Moselio Schaechter

  • The purpose of this blog is to share my appreciation for the width and depth of the microbial activities on this planet. I will emphasize the unusual and the unexpected phenomena for which I have a special fascination... (more)

    For the memoirs of my first 21 years of life, click here.

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March 20, 2014

Why Do Viruses Cause Disease?

by Vincent Racaniello

This article was first published on 7 FEBRUARY 2014 in the Virology Blog and is reprinted here by gracious permission of the author.


Virulence, the capacity to cause disease, varies markedly among viruses. Some viruses cause lethal disease while others do not. For example, nearly all humans infected with rabies virus develop a disease of the central nervous system which ultimately leads to death. In contrast, most humans are infected with circoviruses with no apparent consequence. Is there a benefit for a virus to be virulent?

One explanation for viral virulence is that it facilitates transmission. However, a comparison of infections caused by two enteric viruses, poliovirus and norovirus, does not support this general view. Both viruses infect the gastrointestinal tract and are spread efficiently among humans by fecal contamination. However, norovirus infection causes vomiting and diarrhea, while poliovirus infection of the intestine is without symptoms (the rare invasion of the nervous system, and subsequent paralysis, is an accidental dead end). Both viruses have successfully colonized humans for many years, so why does only one of them cause gastrointestinal tract disease?

Continue reading "Why Do Viruses Cause Disease?" »

January 27, 2014

Neanderthal Me

by Jamie Henzy

Figure1 Figure 1. This comparison of skulls from a modern human (left) and Neanderthal (right), from the Cleveland Museum of Natural History, shows the larger cranial capacity of Neanderthals. Source.

From the discovery of the first Neanderthal skull in a Belgian cave in 1826, a bone of contention among Homo sapiens has been the extent of our relationship to Homo neanderthalis, who disappeared from the fossil record ~30,000 years ago. Like scrappy cousins we'd rather not claim, we've attempted to distance ourselves and establish our clear superiority, leading at times to suspect interpretations of data. For example, Neanderthal cranial capacity was larger than ours by about 25% (1500-1800 cc, compared to 1300-1500 cc for modern humans). To an unbiased observer, this feature could imply greater intelligence among Neanderthals. However, we have often chosen to depict Neanderthals as grunting brutes whose large heads evolved to allow frequent head-butting, as well as protection from blows from each others' clubs. But history is written by the winners, and as long as bones couldn't talk, we were free to impose upon them our preferred narrative.

Figure2 Figure 2. The subpopulation of humans that left Africa for parts of Europe and Asia encountered Neanderthals and interbred with them, resulting in Neanderthal genetic sequences in modern non-African populations. Source.

Neanderthals Meet the Genomic Era

These days, however, the Genomics Age has given voice to the Stone Age, as Neanderthal DNA from 38,000 to 45,000 years ago has been successfully extracted from teeth and bone marrow, sequenced, and assembled, providing a map of the Neanderthal genome. Several findings require adjustments to the grunting brute narrative. First of all, Neanderthals share with humans the exact variant of a gene, FOXP2, that when absent in humans results in an inability to speak and process language. This allele is not found in chimps and gorillas—our closest living relatives—and along with archeological evidence of symbolic behavior, strongly suggests that they used language. Moreover, materials extracted from Neanderthal teeth indicate that they ate cooked vegetables. And the notion that ancient humans and Neanderthals represented separate species was dealt a blow when it was discovered that 1-4% of the genomic sequence of modern Europeans and Asians was contributed by Neanderthals, strongly suggesting that Neanderthals and the ancestors of modern humans interbred and produced fertile offspring. No separate species, they. In fact, some of the gene variants contributed by Neanderthals are thought to have aided the immune system of early humans.

Continue reading "Neanderthal Me" »

January 20, 2014

Bridges Across the Periplasmic Moat

by Merry Youle

Figure1 Figure 1. Source.

Gram-negative bacteria pose a particular challenge to any enterprising phage. First the phage is met by the outer membrane (OM)—a barrier to surmount that also can be used as a convenient handgrip for adsorption. Next hazard is the nuclease-infested periplasm with its jungle of peptidoglycan. An infecting phage genome needs protection to cross that compartment intact. For this, most tailed phages (the order Caudovirales) use the ‘long straw’ method. These phages are equipped with l-o-n-g tails for bridging the periplasmic moat. But what about the short-tailed ones such as T7?  And what about the roly-poly icosahedral phages that have no tail at all? They all have one innovative solution or another. As evidence, here are three diverse examples of delicious phage ingenuity.

Figure 2. Schematic of a T7 virion before and after ejection of the internal core proteins to extend its tail. Together gene products 16 (gp16) and 17 (gp17) actively translocate approximately the first kbp of the T7 genome across the periplasm and into the cytoplasm. Source.

Extendable Tail

The mechanism used by the short-tailed phage T7 for crossing the host’s envelope layers is to extend the length of its tail upon infection. This tactic has been intensely studied and widely reported (see here and here). In brief, each T7 virion carries tail extension proteins as an internal core that is precisely positioned adjacent to the tail portal. This core is composed of three different proteins, in quantities of ten, eight, and four respectively. Upon adsorption, these proteins exit the capsid in a specific sequence ahead of the DNA to form a tube. This added-on conduit extends T7’s basic 23 nm long tail to 40-55 nm, long enough to easily bridge the periplasm and penetrate the cell membrane (CM). These ejected proteins do more than just extend the tail. As the tail extends, they help clear a path to the CM by digesting the obstructing peptidoglycan. During genome delivery they work in concert to ratchet approximately the first kbp of the genome into the cytoplasm, then put on the brakes. The rest of the genome is then pulled in by transcribing RNA polymerase. Its work finished, the tube disassembles, resealing the punctured cell membrane as it disappears.

Continue reading "Bridges Across the Periplasmic Moat" »

November 11, 2013

Oddly Microbial: Giant Viruses

by Marcia Stone

Viruses are supposed to be small and simple—not even alive, just mobile genetic material after all. So what do we make of giant double-stranded DNA (dsDNA) viruses, one of which—the newly discovered Pandoravirus salinushas an even larger genome than a hunky parasitic eukaryote called Encephalitozoon? The recent identification of P. salinus adds evidence to growing speculation that it and other mammoth viruses evolved from cellular ancestors and represent domains of life that likely existed on Earth before the last universal common ancestor (LUCA). Increasing numbers of scientists are coming around to this point of view; some of whom like Gustavo Caetano-Anollés at the University of Illinois at Urbana-Champaign go even further, asserting in Microbe magazine that “giant viruses not only existed at the same time as the LUCA of cellular life, they’re direct descendants of the lineage that gave rise to it.” Caetano-Anollés does not say this lightly—he has protein data to substantiate the claim.

Mimiviruses and family

Fig. 1. EM section of a Mimivirus, Courtesy of Jean-Michel Claverie.

When they were initially spotted making life miserable for amoebas in a British water tower by Tim Rowbotham in 1993, the first-reported giant viruses were thought to be (yawn) bacteria and largely ignored. New-generation sequencing a decade later revealed their viral nature and because they’re as big as small cocci and stain Gram-positive the identifying scientists Didier Raoult, Jean-Michel Claverie and colleagues at Aix-Marseille Université in France named them “Mimiviruses” for “Mimicking Microbes.”

Mining the Global Ocean Sampling database searching for more giant viruses hinted that Mimiviruses had an extended seafaring family. However, the predicted marine relatives of Mimivirus remained elusive until 2010 when the Cafeteria roenbergenis virus, CroV for short, was discovered infecting the flagellate grazer Cafeteria roenbergenis. Then Megavirus chilensis was isolated from near-shore sediment off the coast of Chile and it, like Mimivirus, happily preys on several species of Acanthamoeba in the laboratory. Which eukaryotes M. Chilensis terrorize in the wild are still unknown.

Continue reading "Oddly Microbial: Giant Viruses " »

October 07, 2013

Parallel ERV-mediated evolution of blue egg color in chickens

by Robert Gifford

The delightful word 'oocyan' refers to the trait of blue-green eggshell color that occurs in native chickens of Chile (Mapuche fowl) and some of their descendants in North America and Europe, as well as certain Asian chicken breeds (e.g. Dongxiang, Lushi).

Oocyan is an autosomal dominant trait, and recent papers in PLoS Genetics and PLoS ONE have established that it's occurrence in chickens from different geographical regions is due to an endogenous retrovirus (ERV) insertion upstream of the SLCO1B3 gene [1, 2].

Remarkably, the ERV insertions responsible for oocyan appear to represent separate integration events in Chinese versus American/European chicken breeds - thus it appears that the oocyan phenotype has evolved on two separate occasions, via the same ERV-mediated mechanism, in distinct populations of chickens.

Ancient navigators - did Polynesians introduce chickens to Chile?

Oocyan and human prehistory

Two long-debated issues among prehistorians are whether there was a pre-Columbian introduction of chickens to the Americas, and whether ancient migrations led to Polynesian contact with South America.

The wild ancestor of the domesticated chicken is the red junglefowl, a South East Asian species. Archeological evidence indicates that domesticated forms of this species had been introduced to China by around 5000 years ago, and were present in Polynesia approximately 1000 years ago.

But how and when did chickens reach the Americas? It is likely that Portuguese and Spanish colonists introduced chickens to the East coast of South America in the 15th century. However, when Francisco Pizarro reached Peru in 1532, he found that chickens were an integral part of Incan economy and culture, suggesting that the species had already been present in the region for a substantial period of time. Consequently, pre-European introductions of chickens to the West coast of South America, involving both Asian and Polynesian contacts, have been proposed [3].

Continue reading "Parallel ERV-mediated evolution of blue egg color in chickens" »

September 12, 2013

Pictures Considered #8. A Shortened Tail

by Elio

A side view of a negatively stained T4 particle whose sheath has contracted. Its base plate has the boat-type profile characteristic of baseplates seen in longitudinal sections of T4 particles adsorbed on host cells, i.e., the tips of the baseplate such as that shown by the arrow are tilted toward the head. A short tail fiber extends downward from the flat part of the baseplate near the arrow while the long kinked tail extends upward from opposite tip of baseplate.  Source.

Electron microscopy of phages came into prominence in the 1950’s and revealed many of their physical attributes such as their particulate nature, morphological complexity, “tail first” attachment to host cells, etc. Among these discoveries was that T-even coliphages contract their tail upon absorption to their E. coli hosts. A 1967 paper by Simon and Anderson reveals this process in splendid detail. The legend of this figure tells the story. 

We are used to seeing well-nigh incredible images taken via the electron microscope, but this one tells us that the early days were not lacking in technical sophistication. Far from it, the clarity of the images approaches that available today. See the paper for other examples of this. The difference between now and then is mainly in the tools available for the analysis of the images. Keep in mind, this work anteceded the availability of practical personal computers by about 10 years.

Suggested by Gail Christie

Simon LD, & Anderson TF (1967). The infection of Escherichia coli by T2 and T4 bacteriophages as seen in the electron microscope. II. Structure and function of the baseplate. Virology, 32 (2), 298-305 PMID: 5337969

September 09, 2013

Teaching Pseudomonas to Endocytose

by Merry Youle

I offer this as an echo to Elio's post from last October, Teaching E. coli to Endocytose. There Elio reported the recent education of E. coli by the heterologous expression of a mammalian gene. I tell of a bacterium instructed by a phage.

Phi6 EM
Figure 1. EM of φ6 virions (uranyl acetate staining). Bar = 50 nm. Source.

Apparently Pseudomonas phage φ6 missed that classic 1952 paper by Hershey and Chase. You know, the one where they radiolabeled either T2 or T4 phages with P32 and S35, mixed them with susceptible E. coli as hosts, let the phages adsorb and begin the infection, then whirred them in a Waring blender. The P32-labeled DNA entered the host cells, while the S35-labeled capsid proteins remained outside. This became the paradigm for phage infection, slightly tempered later to accommodate the entry, along with the genome, of various 'internal proteins' that had been packaged inside the capsid. However, for eukaryotic viruses that have double-stranded RNA (dsRNA) genomes, it's a whole different story. Literally. The whole capsid enters the cell. I discussed some of the benefits of this strategy in my post about the 'viral turtles' that infect yeast. Most dsRNA viruses rely on the host to take up the virion by endocytosis. Since Bacteria, it is widely believed, don't endocytose, this would seem to preclude phage virions from playing this game. But apparently phage φ6 missed this injunction, too.

Continue reading "Teaching Pseudomonas to Endocytose" »

May 27, 2013

Stuck in Phage Heaven

by Merry Youle

Fig 1 stuck in heaven
Figure 1. This image, intended to highlight the mechanism of the DNA packaging motor of phage T4, also provides a vivid representation of the 155 Hoc proteins (yellow) assembled into the capsid with their Ig-like domains extending outward. Green = major capsid protein; purple = vertex protein; blue = outer capsid proteins Soc; yellow = outer capsid protein Hoc. Source.

Ceteris paribus, the more prey, the better the hunting. The successful fisherman fishes where the fish are, the skillful pride of lions hunts where the wildebeest gather, and savvy phage predators hang out where the bacteria are. Such bacteria-rich locations include the protective mucus layer formed by animals to protect their vulnerable exposed surfaces. Bacteria—symbionts and pathogens alike—find mucus hospitable; it offers them food and a structured environment. The congregation of bacteria makes mucus a good place for phages to hunt their prey, and some have evolved to exploit this resource. Thus, while looking after their own interests, phages here also serve as an antimicrobial defense for their metazoan host.

The rule of thumb is that phage virions outnumber bacteria in most environments by roughly ten-to-one. Barr et al. recently reported that this ratio is increased more than four-fold in mucus sampled from a wide range of metazoans, from corals to humans. Unlike chemotactic bacteria, phages can’t actively move towards mucus. That there are more phages in mucus than in the adjacent milieu implies that when good fortune and diffusion brings them to the mucus layer, they adhere and stick around. The obvious question is how.

Continue reading "Stuck in Phage Heaven" »

April 25, 2013

A Good Defense Is Worth Stealing

by Merry Youle

Add phage ICP1 to the list. Source.

One widely-used tactic for defense against phage and other mobile genetic elements is to deploy a CRISPR-Cas system (click here and here) to recognize and chop them into pieces. Based on sequenced genomes, 60% of Bacteria and 90% of Archaea have the wherewithal to dispatch invaders this way. But phages also have to protect themselves against enemies, including other mobile elements. Knowing a good thing when they see it—and they have seen it from the receiving end often—some phages have stolen the entire CRISPR-Cas structure and use it to inactivate genetic elements that would interfere with their replication.

What sorts of genetic elements challenge phage supremacy? Some bacteria harbor chromosomal islands that, like prophages, excise and replicate when induced by cellular stress or damage. When phage infection is what triggers the activation, the island is classified as a PICI, a phage-inducible chromosomal island. The ungrateful PICI sometimes then proceeds to interfere with phage replication. One subset of these PICIs includes the SaPIs, Staphylococcus aureus pathogenicity islands, that I introduced here and wrote more about here.

Continue reading "A Good Defense Is Worth Stealing" »

March 18, 2013

When a Good Peptide Deformylase Gets Better

by Merry Youle

In bacteria, the ribosome-associated peptide deformylase (PDF) removes the formyl group of the N-terminal formyl methionine of nascent proteins. This process is a prerequisite for the proteolytic removal of the unmasked methionine by methionine aminopeptidase (MAP). The enlargement shows PDF (cyan ribbon) bound to ribosomal protein L22 (magenta) next to the ribosomal tunnel exit (white star). The second interaction site of PDF on the ribosome, protein L32, is not visible in this view of the ribosome, which is sliced along the tunnel. The path of the nascent chain is indicated by yellow spheres. Source.

When a phage invades a host’s premises, it delivers only its genome and perhaps a few specialized proteins needed immediately upon arrival. Its plan is simply to supervise production. The host is relied on to provide not only the raw materials and energy, but also the production equipment needed to synthesize phage proteins and nucleic acids. This includes the machinery for further processing each protein as it leaves the ribosome. Sometimes, as in the case of the cyanophages, the host’s equipment isn’t quite enough.

Uniquely, proteins made on bacterial ribosomes, including those encoded by phage, start with an N-formylmethionine residue donated by a special initiator fMet-tRNA. As the N-terminus of the new peptide chain emerges from the ribosome exit tunnel, the formyl group is removed by the enzyme peptide deformylase (PDF); frequently the remaining N-methionine itself is also removed by a separate enzyme. Many proteins as they exit fold into their functional form with the help of a chaperone, the trigger factor (TF), stationed at the portal. Correct folding is essential for protein function, and the formyl group must be removed for proteins to fold correctly. Deletion of the PDF gene in E. coli is lethal. Likewise, actinonin, a naturally-occurring antibiotic that inhibits PDFs, also inhibits bacterial growth and disrupts photosynthesis in the chloroplasts of plants and green algae.

For most phages, a functionally adequate host PDF is something to be taken for granted. However, there is the danger that intense protein synthesis during phage infection can overwhelm the host’s supply of PDF, the upshot being improperly processed, non-functional proteins. This is more likely a problem for cyanophages. While all phages require the synthesis of various proteins used directly for their replication, cyanophages also depend on active synthesis of other proteins needed to maintain the host’s photosynthesis apparatus. This extra burden further taxes the host’s co-translational processing enzymes. Specifically, the high-turnover D1 protein of photosystem II must be replenished—the subject of an earlier post. For this problem, the cyanophages have a solution.

This story began when Sharon and colleagues searched the publicly-available marine metagenomes generated by the Global Ocean Survey (GOS), making use of their novel method to identify bacterial genes encoded in viral, not bacterial, genomes. Their yield was abundant; they found virally-encoded metabolic genes from 34 gene families. Of these 34, the most numerous were the PDFs, yielding 70 genes—all of which were from cyanophage genomes. Mapping of their data by Frank et al. located these phage PDFs throughout the oceans. Finding homologs of bacterial PDF genes in phage is one thing; demonstrating that these genes encode functional enzymes and are expressed during cyanophage infection is another. As a big step in that direction, Frank and colleagues demonstrated that cyanophage S-SSM7, a phage infecting the cyanobacterium Synechococcus WH8109, encodes a functional PDF with some phage-specific quirks.

Continue reading "When a Good Peptide Deformylase Gets Better" »

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