Posts Tagged ‘Medicine’

A global network of researchers? Not really – small worlds.

Thursday, April 17th, 2014

As science evolves, important scientific achievements require the collaborative effort of an increasing number of researchers. The study of patterns of scientific collaboration allows us to gain further understanding of innovation and knowledge production. Scientific collaboration networks have been the subject of growing interest in the past few years. Collaborative scientific publications have a long history. The first collaborative research paper was published in 1665 in the Philosophical Transactions of the Royal Society. To date, the most multi-authored scientific paper was published in 2010, when 3,222 researchers from 32 different countries contributed to a study of charged-particle multiplicities performed in the Large Hadron Collider at CERN.

A new study finds that the United States was the country with the largest number of international collaborations, particularly with South Africa, Uganda and Brazil. The high global clustering coefficient coupled with a short average distance between nodes suggests a “small-world phenomenon” among HIV and HPV researchers. Researchers from high-income countries seem to have a high number of research collaborations among them and to cluster together in densely connected communities, particularly those from the US. There is a large well-connected community, which encompasses 70% of researchers, and other much smaller communities, including the UK.

Small worlds

International Scientific Collaboration in HIV and HPV: A Network Analysis. (2014) PLoS ONE 9(3): e93376. doi:10.1371/journal.pone.0093376
Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a “small-world phenomenon.” Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries.

Reasons to be cheeful: Influenza treatment

Friday, April 11th, 2014

Lung immunity against influenza virus As we find out that Tamiflu is no more effective than paracetamol or ibuprofen in treating influenza infection (NHS Choices: Effectiveness of Tamiflu and Relenza questioned) – giving Ben Goldacre the right to say I told you so – maybe there is some reason to be more optimistic about treating influenza.

A new paper in Immunity [subscription] shows that prostaglandin E2 (PGE2) is upregulated during influenza A virus infection, and this inhibits macrophage recruitment to the lungs as well as interferon production and apoptosis in influenza virus-infected macrophages. This results in impaired macrophage antigen presentation and reduced adaptive immunity against influenza virus. The good news is that suppression of PGE2 with prostaglandin inhibitors protects against influenza infection. And we’ve got lots of prostaglandin inhibitors, including ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) that work by inhibiting a molecule called cyclooxygenase (COX). The lung innate immune system has a critical role in limiting respiratory viral infections, particularly in the case of the nastier strains of flu such as the 1918 Spanish Influenza virus (and those still to come). So this is potentially very good news.

The catch? Well this paper refers to studies in mice and clinical trials will need to be done in humans to show the same effects. Clinical trials will be easy to do as many COX- and PGE-inhibitors are already approved for human use. All we need to do is avoid Roche doing the trial, or we may never find out the results.

Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages. Immunity, 10 April 2014 doi: http://dx.doi.org/10.1016/j.immuni.2014.02.013
Summary: Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.

[Editorial comment: I can just imaging the authors and journal editors doing the happy dance that this paper came out on sthe same day as the Tamiflu news.]

Exploiting bacteriophages for human health

Thursday, March 27th, 2014

Exploiting bacteriophages for human health Whenever I write about phage therapy – using bacteriophages to treat bacterial infections – readers get overly enthusiastic about injecting patients with phages to produce a miracle cure. Look at it this way – that hasn’t worked for the last 100 years and it’s not likely to suddenly start working now. This short review is worth reading because it takes a much more thoughtful and holistic approach to the idea of phage therapy than the simple minded “phage as wonder cure” idea.

Exploiting gut bacteriophages for human health. Trends Microbiol. 20 Mar 2014 pii: S0966-842X(14)00045-6. doi: 10.1016/j.tim.2014.02.010
The human gut contains approximately 1015 bacteriophages (the ‘phageome’), probably the richest concentration of biological entities on earth. Mining and exploiting these potential ‘agents of change’ is an attractive prospect. For many years, phages have been used to treat bacterial infections in humans and more recently have been approved to reduce pathogens in the food chain. Phages have also been studied as drug or vaccine delivery vectors to help treat and prevent diseases such as cancer and chronic neurodegenerative conditions. Individual phageomes vary depending on age and health, thus providing a useful biomarker of human health as well as suggesting potential interventions targeted at the gut microbiota.

HIV cure research – advances and prospects

Thursday, March 20th, 2014

HIV reservoirs Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) (=HAART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.

Highlights:

  • Some cases of cure or remission of infection have boosted the search for an HIV cure.
  • cART intensification has not shown significant impact in the reservoirs, but early cART may limit them.
  • Strategies to purge the reservoirs face difficulties linked to the complexity of latency mechanisms and drug non-specificity.
  • Repression of reservoirs or cell manipulation to render them less permissive to HIV may facilitate HIV remission.
  • HIV cure/remission may require boosting immune responses while keeping inflammation in check.

 

HIV cure research: Advances and prospects. (2014) Virology pii: S0042-6822(14)00065-8. doi: 10.1016/j.virol.2014.02.021

HSV-1 evasion of the host humoral immune system

Thursday, March 13th, 2014

HSV-1 evasion of the host humoral immune system I’ve been banging on to my final year students about how clever heresviruses are at evading the immune response. No sooner do I close my mouth than another one comes along:

Herpes Simplex Virus 1 (HSV-1) infects 40–80% of adults worldwide. HSV-1 initiates infection at mucosal surfaces and spreads along sensory neurons to establish a life-long latent infection that can lead to neurological diseases. Humans usually develop IgG antibodies that specifically recognize pathogens via fragment antigen binding (Fab) variable regions. HSV-1 can avoid the protective effects of antibodies by producing gE-gI, a receptor that binds to the constant portion of IgGs (Fc), tethering the antibody in a position where it cannot trigger downstream immune functions. A gE-gI–bound IgG can participate in antibody bipolar bridging (ABB) such that the Fabs bind a viral antigen and the Fc binds gE-gI. The fate of ABB complexes had been unknown. This paper uses used live cell fluorescent imaging to follow ABB complexes during their formation and transport within a cell. ABB assemblies were internalized into acidic intracellular compartments, where gE-gI dissociated from IgG–viral antigen complexes and the IgG and antigen were targeted for degradation within lysosomes. These results suggest that gE-gI mediates clearance of infected cell surfaces of both anti-viral IgGs and viral antigens, a general mechanism to facilitate latent infection by evading IgG-mediated responses.

The Herpes Virus Fc Receptor gE-gI Mediates Antibody Bipolar Bridging to Clear Viral Antigens from the Cell Surface. (2014) PLoS Pathog 10(3): e1003961. doi:10.1371/journal.ppat.1003961

Remember what happened last time we “cured” AIDS?

Thursday, March 6th, 2014

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.

 

From Scourge to Cure: Viruses Versus Cancer

Thursday, February 13th, 2014

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

Wednesday, February 5th, 2014

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

Thursday, January 30th, 2014

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.