Enteroviruses as causative agents in type 1 diabetes: loose ends or lost cause?

Coxsackie virus I’ve just been marking some student work about Group B coxsackieviruses as the cause of type 1 diabetes (T1D). This is a very old story, going back to the 1960s. In 1973 the discovery that Coxsackie virus B4 could induce insulin-dependent diabetes in suckling mice caused a lot of excitement, some of which is still bubbling away. The problem is that it is clear that Group B coxsackievirus infection in humans does not “cause” diabetes – in the sense of get infected, get diabetes. But the link won’t go away, so what is the connection between CVB and type 1 diabetes. A recent paper proposes a model which could explain the involvement of CVB as a contributory factor – if not the cause – of diabetes:

Summary:

  • Human β cells express enterovirus entry receptors and can sustain enterovirus replication.
  • Acute infection of β cells can lead to extensive islet damage and to fulminant diabetes.
    Persistent infection of β cells could drive islet autoimmunity and the development of T1D.
  • The ‘strength’ of the β cell antiviral response may determine whether autoimmunity and T1D develop.

Enteroviruses as causative agents in type 1 diabetes: loose ends or lost cause? (2014) Trends in Endocrinology & Metabolism, 25(12), 611-619
Considerable evidence implies that an enteroviral infection may accelerate or precipitate type 1 diabetes (T1D) in some individuals. However, causality is not proven. We present and critically assess evidence suggesting that islet β cells can become infected with enterovirus, and argue that this may result in one of several consequences. Occasionally, a fully lytic infection may arise and this culminates in fulminant diabetes. Alternatively, an atypical persistent infection develops which can be either benign or promote islet autoimmunity. We propose a model in which the ‘strength’ of the β cell response to the establishment of a persistent enteroviral infection determines the final disease outcome.

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Malassezia Yeast Infections in Humans and Animals

Malassezia globosa Malassezia yeasts have been found in human dandruff, deep-sea vents, and pretty much everywhere in between. The skin of most if not all warm-blooded animals is covered with these microbes, and while they mostly live in peaceful co-existence with their hosts, they can cause serious diseases in humans and animals. While treatments exist for most of these, when treating Malassezia skin diseases, one should always bear in mind that Malassezia yeasts are integral components of the skin microbiota, and therefore the therapeutic target should be controlling the Malassezia population rather than eradicating it.

Malassezia bloodstream infections are less common, but premature infants and immunocompromised patients with extended stays in intensive care are at risk. Such infections are often linked to catheterization that facilitates internalization of the yeasts, either from the patient’s own skin or from someone else’s. Because routine tests in patients with blood infections of un-known origin often do not detect Malassezia right away, diagnosis might be delayed, which can be dangerous. However, once Malassezia is identified as the culprit, therapy with antifungal drugs is usually successful in eliminating the pathogen from the bloodstream.

Humans are covered from head-to-toe with Malassezia. Healthy skin is actually cultivated by a well-balanced mix of bacteria and fungi (yeasts and molds), and this “skin flora” does not appear to elicit defense reactions by our immune system. How Malassezia interacts with other skin microbes is not yet known, but researchers think that both changes in the flora and changes in the immune system can disturb this peaceful equilibrium and lead to a range of skin diseases.

Malassezia Infections in Humans and Animals: Pathophysiology, Detection, and Treatment. (2015) PLoS Pathog 11(1): e1004523. doi: 10.1371/journal.ppat.1004523

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Cell-Size Control in Bacteria

Cell-Size Control in Bacteria How cells control their size is an important open question. Cell-size homeostasis has been discussed in the context of two major paradigms: “sizer,” in which the cell actively monitors its size and triggers the cell cycle once it reaches a critical size, and “timer,” in which the cell attempts to grow for a specific amount of time before division. These paradigms, in conjunction with the “growth law” and the quantitative bacterial cell-cycle model, inspired numerous theoretical models and experimental investigations, from growth to cell cycle and size control. However, experimental evidence involved difficult-to-verify assumptions or population-averaged data, which allowed different interpretations or limited conclusions. In particular, population-averaged data and correlations are inconclusive as the averaging process masks causal effects at the cellular level.

A recent paper monitors hundreds of thousands of Gram-negative Escherichia coli and Gram-positive Bacillus subtilis cells under a wide range of steady-state growth conditions. The results and demonstrate that cells add a constant volume each generation, irrespective of their newborn sizes, conclusively supporting the so-called constant Δ model. Bacteria (and probably other cells) don’t double in mass before dividing. Instead they add a constant volume (or mass) no matter what their initial size. A small cell adds the same volume as a large cell. By following this rule a cell population quickly converges on a common size.

Cell-Size Control and Homeostasis in Bacteria. Current Biology 24 December 2014 doi: 10.1016/j.cub.2014.12.009

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Solving the mystery of reverse transcription

Cytoplasmic reverse-transcription and pre-integration complexes The biology of retroviruses is really all about the processes of reverse transcription, so it’s frustrating that nearly 50 years after their discovery, the steps from cytoplasmic entry until integration of the reverse transcribed genome are still mysterious. They occur in ill-defined reverse-transcription- and pre-integration-complexes (RTC, PIC) with various host and viral proteins implicated.

A new paper in eLife describes quantitative detection of functional RTC/PIC by labeling nascent DNA combined with detection of viral integrase. Interestingly, the virus capsid (CA) protein remains associated with cytoplasmic RTC/PIC in primary human macrophages, but is lost from nuclear PIC in a HeLa-derived cell line. The capsid-targeted inhibitor PF74 exhibits a bimodal mechanism, blocking RTC/PIC association with the host factor CPSF6 and nuclear entry at low, and abrogating reverse transcription at high concentrations. This newly developed system is ideally suited for studying retroviral post-entry events and the roles of host factors including DNA sensors and signaling molecules.

Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. eLife December 17, 2014 doi: 10.7554/eLife.04114

 

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Human Viruses and Cancer

The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses – EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV – have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers.

Morales-Sánchez, A., and Fuentes-Pananá, E.M. (2014) Human Viruses and Cancer. Viruses, 6(10): 4047-4079.

Bradford Hill's postulates for causative relations

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Oncolytic viruses as anticancer vaccines

Oncolytic viruses as anticancer vaccines
Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy.
Oncolytic viruses as anticancer vaccines. (2014) Front Oncol. 4:188. doi: 10.3389/fonc.2014.00188

 

Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.

Trial Watch: Oncolytic viruses for cancer therapy. Oncoimmunology. 2014 3: e28694. doi: 10.4161/onci.28694

 

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Garlic for the common cold

Garlic I’ve been suffering with a cold for the past week so I was quite interested to see this updated metastudy from the Cochrane Database. I’m not convinced garlic can cure the comon cold, but I certainly haven’t been troubled by vampires recently. But on another note: what the heck is “the common cold” exactly, and what are these trials testing?

Listen to the podcast here:

Lissiman E, Bhasale AL, Cohen M. Garlic for the common cold. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD006206. DOI: 10.1002/14651858.CD006206.pub4
Background: Garlic is popularly believed to be useful for the common cold. This belief is based on traditional use and some laboratory evidence that garlic has antibacterial and antiviral properties. On average, adults have two to four common colds per year.
Study characteristics: The evidence is current to the 7 August 2014. Of the eight studies identified, only one fulfilled the criteria for the review. This study assessed 146 participants over a three-month period. Half the participants took a placebo tablet and half took a garlic tablet during this time. The participants then wrote in a diary when they had symptoms of a cold.
Key results: The included study found that people who took garlic every day for three months (instead of a placebo) had fewer colds. That is, over the three-month period, there were 24 occurrences of the common cold in the garlic group, compared to 65 in the placebo group. When participants experienced a cold, the length of illness was similar in both groups (4.63 versus 5.63 days).
Quality of the evidence: More participants in the garlic group (four) than the placebo group (one) noted a smell when burping, so it is possible that blinding of participants was not adequate. However, other potential biases were well controlled. The only included study is directly relevant to the review question. Although the trial is small, there were enough participants to provide precise, reliable results. There is no evidence that results were selectively reported. However, this was possible as the outcomes do not appear to have been decided in advance. Considering the financial incentive for supplement companies to produce positive trials, it is also possible that trials that showed no effect of garlic were never published. Overall, the quality of the evidence is moderate.
Side effects: Possible side effects in this small trial included odour and a skin rash. More information is needed about the possible side effects of garlic.

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The threat of zoonotic diseases

Crossing the species barrier Zoonotic infectious diseases have been important concerns to humans since the beginning of the domestication of animals 10,000 years ago. Approximately 75% of emerging infectious diseases are zoonoses. The phenomenon of emerging and reemerging infectious diseases is driven by various anthropogenic factors, including: genetic and biological factors, such as microbial adaptation to macro- and microenvironmental changes along with changes in host susceptibility to infection; environmental factors, including climate change, changes in ecosystems, and changes in human and animal population densities; and socioeconomic and political factors, such as increasing international travel and commerce, social inequality, poverty, conflict, famine, lack of political will, and changes in economic development and land use.

Over the last 15 years, our planet has faced more than 15 deadly zoonotic or vector-borne global outbreaks, both viral (e.g., Ebola, Hanta, highly pathogenic avian influenza [H5N1 and H7N9], West Nile, Rift Valley fever, norovirus, severe acute respiratory syndrome [SARS], Marburg, influenza A [H1N1]) and bacterial (e.g. Escherichia coli O157:H7, Yersinia pestis, and Bacillus anthracis). Since 1980, more than 87 new zoonotic and/or vector-borne EIDs have been discovered.

The global economic burden due to zoonotic diseases is very high. According to a recent World Bank estimate, the economic burden due to six of the zoonotic diseases that have occurred in specific countries between 1997 and 2009 is estimated to be US$80,000,000,000. In a worst-case scenario, potential losses from a pandemic influenza outbreak could be US$3 trillion, which is equivalent to 5% of the global GDP. A recent report from the International Livestock Research Institute highlighted zoonoses as major obstacles to poverty alleviation, affecting 1,000,000,000 livestock keepers. The report estimated that there are over 2,500,000,000 cases of human illness and 2.7 million deaths annually due to the top 56 zoonoses.

While zoonotic EIDs are a major concern globally, their impact in less developed countries is disproportionately high because of the occurrence of risk factors such as a high rate of population growth, lack of infrastructure and skilled-manpower capacity to tackle disease outbreaks, a high proportion of people with compromised immunity due to comorbidities such as HIV/AIDS or parasitic diseases, and lifestyles in which daily life depends on animals.

The Global One Health Paradigm: Challenges and Opportunities for Tackling Infectious Diseases at the Human, Animal, and Environment Interface in Low-Resource Settings. (2014) PLoS Negl Trop Dis 8(11): e3257. doi:10.1371/journal.pntd.0003257
Zoonotic infectious diseases have been an important concern to humankind for more than 10,000 years. Today, approximately 75% of newly emerging infectious diseases (EIDs) are zoonoses that result from various anthropogenic, genetic, ecologic, socioeconomic, and climatic factors. These interrelated driving forces make it difficult to predict and to prevent zoonotic EIDs. Although significant improvements in environmental and medical surveillance, clinical diagnostic methods, and medical practices have been achieved in the recent years, zoonotic EIDs remain a major global concern, and such threats are expanding, especially in less developed regions. The current Ebola epidemic in West Africa is an extreme stark reminder of the role animal reservoirs play in public health and reinforces the urgent need for globally operationalizing a One Health approach. The complex nature of zoonotic diseases and the limited resources in developing countries are a reminder that the need for implementation of Global One Health in low-resource settings is crucial. The Veterinary Public Health and Biotechnology (VPH-Biotec) Global Consortium launched the International Congress on Pathogens at the Human-Animal Interface (ICOPHAI) in order to address important challenges and needs for capacity building. The inaugural ICOPHAI (Addis Ababa, Ethiopia, 2011) and the second congress (Porto de Galinhas, Brazil, 2013) were unique opportunities to share and discuss issues related to zoonotic infectious diseases worldwide. In addition to strong scientific reports in eight thematic areas that necessitate One Health implementation, the congress identified four key capacity-building needs: (1) development of adequate science-based risk management policies, (2) skilled-personnel capacity building, (3) accredited veterinary and public health diagnostic laboratories with a shared database, and (4) improved use of existing natural resources and implementation. The aim of this review is to highlight advances in key zoonotic disease areas and the One Health capacity needs.

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Small Is Beautiful

Influenza M2 Small Proteins Can No Longer Be Ignored. (2014) Annual Review of Biochemistry 83: 753-777 doi: 10.1146/annurev-biochem-070611-102400
Small proteins, here defined as proteins of 50 amino acids or fewer in the absence of processing, have traditionally been overlooked due to challenges in their annotation and biochemical detection. In the past several years, however, increasing numbers of small proteins have been identified either through the realization that mutations in intergenic regions are actually within unannotated small protein genes or through the discovery that some small, regulatory RNAs encode small proteins. These insights, together with comparative sequence analysis, indicate that tens if not hundreds of small proteins are synthesized in a given organism. This review summarizes what has been learned about the functions of several of these bacterial small proteins, most of which act at the membrane, illustrating the astonishing range of processes in which these small proteins act and suggesting several general conclusions. Important questions for future studies of these overlooked proteins are also discussed.

Viral miniproteins. Annual Review of Microbiology (2014) 68: 21-43. doi: 10.1146/annurev-micro-091313-103727
Many viruses encode short transmembrane proteins that play vital roles in virus replication or virulence. Because many of these proteins are less than 50 amino acids long and not homologous to cellular proteins, their open reading frames were often overlooked during the initial annotation of viral genomes. Some of these proteins oligomerize in membranes and form ion channels. Other miniproteins bind to cellular transmembrane proteins and modulate their activity, whereas still others have an unknown mechanism of action. Based on the underlying principles of transmembrane miniprotein structure, it is possible to build artificial small transmembrane proteins that modulate a variety of biological processes. These findings suggest that short transmembrane proteins provide a versatile mechanism to regulate a wide range of cellular activities, and we speculate that cells also express many similar proteins that have not yet been discovered.

 

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