Remember what happened last time we “cured” AIDS?

Immune Timothy Brown, the “Berlin patient” was freed of HIV infection via a bone marrow transfusion from a compatible CCR5Δ32 donor in 2007.

Last year there was a report of a newborn baby cured by very early drug therapy. The news today carries reports of a second case in a baby which confirms that this approach can work in newborns, although not in adults with established HIV infections.

Also in the news today is the story of the phase I clinical trial of gene-editing technology to control (but not eliminate) HIV infection using autologous donation to create CCR5Δ32 in the patient’s own cells (Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. (2014) N Engl J Med 2014; 370: 901-910 doi: 10.1056/NEJMoa1300662). But as Nature News correctly points out, the big story here is the relatively crude zinc-finger nuclease (ZFN) technology used in this study as opposed to the much more powerful transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats (CRISPRs) technologies under development to edit the somatic genome.

Watch this space for further updates.

 

Microbiology Today – microbial superheroes

The latest issue of Microbiology Today – microbial superheroes is available for download from http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm

Microbiology Today - microbial superheroes

In this issue:

The shape-shifting superhero: Dictyostelium discoideum
This social amoeba has superhero, shape-shifting qualities, and is able to switch between a unicellular and a multicellular existence.

Diatoms: glass-dwelling dynamos
Superheroes have a reputation for being larger than life, but it is the unseen micro- organisms such as diatoms that can have a substantial impact on our lives.

The immortal, halophilic superhero: Halobacterium salinarum – a long-lived poly-extremophile
Halobacterium salinarum is an extremophile superhero on at least three counts: how are its extreme halophily, radiation resistance and longevity interconnected?

Heroic exertion of radiation-resistant extremophiles
An overview of ‘super’ radiation-resistant extremophiles and their potential uses in biotechnology and medicine.

Herpes simplex virus – master of disguise and invisibility
Invisibility would probably be high on anyone’s wish list of superpowers. But HSV has got there first.

 

From Scourge to Cure: Viruses Versus Cancer

Oncolytic Viruses I’m hoping to have a final year student working with me next year on a project about oncolytic viruses. This short review is a very nice overview of this developing field:

“With [oncolytic viruses] OV cancer therapeutics entering advanced-stage trials and showing clinical efficacy, strategies that further broaden OV targeting and replication capacity to address the heterogeneous nature of tumours and their associated vascular and stromal architecture will be extremely useful. Since such heterogeneity not only exists between patients but also within a given tumour/patient, where the metabolism, signal transduction, and antiviral states of cancer cells can be variably abnormal and, therefore, variably support OV replication, combinatorial strategies will be essential to promoting reliable tumour control and regression. Finally, continued efforts to identify components innate to the complex tumour microenvironment that promote OV replication will be critical to further improving OVs and developing new engineering strategies.”

From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer. (2014) PLoS Pathog 10(1): e1003836. doi:10.1371/journal.ppat.1003836
Tumour mutations corrupt cellular pathways, and accumulate to disrupt, dysregulate, and ultimately avoid mechanisms of cellular control. Yet the very changes that tumour cells undergo to secure their own growth success also render them susceptible to viral infection. Enhanced availability of surface receptors, disruption of antiviral sensing, elevated metabolic activity, disengagement of cell cycle controls, hyperactivation of mitogenic pathways, and apoptotic avoidance all render the malignant cell environment highly supportive to viral replication. The therapeutic use of oncolytic viruses (OVs) with a natural tropism for infecting and subsequently lysing tumour cells is a rapidly progressing area of cancer research. While many OVs exhibit an inherent degree of tropism for transformed cells, this can be further promoted through pharmacological interventions and/or the introduction of viral mutations that generate recombinant oncolytic viruses adapted to successfully replicate only in a malignant cellular environment. Such adaptations that augment OV tumour selectivity are already improving the therapeutic outlook for cancer, and there remains tremendous untapped potential for further innovation.

 

Up close and three-dimensional: HIV inside the gut

HIV HIV/AIDS remains a global public health problem with over 33 million people infected worldwide. High-resolution imaging of infected tissues by three-dimensional electron microscopy can reveal details of the structure of HIV-1, how it infects cells, and how and where the virus accumulates within different tissue sub-structures.

Three-dimensional electron microscopy had previously only been performed to image infected cultured cells or purified virus. This paper uses electron tomography (ET) to examine an active infection in the gastrointestinal tract of HIV-1–infected mice with humanized immune systems, allowing visualization of the interplay between the virus and host immune cells. Not only does it reveal details on how the virus quickly infects immune cells in the gut, using them as virus-producing factories, but it also highlights where the virus “hides out” deep within the intestinal tissue.

Three-dimensional imaging of an HIV-1 infection in tissue uncovers differences between cultured cell and tissue models of HIV-1 infection and in vivo infections and furthers our understanding of HIV-1/AIDS as a disease of mucosal tissues.

Electron Tomography of HIV-1 Infection in Gut-Associated Lymphoid Tissue. (2014) PLoS Pathog 10(1): e1003899. doi:10.1371/journal.ppat.1003899

 

Quorum Sensing Genes Discovered in a Bacteriophage

phiCDHM1 Some groundbreaking new research from my Leicester colleagues that’s too good to resist blogging about:

The incorporation of host DNA into phage genomes occurs across diverse bacteria, and acquisition of bacterial genes facilitates phage evolution. Although small, phage genomes have a high proportion of coding sequence relative to their size. The extent by which virus genomes can increase is constrained physically by the dimensions of their virion particles in which their DNA is packaged, by fitness costs associated with phage production, and by their packaging strategy. Although genetic material can be acquired via transduction and during DNA packaging, phage genomes are considered to be highly reduced and non-beneficial genes are lost through selective evolution. Therefore, discoveries of bacterial gene homologs in addition to the “core” phage genome are interesting, as is the diverse nature of these host associated genes.

Clostridium difficile is a major pathogen in healthcare settings, causing antibiotic associated diarrheal disease which can be fatal. Novel strains continue to emerge in clinical settings, and potential reservoirs of the bacterium include asymptomatic humans, wild and domesticated animals, and the natural environment. C. difficile pathogenicity can also be altered by the differential expression of their virulence genes, controlled via quorum sensing (QS) which is a form of bacterial communication. Through quorum sensing, cells communicate to the surrounding population via the release and detection of signalling molecules which elicit a physiological response. This paper describes the discivery of homologs of QS genes in a phage of C. difficile.

While the action and consequences of these phage QS genes is unclear, their presence and transcription during infection in a lysogenic and lytic background presents an exciting method by which phages can manipulate their hosts.

 

What Does the Talking?: Quorum Sensing Signalling Genes Discovered in a Bacteriophage Genome. (2014) PLoS ONE 9(1): e85131. doi:10.1371/journal.pone.0085131
The transfer of novel genetic material into the genomes of bacterial viruses (phages) has been widely documented in several host-phage systems. Bacterial genes are incorporated into the phage genome and, if retained, subsequently evolve within them. The expression of these phage genes can subvert or bolster bacterial processes, including altering bacterial pathogenicity. The phage phiCDHM1 infects Clostridium difficile, a pathogenic bacterium that causes nosocomial infections and is associated with antibiotic treatment. Genome sequencing and annotation of phiCDHM1 shows that despite being closely related to other C. difficile myoviruses, it has several genes that have not been previously reported in any phage genomes. Notably, these include three homologs of bacterial genes from the accessory gene regulator (agr) quorum sensing (QS) system. These are; a pre-peptide (AgrD) of an autoinducing peptide (AIP), an enzyme which processes the pre-peptide (AgrB) and a histidine kinase (AgrC) that detects the AIP to activate a response regulator. Phylogenetic analysis of the phage and C. difficile agr genes revealed that there are three types of agr loci in this species. We propose that the phage genes belonging to a third type, agr3, and have been horizontally transferred from the host. AgrB and AgrC are transcribed during the infection of two different strains. In addition, the phage agrC appears not to be confined to the phiCDHM1 genome as it was detected in genetically distinct C. difficile strains. The discovery of QS gene homologs in a phage genome presents a novel way in which phages could influence their bacterial hosts, or neighbouring bacterial populations. This is the first time that these QS genes have been reported in a phage genome and their distribution both in C. difficile and phage genomes suggests that the agr3 locus undergoes horizontal gene transfer within this species.

The Role of Archaea in Human Disease

Archaea The Archaea, the so-called Third Domain of life, are thought of in an environmental context, influencing natural environments and ecosystems including extreme environments such as salt lakes and soda lakes. But what if some species were capable of capable of causing human disease? Currently, there is no substantial evidence supporting the pathogenic properties of Archaea. This free review article considers why.

 

Role of archaea in human disease. (2013) Front Cell Infect Microbiol. 3:42. doi: 10.3389/fcimb.2013.00042

 

Retroviruses – NCBI Bookshelf

Retroviruses - NCBI Bookshelf Earlier today I needed to look something up. You know, in a real book, not Wikipedia. Except that the book was electronic, online and free.

Many people will have seen the NCBI Bookshelf, but it’s always a surprise to me that a resource of this quality has existed, for free, for so long. It’s also a reminder of how long I’ve been in this microbiology game and how much has changed.

Like many of the other NCBI resources, Retroviruses could be viewed as a bit long in the tooth these days. Certainly everything in it needs to be checked for currency by following citation trails to later knowledge (you do have the information skills that allow you to do that, don’t you?) but as an authorative resource it’s second to none.

I’ve had some good days and some bad days this week. The NCBI Bookshelf has certainly helped to make this one of the better ones.

 

Communication between bacteria and their hosts

Bacteria Although bacterial growth and virulence are influenced by local environmental parameters such as temperature, pH, and nutrient availability, the influence of host signals on bacterial behaviour has only recently become apparent. Microbial endocrinology is a newly recognised research area that has as its foundation the idea that through their long coexistence with animals and plants, microorganisms have evolved systems for sensing host-associated chemicals such as hormones. These hormone sensors enable the microbe to recognise that they are within the locality of a suitable host and, for commensals, that it is the appropriate time to initiate expression of genes involved in host colonisation or in the case of pathogens, genes for virulence determinants. This review by my Leicester colleague Primrose Freestone explores the discusses the bidirectional communication taking place between microorganisms and their hosts via chemical signals.

Freestone, P. (2013) Communication between bacteria and their hosts. Scientifica, 2013. http://dx.doi.org/10.1155/2013/361073
It is clear that a dialogue is occurring between microbes and their hosts and that chemical signals are the language of this interkingdom communication. Microbial endocrinology shows that, through their long coexistence with animals and plants, microorganisms have evolved sensors for detecting eukaryotic hormones, which the microbe uses to determine that they are within proximity of a suitable host and to optimally time the expression of genes needed for host colonisation. It has also been shown that some prokaryotic chemical communication signals are recognized by eukaryotes. Deciphering what is being said during the cross-talk between microbe and host is therefore important, as it could lead to new strategies for preventing or treating bacterial infections.

MicrobiologyBytes – In The News This Week

MicrobiologyBytes This week’s MicrobiologyBytes roundup:

 

 

 

 

 

 

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