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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Understanding the next Ebola virus rather than panicking about the current one

Parvovirus Canine parvovirus (CPV) emerged as a new pandemic pathogen of dogs in the 1970s and is closely related to feline panleukopenia virus (FPV), a parvovirus of cats and related carnivores. This is an important example of a viral pathogen that evolved by cross-species transmission and mutation to initiate a disease pandemic, something virologists have been writing about for years but is now highly fashionable (think: Ebola: Will ebola come to the UK? Yes. And will it kill us all? No).

Carnivore parvoviruses infect many species, and their passage in different hosts may select mutations that facilitate host jumping; for example, natural passage of CPV in raccoons may have facilitated its adaptation to dogs. A new papers demonstrates that these barriers can be overcome by only a few mutations in the virus that probably alter host receptor binding, and that host adaptation can differ dramatically among very similar viruses.

Passage of viruses in cell cultures of different hosts results in mutations at the same sites that vary in nature and confer fitness increases, strongly suggesting that they are adaptively important. This shows that parvoviruses may cross species barriers to infect less susceptible hosts through single or only a few mutations, and that differences in the genetic background, host range, and/or evolutionary history of the viruses influence their propensity to jump hosts. These discoveries help reveal the mechanisms that control host switching and virus emergence.

Host-Specific Parvovirus Evolution in Nature Is Recapitulated by In Vitro Adaptation to Different Carnivore Species. (2014) PLoS Pathog 10(11): e1004475. doi:10.1371/journal.ppat.1004475
Canine parvovirus (CPV) emerged as a new pandemic pathogen of dogs in the 1970s and is closely related to feline panleukopenia virus (FPV), a parvovirus of cats and related carnivores. Although both viruses have wide host ranges, analysis of virus sequences recovered from different wild carnivore species, as shown here, demonstrated that 95% were derived from CPV-like viruses, suggesting that CPV is dominant in sylvatic cycles. Many viral sequences showed host-specific mutations in their capsid proteins, which were often close to sites known to control binding to the transferrin receptor (TfR), the host receptor for these carnivore parvoviruses, and which exhibited frequent parallel evolution. To further examine the process of host adaptation, we passaged parvoviruses with alternative backgrounds in cells from different carnivore hosts. Specific mutations were selected in several viruses and these differed depending on both the background of the virus and the host cells in which they were passaged. Strikingly, these in vitro mutations recapitulated many specific changes seen in viruses from natural populations, strongly suggesting they are host adaptive, and which were shown to result in fitness advantages over their parental virus. Comparison of the sequences of the transferrin receptors of the different carnivore species demonstrated that many mutations occurred in and around the apical domain where the virus binds, indicating that viral variants were likely selected through their fit to receptor structures. Some of the viruses accumulated high levels of variation upon passage in alternative hosts, while others could infect multiple different hosts with no or only a few additional mutations. Overall, these studies demonstrate that the evolutionary history of a virus, including how long it has been circulating and in which hosts, as well as its phylogenetic background, has a profound effect on determining viral host range.

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Let’s get things in perspective

Chromobacterium While the current outbreak of Ebola virus in West Africa is very serious, in the current panic people have forgotten that malaria kills thousands of times more people than Ebola each year. In spite of decades of effort, we are still struggling with malaria vaccines, so attention is starting to switch to a new strategy, targeting the mosquitoes that spread malaria.

Just like those of humans, insect guts are full of microbes, and this microbiota can influence the insect’s ability to transmit diseases. A new study reports that a bacterium (Chromobacterium Csp_P) isolated from the gut of an Aedes mosquito can reduce infection of mosquitoes by malaria parasites and dengue virus. The bacterium can also directly inhibit these pathogens in the test tube, and shorten the life span of the mosquitoes that transmit both diseases.

Chromobacterium Csp_P can effectively colonize the midguts of Anopheles gambiae and Aedes aegypti mosquitoes and can, when ingested by the mosquito, significantly reduce the mosquito’s susceptibility to infection with the malaria parasite and dengue virus. We also show that exposure to, and ingestion of, Csp_P can reduce the lifespan of larval and adult mosquitoes. Csp_P has anti-Plasmodium and anti-dengue activity independent of the mosquito, suggesting that the bacterium secretes metabolites that could potentially be exploited to prevent disease transmission or to treat infection.

This comes on top of earlier work involving the use of Wolbachia to attack mosquitoes. We may be some way away from an effective malaria vaccine, but the development of novel control strategies for vector-borne diseases is gaining ground rapidly.

 

Chromobacterium Csp_P Reduces Malaria and Dengue Infection in Vector Mosquitoes and Has Entomopathogenic and In Vitro Anti-pathogen Activities. (2014) PLoS Pathog 10(10): e1004398. doi: 10.1371/journal.ppat.1004398
Plasmodium and dengue virus, the causative agents of the two most devastating vector-borne diseases, malaria and dengue, are transmitted by the two most important mosquito vectors, Anopheles gambiae and Aedes aegypti, respectively. Insect-bacteria associations have been shown to influence vector competence for human pathogens through multi-faceted actions that include the elicitation of the insect immune system, pathogen sequestration by microbes, and bacteria- produced anti-pathogenic factors. These influences make the mosquito microbiota highly interesting from a disease control perspective. Here we present a bacterium of the genus Chromobacterium (Csp_P), which was isolated from the midgut of field-caught Aedes aegypti. Csp_P can effectively colonize the mosquito midgut when introduced through an artificial nectar meal, and it also inhibits the growth of other members of the midgut microbiota. Csp_P colonization of the midgut tissue activates mosquito immune responses, and Csp_P exposure dramatically reduces the survival of both the larval and adult stages. Ingestion of Csp_P by the mosquito significantly reduces its susceptibility to Plasmodium falciparum and dengue virus infection, thereby compromising the mosquito’s vector competence. This bacterium also exerts in vitro anti-Plasmodium and anti-dengue activities, which appear to be mediated through Csp_P-produced stable bioactive factors with transmission-blocking and therapeutic potential. The anti-pathogen and entomopathogenic properties of Csp_P render it a potential candidate for the development of malaria and dengue control strategies.

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How to stop the spread of Ebola [video]

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Cytomegalovirus

HCMV I’m a little out of date with my cytomegalovirus (CMV) knowledge. As I currently have a student working on a project on virus infections in pregnancy, this short review – focussing on new treatment options for cytomegalovirus infection, recent clinical trials and bone marrow transplantation, congenital infections and interventions during pregnancy – is most welcome.

Cytomegalovirus. Curr Opin Infect Dis. 08 Oct 2014. doi: 10.1097/QCO.0000000000000107
Three double-blind randomized placebo-controlled phase 2 proof-of-concept studies have each identified a novel antiviral drug with activity against CMV infection in bone marrow transplant patients. One of these (brincidofovir) inhibits the DNA polymerase that is the target of the currently licensed drug ganciclovir. Another new drug (maribavir) inhibits a protein kinase which, coincidentally, is the enzyme responsible for activating ganciclovir through phosphorylation. The third drug (letermovir) inhibits the terminase enzyme complex responsible for packaging unit length DNA into assembling virions.In addition, in a double-blind randomized placebo-controlled trial in neonates with symptomatic congenital CMV infection, a 6-month course of valganciclovir was superior to the standard 6-week course of the same drug. In pregnant women with primary CMV infection, administration of hyperimmune immunoglobulin did not significantly reduce transmission of CMV across the placenta. The ability to diagnose CMV infections reliably in different clinical settings through application of molecular laboratory methods has ushered in new ways of evaluating potential new treatments for CMV. Several of these may help control the diseases caused by this important human pathogen.

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Viroids: Survivors from the RNA World?

Viroid A new review in Annual Review of Microbiology gives an excellent introduction to viroids.

Contents:

  • Introduction: Why The Need For An RNA World?
  • Viroids: Essential Features
  • Discovery of a Subviral World
  • Structure: Small Circular RNAs with Compact Folding
  • Replication: Rolling-Circle Mechanism Catalyzed by Enzymes and Ribozymes
  • Sequence Diversity
  • Viroid-Related Replicons
  • Viroid-Like Satellite RNAs
  • Retroviroid-Like Elements
  • Hepatitis δ virus
  • Why Are Viroids And Viroid-Related Replicons Regarded As Survivors Of The RNA World?
  • Early Speculations on the Origin of Viroids
  • Circular RNAs: Relics of Precellular Evolution?
  • Viroid-Related Replicons
  • Summary

 

Viroids: Survivors from the RNA World? (2014) Annual Review of Microbiology, 68(1): 395-414. doi: 10.1146/annurev-micro-091313-103416

 

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The Flawed Prokaryote

Bacterial origins There are two types of biologist – those who think that prokaryotes exist and those who don’t.

The simple binary divide between prokaryotes and eukarotes is an old (19th Century) idea. Splitting all life forms into two headings (let’s leave viruses out of this for now) is seductive. The problem is that this old idea – still trotted out in textbooks – doesn’t stand up to molecular data. Even though we only need three domains (bacteria, eukarya and archaea) to account for scientific observations, the old prokaryote-eukaryote idea just won’t die. Think about that when you’re writing your essays…

 

Pace, N.R. (2006) Time for a change. Nature, 441(7091), 289-289. doi:10.1038/441289a

Close Encounters of the Third Domain: The Emerging Genomic View of Archaeal Diversity and Evolution. Archaea, 2013. http://dx.doi.org/10.1155/2013/202358

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Welcome to new microbiology students

MicrobiologyBytes MicrobiologyBytes has been explaining the latest news about microbiology for nearly ten years and is read by thousands of people worldwide each month. I hope that you will become one of them. You can read MicrobiologyBytes on this website, or if you prefer, get notification of new items on Facebook or Twitter or by email (click the Follow button top right). And it’s all free and always will be.

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So whether you’re a student (or a teacher) of microbiology, welcome to MicrobiologyBytes. Remember to ask lots of questions, and most importantly – enjoy learning. And if you, like me, are not so new to microbiology, thanks for sticking around. i’d appreciate it if you left me a brief comment on how you use MicrobiologyBytes and if there’s anything else you’d lie to see here – because while the content is microbiology, MicrobiologyBytes is really all about you.

 

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