Posts Tagged ‘disease’

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.]

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

The battle against TB

Tuesday, December 3rd, 2013

The Guardian I have written a lot on MicrobiologyBytes about tuberculosis (TB) as a remerging disease, but the global TB situation is still poor, so it’s always worth bringing this issue to people’s attention again. Writing in The Guardian, Nick Herbert points out the painfully slow progress which has been made (The fight against TB is not over):

The rate of new cases of TB has been falling worldwide for about a decade, enough to hit a UN millennium development goal target, and deaths will have nearly halved since 1990. But a decline of 2% a year in the estimated incidence rate suggests that the disease is being beaten at a shamefully slower rate than when the west tackled it a century ago. On current progress it will take at least another 100 years. The latest World Health Organisation report, published last month, warned that 3 million people a year who develop TB are being missed by health programmes. Most worryingly, less than a quarter of drug-resistant cases are being detected and less than half of those that are detected are successfully treated.

So hats off to Mr Herbert for highlighting this important issue. But this is The Guardian, and the byline to this story includes the phrase “western leaders need to act now“. Mr Herbert points out that:

London has the highest rates of TB of any city in western Europe. The borough of Newham has rates equivalent to Nigeria.

All of which is true. Commenters on The Guardian article weren’t slow to mention that Nick Herbert is a serving Tory MP, who was previously director of public affairs at the British Field Sports Society for six years. While the editorial process at The Guardian has ensured that the facts in Mr Herbert’s article are correct, it’s hard to disentangle this piece from the Tory agenda on limiting immigration and the aftermath of the failed badger cull.

So yes, we need to do more about TB, as some of us have been pointing out for years. But we also need to be critical and questioning about where we acquire information and how we react to it. Politicians and science generally don’t mix. On the whole, that’s a good thing – there’s already too much politics in science.

 

Bacteria-eating viruses aid war on superbugs

Thursday, October 17th, 2013

University of Leicester researchers use phages to fight Clostridium difficile

Since the discovery of the first antibiotic – penicillin – antibiotics have been heralded as the ‘silver bullets’ of medicine. They have saved countless lives and impacted on the well-being of humanity. This was beautifully illustrated in Michel Mosley’s TV series Pain Pus and Poison this week. But less than a century following their discovery, the future impact of antibiotics is dwindling at a pace that no one anticipated, with more and more bacteria out-smarting and ‘out-evolving’ these miracle drugs. This has re-energised the search for new treatments, such as phages. The key advantage of using phages over antibiotics lies in their specificity. A phage will infect and kill only a specific strain/species of bacteria. This is particularly important when treating conditions like C. difficile infections:

More information

Emergence of the Middle East Respiratory Syndrome Coronavirus (MERS)

Monday, October 14th, 2013

MERS-CoV Nice summary post from PLOS Pathogens explaining where we’re at with MERS:

It began routinely enough. A patient with severe respiratory disease at the Dr. Soliman Fakeeh Hospital in Jeddah, Saudi Arabia was getting worse and no one knew why. A sample of sputum was sent to Dr. Ali Mohamed Zaki to identify the culprit, as he had identified these diseases many times before. However, this time would be different. The sample showed no positive hits on any of the virus assays he normally used. He contacted Dr. Ron Fouchier, at Erasmus Medical College in Rotterdam, Netherlands, to see if he could be of help. Dr. Zaki’s initial idea was that the virus was a paramyxovirus, and Dr Fouchier had recently published a Pan-paramyxovirus polymerase chain reaction (PCR) assay. In Dr. Fouchier’s lab, the virus was identified as a novel coronavirus, one that had never been seen before…

Emergence of the Middle East Respiratory Syndrome Coronavirus. (2013) PLoS Pathog 9(9): e1003595. doi:10.1371/journal.ppat.1003595

 

Burkholderia, evolution and chronic disease

Thursday, October 3rd, 2013

Burkholderia pseudomallei The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. Once considered an esoteric tropical disease confined to Southeast Asia and northern Australia, research on B. pseudomallei has recently gained global prominence due to its classification as a potential bioterrorism agent by countries such as the United States and also by increasing numbers of case reports from regions where it is not endemic.

An environmental bacterium typically found in soil and water, assessing the true global prevalence of melioidosis is challenged by the fact that clinical symptoms associated with B. pseudomallei infection are extremely varied and may be confused with diverse conditions such as lung cancer, tuberculosis, or Staphyloccocus aureus infection. These diagnostic challenges, coupled with lack of awareness among clinicians, have likely contributed to underdiagnosis and the high mortality rate of melioidosis, as initial treatment is often either inappropriate or delayed. Even after antibiotic treatment, relapses are frequent, and after resolution of acute symptoms, chronic melioidosis can also occur, and the symptoms can persist for months to years.

In a recent article, Price et al. demonstrate how comparative genomic sequencing can reveal the repertoire of genetic changes incurred by B. pseudomallei during chronic human infection. Their results have significant clinical ramifications and highlight B. pseudomallei’s ability to survive in a wide range of potential niches within hosts, through the acquisition of genetic adaptations that optimize fitness and resource utilization. These studies demonstrate B. pseudomallei’s remarkable ability to evolve genetically even within the same human host.

Less Is More: Burkholderia pseudomallei and Chronic Melioidosis. (2013) MBio. doi: 10.1128/mBio.00709-13

 

Are there are lots more emerging viruses now or is there another explanation?

Thursday, September 5th, 2013

Virus dioscovery

Historically, new viruses were discovered when they popped up and did something nasty of humans, their animals, or occasionally, to plants. But for the last few decades, most new viruses have been discovered as a result of people going looking for them. Awareness of emerging human pathogens as public health threats has grown rapidly since HIV was identified in the 1980s. Annual references to “emerging disease” in the medical literature have risen a hundred-fold, from 11 in 1993 to 313 in 2012; a similar search of popular print media uncovered two references in 1993 and 241 in 2012. Does this really mean there are lots more emerging viruses these days, or is there another explanation? A new paper in PNAS looks a some of the factors behind this increase.

By one estimate, 335 “emergent events” occurred during 1940–2004. If the definition is limited to only newly recognized causes of human disease, viruses now predominate. Of the six classes of agents causing disease (prions, viruses, bacteria, fungi, protozoa, and helminths), viruses comprised 67% of the 87 pathogens discovered during 1980–2005, a period that saw the first descriptions of HIV, severe acute respiratory syndrome, hepatitis C, and Nipah viruses. Nearly 85% of these emergent viruses had single-stranded RNA (ssRNA) genomes. In an analysis of 188 viruses first found to cause human disease between 1900 and 2005, the rate at which new viruses were identified in humans appeared to quicken between 1950 and 1970 but then to slow. To examine if changes in approach or methods might account for the change in pace, the authors compiled a list of the viruses found to cause human illness from 1897, when the first virus infecting vertebrates (foot-and-mouth disease virus) was discovered, through 2010 – take a look at the list, your favourite virus is likely to be on there! Not surprisingly, when people go looking for viruses, they find them.

There are some interesting gems in this data. West Nile virus, first discovered in Uganda in 1937, rapidly spread across the United States after its introduction in 1999; in 2012 it produced severe neuroinvasive disease in about 3,000 Americans, which has been estimated to represent only about 1% of infections. The unprecedented 2004–2009 pandemic of chikungunya virus, also first described in East Africa in 1957, infected at least 2 million people in the Indian Ocean region. This analysis implies that not only has the emergence of arboviruses in the tropics been underestimated over the last 40 years but that the discovery of nonarboviruses has lagged as well because of the lack of systematic searching. The development of faster, more sensitive methods for virus identification will continue to be important in discovering new pathogens, but strategy, support, and commitment for looking in the right places in the right ways will be critical to their most effective use.

 

Search strategy has influenced the discovery rate of human viruses (2013) PNAS USA 05 August doi: 10.1073/pnas.1307243110
A widely held concern is that the pace of infectious disease emergence has been increasing. We have analyzed the rate of discovery of pathogenic viruses, the preeminent source of newly discovered causes of human disease, from 1897 through 2010. The rate was highest during 1950-1969, after which it moderated. This general picture masks two distinct trends: for arthropod-borne viruses, which comprised 39% of pathogenic viruses, the discovery rate peaked at three per year during 1960-1969, but subsequently fell nearly to zero by 1980; however, the rate of discovery of nonarboviruses remained stable at about two per year from 1950 through 2010. The period of highest arbovirus discovery coincided with a comprehensive program supported by The Rockefeller Foundation of isolating viruses from humans, animals, and arthropod vectors at field stations in Latin America, Africa, and India. The productivity of this strategy illustrates the importance of location, approach, long-term commitment, and sponsorship in the discovery of emerging pathogens.

 

Could bacteria give you cancer?

Monday, July 29th, 2013

Fusobacterium Is Associated with Colorectal Cancer We know of at least eight viruses which cause cancer in humans, but apart from Helicobacter pylori there are no firmly established cases of bacteria causing tumours. Having said that, there are a number of bacteria which have been shown to be associated with certain cancers, but the relationship between cancer and bacteria is not as clear cut as in the casue of human tumour viruses. A recent paper in PLOS ONE adds to the list of bacteria associated with particular tumours.

The human intestinal microbiota inhabits a complex and diverse environment populated by hundreds of different bacterial species. These bacteria are regulated in the gut by the mucosal immune system, which is made up of a complex network of functions and immune responses aimed at maintaining a cooperative system between the intestinal microbiota and the host. In a healthy gut these bacteria maintain homeostasis with the host. However, when an imbalance, or bacterial dysbiosis, occurs in the gut, the host may experience inflammation and a loss of barrier function. Bacterial dysbioses have been linked to several diseases including ulcerative colitis, Crohn’s disease and colorectal cancer (CRC).

No single bacterial species has been identified as a risk factor for CRC, but recent studies report an increase in the abundance of Fusobacterium in human colorectal tumors compared to controls. These studies suggest that Fusobacterium may be associated with the later stages of CRC, but it is unknown if they play a role in the early stages of colorectal carcinogenesis. While the causes of colorectal cancer are not fully known, it is becoming increasingly clear that the gut microbiota provide an important contribution.

 

Fusobacterium Is Associated with Colorectal Adenomas. (2013) PLoS ONE 8(1): e53653. doi:10.1371/journal.pone.0053653
The human gut microbiota is increasingly recognized as a player in colorectal cancer (CRC). While particular imbalances in the gut microbiota have been linked to colorectal adenomas and cancer, no specific bacterium has been identified as a risk factor. Recent studies have reported a high abundance of Fusobacterium in CRC subjects compared to normal subjects, but this observation has not been reported for adenomas, CRC precursors. We assessed the abundance of Fusobacterium species in the normal rectal mucosa of subjects with (n = 48) and without adenomas (n = 67). We also confirmed previous reports on Fusobacterium and CRC in 10 CRC tumor tissues and 9 matching normal tissues by pyrosequencing. We extracted DNA from rectal mucosal biopsies and measured bacterial levels by quantitative PCR of the 16S ribosomal RNA gene. Local cytokine gene expression was also determined in mucosal biopsies from adenoma cases and controls by quantitative PCR. The mean log abundance of Fusobacterium or cytokine gene expression between cases and controls was compared by t-test. Logistic regression was used to compare tertiles of Fusobacterium abundance. Adenoma subjects had a significantly higher abundance of Fusobacterium species compared to controls (p = 0.01). Compared to the lowest tertile, subjects with high abundance of Fusobacterium were significantly more likely to have adenomas (OR 3.66, 95% CI 1.37–9.74, p-trend 0.005). Cases but not controls had a significant positive correlation between local cytokine gene expression and Fusobacterium abundance. Among cases, the correlation for local TNF-α and Fusobacterium was r = 0.33, p = 0.06 while it was 0.44, p = 0.01 for Fusobacterium and IL-10. These results support a link between the abundance of Fusobacterium in colonic mucosa and adenomas and suggest a possible role for mucosal inflammation in this process.

Asthma and Fungal Spores

Monday, June 10th, 2013

Fungal Spores My Leicester colleague Catherine Pashley has done a lot of work in this area, so I was interested in this recent minireview in PLOS Pathogens.

  • 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.