the wild type, showing that this strain is a good host for heterologous antibiotic production. Thus, this genetically modified strain could be interesting for the biotechnology industry.

Discussion points:
1. Is the paper well written?
2. Were the methods appropriate?
3. Do the results reflect the conclusion?
4. What else could be done?

Hi everyone!

Welcome to #MicroTwJC 55, hosted on 14/10/2014 by @_LisaKWilliams_ and @Stewart_Barker.

This week we will be discussing the fascinating world of virophages – that is viruses which attack other viruses. The paper can be found here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0094923

Following a previous #MicroTwJC discussion on the largest discovered viruses, this fairly recent paper describes a satellite virus (or virophage) named Zamilon that is associated with the giant virus family Mimiviridae. Zamilon is similar to other described virophages which have negative effects on their host – Sputnik virophages, yet does not appear to inhibit it’s host in any way…

 

“The host-specificity of the Zamilon virophage supports the distinction between satellite viruses (opportunistic entities associated with a virus) and virophages, which target specific hosts.”

 

Aside from what we think is an interesting paper and concept, the above quote is a crucial point of the paper. We leave you with the abstract and questions to consider below, and look forward to a lively debate!

Abstract

Virophages, which are potentially important ecological regulators, have been discovered in association with members of the order Megavirales. Sputnik virophages target the Mimiviridae, Mavirus was identified with the Cafeteria roenbergensis virus, and virophage genomes reconstructed by metagenomic analyses may be associated with the Phycodnaviridae. Despite the fact that the Sputnik virophages were isolated with viruses belonging to group A of theMimiviridae, they can grow in amoebae infected by Mimiviridae from groups A, B or C. In this study we describe Zamilon, the first virophage isolated with a member of group C of theMimiviridae family. By co-culturing amoebae with purified Zamilon, we found that the virophage is able to multiply with members of groups B and C of the Mimiviridae family but not with viruses from group A. Zamilon has a 17,276 bp DNA genome that potentially encodes 20 genes. Most of these genes are closely related to genes from the Sputnik virophage, yet two are more related to Megavirus chiliensis genes, a group B Mimiviridae, and one to Moumouvirus monve transpoviron.

 

Points to consider

  1. Is the paper well written?
  2. Do the methods fully investigate whether the Zamilon virophage has a disruptive effect on its host?
  3. Are the results and discussion appropriate?
  4. Is Zamilon a virophage, or a satellite virus? Is there actually a difference between the two terms?

 

Streptococcus_pyogenesThis Tuesday’s paper will be on the consequences of viral/bacterial co-infection in a mouse model, focusing on bacterial transmission and its genetic determinants. As you can imagine, pathogen transmission is a hot-topic right now, especially when viruses such as influenza are involved. So have a read, critique the paper and join us on Tuesday night at 8 pm BST on the 30th of September.

The paper was published recently in PloS pathogens, see link.

For discussion, I think we should focus on these points:

  • what is the model telling us? and is it a good model for this important question?
  • does this paper providing convinving evidence for the role or TLR2-driven inflammation? and what is the role of influenza virus in this?
  • what are the real-world consequences of viral/bacterial co-infection?

TLR2 Signaling Decreases Transmission of Streptococcus pneumoniae by Limiting Bacterial Shedding in an Infant Mouse Influenza A Co-infection Model.

  • Aimee L. Richard,
  • Steven J. Siegel,
  • Jan Erikson,
  • Jeffrey N. Weiser mail

Abstract

While the importance of transmission of pathogens is widely accepted, there is currently little mechanistic understanding of this process. Nasal carriage of Streptococcus pneumoniae (the pneumococcus) is common in humans, especially in early childhood, and is a prerequisite for the development of disease and transmission among hosts. In this study, we adapted an infant mouse model to elucidate host determinants of transmission of S. pneumoniae from inoculated index mice to uninfected contact mice. In the context of co-infection with influenza A virus, the pneumococcus was transmitted among wildtype littermates, with approximately half of the contact mice acquiring colonization. Mice deficient for TLR2 were colonized to a similar density but transmitted S. pneumoniae more efficiently (100% transmission) than wildtype animals and showed decreased expression of interferon α and higher viral titers. The greater viral burden intlr2−/− mice correlated with heightened inflammation, and was responsible for an increase in bacterial shedding from the mouse nose. The role of TLR2 signaling was confirmed by intranasal treatment of wildtype mice with the agonist Pam3Cys, which decreased inflammation and reduced bacterial shedding and transmission. Taken together, these results suggest that the innate immune response to influenza virus promotes bacterial shedding, allowing the bacteria to transit from host to host. These findings provide insight into the role of host factors in the increased pneumococcal carriage rates seen during flu season and contribute to our overall understanding of pathogen transmission.

Author Summary

In this study, we sought to identify factors contributing to the transmission of the bacterial pathogen Streptococcus pneumoniae (the pneumococcus), a major cause of otitis media, pneumonia, and septicemia. Often found as a co-infection with other bacterial and viral pathogens, the pneumococcus is commonly carried by young children and is spread by close human contact, most likely through large droplet respiratory secretions. The specific determinants of bacterial transmission, however, have not been identified. This report details our use of an infant mouse model of transmission, which includes influenza A co-infection, to elucidate the mechanism of host-to-host transmission. We found that the inflammatory response to influenza, which is aggravated in the context of weakened host defense, promotes transmission by inducing bacterial shedding from the mouse nose. These results show how a bacterial pathogen exploits the host immune response to spread from one host to the next.

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