MicrobiologyBytes

Human adenoviruses (HAdV) are non-enveloped double-stranded DNA (dsDNA) viruses associated with acute infections. Although these infections are generally self-limiting, the re-emergence of certain HAdV types has also been linked to potentially fatal respiratory infections in both civilian and military populations. In addition to their disease associations, replication-defective or conditionally replicating HAdVs continue to be evaluated in ~25% of approved phase I to III clinical trials for vaccine and therapeutic gene transfer. However, the lack of accurate details of the virus structure limits the reengineering of HAdV vectors and prevents a better understanding of the virus life cycle. High-resolution HAdV structure determination presents a challenge because of the large size (910 Å average diameter, 150 megadalton) and complexity (pseudo-T = 25) of the virus.

After more than a decade of research, scientists have pieced together the structure of a human adenovirus – the largest complex ever determined at atomic resolution. The new findings about the virus, which causes respiratory, eye, and gastrointestinal infections, may lead to more effective gene therapy and to new anti-viral drugs.

Crystal Structure of Human Adenovirus at 3.5 Å Resolution. (2010) Science 329(5995): 107 -1075 doi: 10.1126/science.1187292
Rational development of adenovirus vectors for therapeutic gene transfer is hampered by the lack of accurate structural information. Here, we report the x-ray structure at 3.5 angstrom resolution of the 150-megadalton adenovirus capsid containing nearly 1 million amino acids. We describe interactions between the major capsid protein (hexon) and several accessory molecules that stabilize the capsid. The virus structure also reveals an altered association between the penton base and the trimeric fiber protein, perhaps reflecting an early event in cell entry. The high-resolution structure provides a substantial advance toward understanding the assembly and cell entry mechanisms of a large double-stranded DNA virus and provides new opportunities for improving adenovirus-mediated gene transfer.

Related:

• Adenovirus vectors – new genes, new vaccines
• MicroRNA regulation of tumor-killing viruses

Researchers examined the responses of various microorganisms (viruses, bacterial cells, bacterial and fungal spores, and lichens) to selected factors of space (microgravity, galactic cosmic radiation, solar UV radiation, and space vacuum) in space and laboratory simulation experiments. In general, microorganisms tend to thrive in the space flight environment in terms of enhanced growth parameters and a demonstrated ability to proliferate in the presence of normally inhibitory levels of antibiotics. The mechanisms responsible for the observed biological responses, however, are not yet fully understood. A hypothesized interaction of microgravity with radiation-induced DNA repair processes was experimentally refuted.

The survival of microorganisms in outer space was investigated to tackle questions on the upper boundary of the biosphere and on the likelihood of interplanetary transport of microorganisms. It was found that extraterrestrial solar UV radiation was the most deleterious factor of space. Among all organisms tested, only lichens (Rhizocarpon geographicum and Xanthoria elegans) maintained full viability after 2 weeks in outer space, whereas all other test systems were inactivated by orders of magnitude. Using optical filters and spores of Bacillus subtilis as a biological UV dosimeter, it was found that the current ozone layer reduces the biological effectiveness of solar UV by 3 orders of magnitude. If shielded against solar UV, spores of B. subtilis were capable of surviving in space for up to 6 years, especially if embedded in clay or meteorite powder (artificial meteorites). The data support the likelihood of interplanetary transfer of microorganisms within meteorites, the so-called lithopanspermia hypothesis.

Space microbiology. (2010) Microbiol Mol Biol Rev. 74(1): 121-56

Related:

• They Came From Space – or did they?
• Bugs in space
• Is microbial life on Mars possible?

An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Such changes are mediated by chemical modifications to chromatin on both DNA and DNA-associated histones. Post-translational covalent modifications to the flexible NH2 terminus (tail) of histones include methylation, acetylation, phosphorylation and ubiquitylation, and these are associated with the structural organization of chromatin and its transcriptional status. However, not all histone modifications are truly epigenetic, as very few satisfy the heritable part of the definition. To establish and mediate epigenetic memory, such modifications must be transmitted during DNA replication. Methylation of cytosine in CpG dinucleotides (often referred to as DNA methylation) also contributes to the epigenetic status of a gene locus. When this occurs in a CpG island adjacent to a transcription initiation site, it is generally associated with repression or silencing of transcription. Histone modification, DNA methylation and the resulting reorganisation of chromatin are closely interlinked enzyme-driven processes that determine the transcriptional status of genes, gene clusters and noncoding RNAs such as micro (mi)RNAs. Most of the epigenetic markers mentioned above are associated with transcriptional repression. Multiple additional covalent modifications to histones exist in parallel to these, resulting in a complex and context-influenced ‘histone code’ that dictates transcriptional state.

One of the key questions in the study of mammalian gene regulation is how epigenetic methylation patterns on histones and DNA are initiated and established. These stable, heritable, covalent modifications are largely associated with the repression or silencing of gene transcription, and when deregulated can be involved in the development of human diseases such as cancer. This article reviews examples of viruses and bacteria known or thought to induce epigenetic changes in host cells, and how this might contribute to disease. The heritable nature of these processes in gene regulation suggests that they could play important roles in chronic diseases associated with microbial persistence; they might also explain so-called ‘hit-and-run’ phenomena in infectious disease pathogenesis.

Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol. Aug 17 2010

Related:

• Antigenic Variation in African Trypanosomes
• Hepatitis B virus X protein (HBx)
• Bacteria hedge their bets

Virus factories are complex structures in the infected cell where viruses compartmentalize their life cycle. Rubella virus (RUBV) assembles factories by recruitment of rough endoplasmic reticulum (RER), mitochondria and Golgi around modified lysosomes known as cytopathic vacuoles or CPVs. These organelles contain active replication complexes that transfer replicated RNA to assembly sites in Golgi membranes.

Researchers studied the structure of RUBV factory in three dimensions by electron tomography and freeze-fracture. CPVs contain stacked membranes, rigid sheets, small vesicles and large vacuoles. These membranes are interconnected and in communication with the endocytic pathway since they incorporate endocytosed BSA-gold. RER and CPVs are coupled through protein bridges and closely apposed membranes. Golgi vesicles attach to the CPVs but no tight contacts with mitochondria were detected. Immunogold labelling shows the presence of significant amounts of the mitochondrial protein p32 inside and around the CPVs, which suggests a role for this protein in the assembly and activities of the viral factory.

Three-dimensional structure of Rubella virus factories. Virology. Jul 22 2010

Related:

• Poxvirus DNA factories

Even if we have never succumbed to it, we are all familiar with the sickness caused by noroviruses due to high-profile media coverage of outbreaks in various closed communities, such as hospitals and cruise ships. In this article in Microbiology Today, Ian Goodfellow and David Brown ask, how extensive are noroviruses in our food chain and what can be done to prevent outbreaks in future?

In the catering industry, education of food handlers is key. Clear guidelines for good practice in food preparation need to be strictly adhered to and policed. Whilst it is generally accepted that there remains an ongoing risk from oysters, etc, since sewage contamination of estuarine waters is likely to continue and depuration is ineffective for viruses, the development of sensitive screening procedures for identifying contamination has the potential to reduce the risk. Further improvements in decontamination of contaminated food and environmental settings will undoubtedly aid in minimizing the effects of norovirus contamination and outbreaks. Until such times that vaccines and/or antivirals are available, as consumers, good hygiene and common sense are the most effective protection against norovirus infection, i.e. increased hand washing, as well as avoidance of shared food sources/ utensils and pre-prepared food during outbreaks.

Read More

Related:

• Pathogenesis of Noroviruses
• How Noroviruses cause repeated outbreaks of gastroenteritis
• Norovirus evasion of the immune system

Hepatocarcinogenesis (liver cancer) is, and will continue to be a major worldwide health problem. With chronic HBV and HCV infections being responsible for a significant proportion of HCC cases, the development of new and relevant cell culture and animal models to study the interactions of HBV and HCV with their host and the development of efficient means to combat chronic infections will remain major tasks to tackle. This publication gives an overview of our current state of knowledge in respect to the basic biology of these viruses, as well as the clinical and therapeutic options that have been, and are being developed, and highlights the major current technical and biological limitations that the field needs to overcome.

Hepatitis B and C Viruses and Hepatocellular Carcinoma. (2010) Viruses 2(8): 1504-1509 doi:10.3390/v2081504

Related:

• Hepatitis B virus integration and hepatocarcinogenesis
• The search for infectious causes of human cancers
• Liver flukes and cancer

Viruses with genomes greater than 300 kb and up to 1200 kb are being discovered with increasing frequency. These large viruses (often called giruses) can encode up to 900 proteins and also many tRNAs. Consequently, these viruses have more protein-encoding genes than many bacteria, and the concept of small particle/small genome that once defined viruses is no longer valid. Giruses infect bacteria and animals although most of the recently discovered ones infect protists. Thus, genome gigantism is not restricted to a specific host or phylogenetic clade. To date, most of the giruses are associated with aqueous environments. Many of these large viruses (phycodnaviruses and Mimiviruses) probably have a common evolutionary ancestor with the poxviruses, iridoviruses, asfarviruses, ascoviruses, and a recently discovered Marseillevirus. One issue that is perhaps not appreciated by the microbiology community is that large viruses, even ones classified in the same family, can differ significantly in morphology, lifestyle, and genome structure. This review focuses on some of these differences rather than provides extensive details about individual viruses.

DNA Viruses: The Really Big Ones (Giruses). Annu Rev Microbiol. May 12 2010 | PDF

Related:

• DNA Viruses
• Marine mimivirus relatives are large algal viruses
• Marvellous mimivirus

In the past three years, remarkable discoveries have added three new human polyomaviruses (KI virus (KIV), WU virus (WUV) and Merkel cell virus (MCV)) to a class that previously had only two disease-causing members (BK virus (BKV) and JC virus (JCV)) identified. Two monkey polyomaviruses, simian virus (SV)40 and B-cell lymphotropic polyomavirus (LPV) are also present in humans. KIV and WUV lack the agnoprotein coding sequence and regulatory micro (mi)RNA clusters of BKV, JCV and SV40. MCV lacks the agnoprotein sequence but generates miRNAs. KIV, WUV and MCV are all widespread in humans. Although they have distinctive tissue tropisms, all these viruses are probably acquired in childhood. Of these viruses, only MCV has thus far been strongly linked to cancer. Marshalled evidence from diverse sources implicates MCV as an etiological agent of Merkel cell carcinoma. This review compares the structural features of the new and previously known polyomaviruses, with the aim of identifying approaches to molecular pathology.

Structural evaluation of new human polyomaviruses provides clues to pathobiology. Trends Microbiol. 2010 18(5): 215-223

Related:

• High prevalence of infection with three new human polyomaviruses
• Polyomavirus and Human Merkel Cell Carcinoma
• Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections

The C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection due to its involvement in the infection process. Investigations into the role of the CCR5 coreceptor first focused on its binding to the virus and the molecular mechanisms leading to the entry and spread of HIV. The identification of naturally occurring CCR5 mutations has allowed scientists to address the CCR5 molecule as a promising target to prevent or limit HIV infection in vivo. Naturally occurring CCR5-specific antibodies have been found in exposed but uninfected people, and in a subset of HIV seropositive people who show long-term control of the infection. This suggests that natural autoimmunity to the CCR5 coreceptor exists and may play a role in HIV control. Such natural immunity has prompted strategies aimed at achieving anti-HIV humoral responses through CCR5 targeting.

From Natural Resistance to a New Anti-HIV Strategy. Viruses 2010, 2(2), 574-600 doi:10.3390/v2020574

Related:

• Chemokines, receptors and virus infection
• Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss