Rabies Rapid Transit System

Rabies virus Negri bodies Rabies virus hijacks the transport systems of neurons, manipulating axonal transport machinery to get to the central nervous system at maximum speed. 

Rabies virus is a neurotropic negative-strand RNA rhabdovirus. It is transmitted mostly via bites from diseased animals and causes a fatal infection of the nervous system in both animals and humans. A key step in rabies virus pathogenesis is rapid transfer to the Central Nervous System (CNS) through the Peripheral Nervous System. Due to its extraordinary properties in directed axonal transport and trans-synaptic spread, rabies virus has also been used as a neuro-tracing agent to map neuronal circuitry. Understanding the mechanism of rabies virus neuronal transport is important for both basic and applied fields.

Rabies virus enters the peripheral nervous system and undergoes long-distance transport before arriving at the cell body and subsequently the CNS. Axonal transport is the cellular process of trafficking proteins, organelles, vesicles, RNA and other cellular factors to and from the neuronal cell body. The molecular motor kinesin drives transport from the cell body anterogradely, supplying proteins, lipids and other essential materials to the cell periphery. Dynein/dynactin complexes drive retrograde transport, moving damaged proteins for degradation and critical signaling molecules such as neurotrophins to the cell body. Although rabies virus phosphoprotein P, a component of the viral nucleocapsid of infecting virions, was shown to directly interact with a light chain of the dynein motor complex, axonal RABV transport and CNS infection are independent of that interaction and long distance transport of complete enveloped virions within internalized endosomes is more likely. The cellular and molecular mechanisms involved in rabies virus’ infection and retrograde trafficking are yet to be understood.

A new paper in PLOS Pathogens shows that rabies virus interacts with the p75 neurotrophin receptor (p75NTR) at peripheral neuron tips to enter the axon. Then the virus moves in acidic compartments, mostly with p75NTR. Rabies virus is transported faster than NGF, an endogenous p75NTR ligand. p75NTR-dependent transport of rabies virus is faster and more directed than p75NTR-independent rabies virus transport. Hence, rabies virus not only exploits the neurotrophin transport machinery, but also has a positive influence on transport kinetics, facilitating its own arrival at the CNS. These findings reveal how RABV can spread from the periphery, describe a novel role for the RABV-p75NTR interaction beyond ligand-receptor binding, and define a mechanism that allows proficient long-distance accelerated transport in axons.

Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. (2014) PLoS Pathog 10(8): e1004348. doi:10.1371/journal.ppat.1004348
Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS). The strategy RABV uses to hijack the cellular transport machinery is still not clear. It is thought that RABV interacts with membrane receptors in order to internalize and exploit the endosomal trafficking pathway, yet this has never been demonstrated directly. The p75 Nerve Growth Factor (NGF) receptor (p75NTR) binds RABV Glycoprotein (RABV- G) with high affinity. However, as p75NTR is not essential for RABV infection, the specific role of this interaction remains in question. Here we used live cell imaging to track RABV entry at nerve terminals and studied its retrograde transport along the axon with and without the p75NTR receptor. First, we found that NGF, an endogenous p75NTR ligand, and RABV, are localized in corresponding domains along nerve tips. RABV and NGF were internalized at similar time frames, suggesting comparable entry machineries. Next, we demonstrated that RABV could internalize together with p75NTR. Characterizing RABV retrograde movement along the axon, we showed the virus is transported in acidic compartments, mostly with p75NTR. Interestingly, RABV is transported faster than NGF, suggesting that RABV not only hijacks the transport machinery but can also manipulate it. Co-transport of RABV and NGF identified two modes of transport, slow and fast, that may represent a differential control of the trafficking machinery by RABV. Finally, we determined that p75NTR-dependent transport of RABV is faster and more directed than p75NTR-independent RABV transport. This fast route to the neuronal cell body is characterized by both an increase in instantaneous velocities and fewer, shorter stops en route. Hence, RABV may employ p75NTR-dependent transport as a fast mechanism to facilitate movement to the CNS.

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HIV-Mediated Apoptosis: New Therapeutic Targets

Involvement of HIV proteins in apoptotic pathways Currently, there is no cure for HIV infection. Antiretroviral therapy against HIV has been successful, but now research is focusing on achieving the ultimate goal, a cure. Consequently, understanding the host factors that control disease progression will be fundamental to the development of new therapeutic strategies. This review discusses the apoptotic pathways that result in the demise of the immune system and possible apoptotic-mediated interventions for therapeutic purposes and looks at the drugs currently under development.

 

Human Immunodeficiency Virus-1 (HIV-1)-Mediated Apoptosis: New Therapeutic Targets. (2014) Viruses, 6(8): 3181-3227; doi:10.3390/v6083181
HIV has posed a significant challenge due to the ability of the virus to both impair and evade the host’s immune system. One of the most important mechanisms it has employed to do so is the modulation of the host’s native apoptotic pathways and mechanisms. Viral proteins alter normal apoptotic signaling resulting in increased viral load and the formation of viral reservoirs which ultimately increase infectivity. Both the host’s pro- and anti-apoptotic responses are regulated by the interactions of viral proteins with cell surface receptors or apoptotic pathway components. This dynamic has led to the development of therapies aimed at altering the ability of the virus to modulate apoptotic pathways. These therapies are aimed at preventing or inhibiting viral infection, or treating viral associated pathologies. These drugs target both the viral proteins and the apoptotic pathways of the host. This review will examine the cell types targeted by HIV, the surface receptors exploited by the virus and the mechanisms whereby HIV encoded proteins influence the apoptotic pathways. The viral manipulation of the hosts’ cell type to evade the immune system, establish viral reservoirs and enhance viral proliferation will be reviewed. The pathologies associated with the ability of HIV to alter apoptotic signaling and the drugs and therapies currently under development that target the ability of apoptotic signaling within HIV infection will also be discussed.

 

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From the dandruffome to deep sea vents

Malassezia globosa Malassezia fungi have been linked to skin diseases like dandruff and eczema. Until recently, they were assumed to have evolved to inhabit mammalian skin. More recently, however, they have been found in a much wider range of habitats, and this short review focuses on what researchers know and would like to know about marine Malassezia.

Discoveries of Malassezia representatives in fish, plankton, sponges, corals, lobster, etc., and the fact that marine Malassezia appear to dominate certain marine habitats, suggest that marine Malassezia should be the focus of future research into the diversity and distribution of this enigmatic group. The paper also discusses the challenges of such research: Malassezia fungi are notoriously difficult to grow in laboratory cultures, especially in “clean” cultures that consist only of a single species, and recreating marine environments with specialized pressure and saltiness are likely to further complicate cultivation efforts.

From Dandruff to Deep-Sea Vents: Malassezia-like Fungi Are Ecologically Hyper-diverse. (2014) PLoS Pathog 10(8): e1004277. doi: 10.1371/ journal.ppat.1004277
As the dominant component of the mycobiota on human skin – both healthy and diseased – the genus Malassezia has received a fair amount of attention. Since the middle of the 19th century, researchers have linked these fungi with skin maladies such as dandruff and eczema, but their difficulty to culture axenically long hampered studies of their systematics and diversity. Malassezia is the sole genus within the fungal order Malasseziales, contained within the proposed subphylum Malasseziomycetes (anonymous reviewer; personal communication). Although Malassezia is sister to the so-called ”smut” plant pathogens, they are markedly divergent in ecological terms. A hallmark of Malassezia species is their incomplete fatty acids synthesis metabolic pathway, and reliance, instead, on a suite of extracellular lipases, phospho-lipases, and acid sphingomyelinases. In fact, only a single species, M. pachydermatis, is able to survive in culture. Until recently, it was assumed that Malassezia evolved into a specialized and narrow niche associated with the skin of mammalian hosts. However, culture-independent studies of fungi from environmental samples show that Malassezia are exceedingly widespread and ecologically diverse. Recent studies in little- characterized marine environments point to extensive diversification of Malassezia-like organisms, providing exciting opportunities to explore the ecology, evolution and diversity of this enigmatic group.

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If I have seen further than others it is because I have a bloody big microscope

Atomic Force Microscopy Microbial cells sense and respond to their environment using their surface constituents. Therefore understanding the assembly and biophysical properties of cell surface molecules is an important research topic. With its ability to observe living microbial cells at nanometer resolution and to manipulate single-cell surface molecules, atomic force microscopy has emerged as a powerful tool in microbiology. This short review surveys major breakthroughs made in cell surface microbiology using AFM techniques, emphasizing the most recent structural and functional insights.

Atomic Force Microscopy in Microbiology: New Structural and Functional Insights into the Microbial Cell Surface. (2014) mBio 5(4) e01363-14 doi: 10.1128/mBio.01363-14

 

And while we’re on the subject of advances in microscopy:

Microscopy: Cryo-EM enters a new era. (2014) eLife 3: e03678 doi: http://dx.doi.org/10.7554/eLife.03678
The development of new detector hardware has led to a resolution revolution in electron cryo-microscopy (cryo-EM). This is evident from a series of striking new structures obtained by cryo-EM at near-atomic resolution: these include ribosomes from human pathogens, mitochondria, ribosomes in complex with a protein translocase, ion channels, or a key enzyme in the biogenesis of methane. The ability to solve such structures in atomic detail is an essential prerequisite for the development of novel antibiotics and drugs.

 

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Bacteriophage behavioral ecology: How phages alter their host’s habits

Bacteriophage behavioral ecology Bacteriophages direct several aspects of bacterial behavior and, considering the diversity and prevalence of the means described to date, we predict that the discovery of novel ways in which phages shape biological interaction networks will continue. As phages have been found that can impact carbon acquisition and metabolism, phages likely have roles in other key metabolic bacterial processes, such as nitrogen fixing. The ability of phages to alter bacterial survival in adverse conditions leads us to surmise that they may have roles in other specific behaviors such as chemotaxis and other adaptations in challenging environments, e.g. to heavy metal poisoning and exposure to irradiation.

Phages can modify bacterial behaviors either by directly introducing additional functions or by indirectly by regulating bacterial genes, e.g. by phage-encoded sigma factors. This paper presents several examples of how phages could increase cells defense, virulence, or survival in particular environments. The agr quorum sensing (QS) system is known to promote many of the behaviors and phenotypes discussed in this article, including toxin production, biofilm formation, motility, and sporulation. Alternatively, the phage QS genes may be a form of informing an expanded population of the same lysogen, (and therefore the phage), of its density within the environment with implications for induction and phage dynamics.

Bacteriophage behavioral ecology: How phages alter their bacterial host’s habits. Bacteriophage (2014) 4: e29866. doi: 10.4161/bact.29866
Bacteriophages have an essential gene kit that enables their invasion, replication, and production. In addition to this “core” genome, they can carry “accessory” genes that dramatically impact bacterial biology, and presumably boost their own success. The content of phage genomes continue to surprise us by revealing new ways that viruses impact bacterial biology. The genome of a Clostridium difficile myovirus, phiCDHM1, contains homologs of three bacterial accessory gene regulator (agr) genes. The agr system is a type of quorum sensing (QS), via which the phage may modify C. difficile interactions with its environment. Although their mechanism of action is unknown, mutants in bacterial versions of these genes impact sporulation and virulence. To explore how phage QS genes may influence C. difficile biology, we examine the main categories of bacterial behavior that phages have been shown to influence and discuss how interactions via QS could influence behavior at a wider level.

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Why HIV Virions Have Low Numbers of Envelope Spikes: Implications for Vaccine Development

HIV particle cartoon The major structural proteins of most viruses, including both naked icosahedral and enveloped types, are present in a dense array on the virion surface. This pattern has likely evolved to promote structural integrity, maximize cell binding and entry, and minimize genome size. HIV and related simian lentiviruses are unusual in having a low density of envelope protein spikes on their surfaces. Why has HIV evolved this unusual virion structure?

This discussion paper suggests that having low numbers of envelope spikes retards the induction of a broad spectrum antibody response. Neutralizing antibodies are exceptionally slow to develop during HIV infection, and nearly all broadly neutralizing antibodies invariably have undergone a large number of hypersomatic mutations. Artificial virus-like particles (VPLs) with a high density of envelope spikes might make a safe and efecting prophylactic vaccine against HIV by allowing the development of a neutralizing antibody response.

Why HIV Virions Have Low Numbers of Envelope Spikes: Implications for Vaccine Development. (2014) PLoS Pathog 10(8): e1004254. doi:10.1371/journal.ppat.1004254

 

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Typhoid: Engage Cloaking Mechanism

Salmonella typhimurium Salmonella enterica serovar Typhi (S. Typhi) is a strictly human-adapted pathogen associated with a disseminated febrile illness, termed typhoid fever. In contrast, S. enterica serovar Typhimurium causes an infection that manifests as a localized gastroenteritis in immunocompetent individuals. To control a bacterial infection, neutrophils have to first migrate toward the microbe and then ingest and kill the intruder. Since Salmonella Typhi has a greater ability than S. Typhimurium to spread from its port of entry, researchers investigated whether both pathogens differ in their ability to evade neutrophil chemotaxis.

Surprisingly, S. Typhi, but not S. Typhimurium, inhibited neutrophil chemotaxis. Investigation of the underlying mechanism revealed that microbe-guided chemotaxis proceeded through a C5a- dependent mechanism, which could be blocked by the Vi capsular polysaccharide of S. Typhi. These data suggest that the chemotactic chase of neutrophils is a host defense mechanism operational during gastroenteritis, but not during the initial stages of typhoid fever.

The Vi Capsular Polysaccharide Enables Salmonella enterica Serovar Typhi to Evade Microbe-Guided Neutrophil Chemotaxis. (2014) PLoS Pathog 10(8): e1004306. doi:10.1371/journal.ppat.1004306
Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a disseminated infection, while the closely related pathogen S. enterica serovar Typhimurium (S. Typhimurium) is associated with a localized gastroenteritis in humans. Here we investigated whether both pathogens differ in the chemotactic response they induce in neutrophils using a single-cell experimental approach. Surprisingly, neutrophils extended chemotactic pseudopodia toward Escherichia coli and S. Typhimurium, but not toward S. Typhi. Bacterial-guided chemotaxis was dependent on the presence of complement component 5a (C5a) and C5a receptor (C5aR). Deletion of S. Typhi capsule biosynthesis genes markedly enhanced the chemotactic response of neutrophils in vitro. Furthermore, deletion of capsule biosynthesis genes heightened the association of S. Typhi with neutrophils in vivo through a C5aR-dependent mechanism. Collectively, these data suggest that expression of the virulence-associated (Vi) capsular polysaccharide of S. Typhi obstructs bacterial-guided neutrophil chemotaxis.

 

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Ebola virus outbreaks

Ebola virus outbreaks

Source: BBC News – Summit to discuss Ebola emergency starts

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Outbreak of Ebola Virus Disease in Guinea: Ecology Meets Economy

Ebola in Africa Ebola virus is back – but why?

Ebola virus is back, this time in West Africa, with over 350 cases and a 69% case fatality ratio. The culprit is the Zaire ebolavirus species, the most lethal Ebola virus known, with case fatality ratios up to 90%. The epicenter and site of first introduction is the region of Guéckédou in Guinea’s remote southeastern forest region, spilling over into various other regions of Guinea as well as to neighboring Liberia and Sierra Leone. News of this outbreak engenders three basic questions: (1) What in the world is Zaire ebolavirus doing in West Africa, far from its usual haunts in Central Africa? (2) Why Guinea, where no Ebola virus has ever been seen before? (3) Why now? We’ll have to wait for the outbreak to conclude and more data analysis to occur to answer these questions in detail, and even then we may never know, but some educated speculation may be illustrative – which a new paper (below) provides.

The precise factors that result in an Ebola virus outbreak remain unknown, but a broad examination of the complex and interwoven ecology and socioeconomics may help us better understand what has already happened and be on the lookout for what might happen next, including determining regions and populations at risk. Although the focus is often on the rapidity and efficacy of the short-term international response, attention to these admittedly challenging underlying factors will be required for long-term prevention and control.

Outbreak of Ebola Virus Disease in Guinea: Where Ecology Meets Economy. (2014) PLoS Negl Trop Dis 8(7): e3056. doi:10.1371/journal.pntd.0003056

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