Risk factors for the chronic neurodegenerative condition known as Alzheimerâ€™s disease (AD) include many cellular genes and pathogenic microbes. Nucleic acids of two ubiquitous human herpesviruses, HHV-6A and HHV-7, have been found at higher levels in AD brains compared with healthy controls, and appear to regulate genes implicated in risk of developing the disease.
Bacteria do not develop transmissible spongiform encephalopathies, but they have been found to produceÂ prions – proteins that can adopt alternative conformations withÂ different functions.
Prion diseases, aÂ frequent topicÂ on this blog, are caused by misfolding of a normal cellular prion protein (illustrated; image copyright ASM Press). Prion proteins are found in other organisms, where the alternative conformation confers a new, non-pathogenic function to the protein. At least 12 different prion proteins have been found in yeast, and they confer the ability to grow more efficiently under certain conditions. Now prions have been discovered in bacteria (link to article).
A search of 60,000 bacterial genomes for proteins with prion-forming domains revealed one in the transcription termination protein Rho from Clostridium botulinum (Cb-Rho). When produced in E. coli, the protein forms amyloid – protein aggregates in the form of fibrilsÂ – that areÂ characteristic of prions. A 68 amino acid stretch of Cb-Rho can functionallyÂ substitute for the prion-forming domain of a yeast prion-forming protein. This protein, called Sup35, can read stop codons in the prion state, and this phenotype was recapitulated in yeast by the Clostridium prion.
The Cb-Rho prion can convert between prion and non-prion conformations in E. coli. This property was demonstrated by placing a Rho-dependent terminator between a promoter and the lacZ gene, the product of which produces a blue color. In the prion state, Rho has decreased activity, leading toÂ blue cells. In the non-prion state, normal termination leads to pale blue colonies. A mixture of blue and pale blue colonies wasÂ observed, showing that Rho exists in the prion and non-prion states.
The prion conformation was also shown to be heritable. Blue colonies always gave rise to blue colonies, while pale blue colonies formed pale blue colonies. The blue colony color lasted for over 120 generations.
The finding of a prion in bacteria indicates that this form of protein-based heredity arose before eukaryotes emerged on Earth. Similar prion-like protein domains have also been found in other phyla of bacteria, suggesting the existence of an important source of epigenetic diversity that can allow bacterial growth underÂ diverse conditions. Exactly how bacterial prions confer new functions will be exciting to discover.
Last time we learned that eukaryotes probably didnâ€™t invent the nucleus. Now we find that prions likely emerged first in bacteria. Did eukaryotes invent anything?
Hosts: Vincent Racaniello, Alan Dove, Dickson Despommier, and Rich Condit
Vincent, Alan, Dickson, and Rich talk about treating arthritis with a tanapox virus protein, Darwinian evolution of prions in cell culture, and the connection between cold weather fronts and outbreaks of avian H5N1 influenza in Europe.
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Click the arrow above to play, or right-click to download TWiV #78 (53 MB .mp3, 73 minutes)
Links for this episode:
- Treating arthritis with a tanapox virus protein that antagonizes TNF (press release and research article)
- Darwinian evolution of prions in cell culture (abstract)
- Simple diagram of prion propagation (Wikipedia)
- Thoughts on the pursuit of success in science by Charles Weissmann
- Cold fronts linked to European H5N1 outbreaks (PLoS Pathogens)
- Simon Singh’s website and letter of support (thanks, Mary!)
- The importance of stupidity in scientific research (thanks, Mary!)
- Sustainable energy – without the hot air (thanks, Bernhard!)
- World Community Grid (thanks Dave!)
- Pre-order The Vertical Farm by Dickson Despommier
- Letters read on TWiV 78
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Fragments of an abundant protein produced by the prostate form amyloid fibrils that enhance infection of cells by human immunodeficiency virus type 1. These fibrils, called semen-derived enhancer of virus infection (SEVI), have been found to boost infection of prostate cells by the retrovirus XMRV. Is this evidence that XMRV causes prostate cancer?
Because most HIV-1 infections are a consequence of genital exposure to semen of virus-infected men, seminal fluid was screened for peptides or proteins that enhance viral infectivity. Peptides (34 – 40 amino acids in length) derived from prostatic acidic phosphates, a common protein found in semen, were found to dramatically enhance HIV-1 infection of cultured cells. These peptide fragments form amyloid fibrils which bind both virions and cells, thereby promoting virus attachment and stimulating infectivity. The prostatic amyloid fibrils, called SEVI, are found at high levels in semen, which also stimulates HIV infection. SEVI is believed to play an important role in sexual transmission of HIV. Inhibitors of the stimulatory effect of SEVI on HIV infection, such as surfen, may have therapeutic value.
Xenotropic murine leukemia virus-related virus (XMRV) has been detected in prostate cancer tissues and is therefore a candidate tumor virus. XMRV, which has also been implicated in chronic fatigue syndrome, was first isolated from prostate tissue. Therefore it made perfect sense to determine whether SEVI, which originates from the prostate gland, enhances XMRV infection.
The observation that SEVI enhances XMRV infection is consistent with the possibility that the virus is sexually transmitted. Men with a history of prostatitis or sexually transmitted infections appear to have a higher risk of acquiring prostate cancer. However, the effect of a prostate-derived peptide on XMRV infection might be coincidental: the amyloid fibrils could stimulate infection by other viruses, as noted by the virologists who discovered SEVI:
…the capability to promote the interaction between virions and the cell surface is independent of the viral Env glycoprotein and hence not restrictedÂ to retroviruses. Thus, further studies on the role of amyloids in the transmission and pathogenesis of envelopedÂ viruses are highly warranted.
About 30 human diseases, including Alzheimer’s, are associated with deposits of amyloid. Bacterial and fungal infections can also lead to formation of amyloid fibrils – which could explain why sexually transmitted diseases increase the likelihood of acquiring prostate cancer. The ability of these fibrils to enhance infection with different viruses should be examined. It’s possible that different amyloid fibrils are a new general risk factor for certain viral infections.
Hong, S., Klein, E., Das Gupta, J., Hanke, K., Weight, C., Nguyen, C., Gaughan, C., Kim, K., Bannert, N., Kirchhoff, F., Munch, J., & Silverman, R. (2009). Fibrils of Prostatic Acid Phosphatase Fragments Boost Infections with XMRV (Xenotropic Murine Leukemia Virus-Related Virus), a Human Retrovirus Associated with Prostate Cancer Journal of Virology, 83 (14), 6995-7003 DOI: 10.1128/JVI.00268-09