Not Just a Passing Phage

Now let’s take a step back. Pathogenic bacteria. Antibiotic resistance. How do we evade this doom and gloom?

Well, someone is here to lend us a helping hand: the big, bad “bacteria-eater!”

In fancy (but, nonetheless cool) science mumbo-jumbo, this translates to “bacteriophage,” or just phage, for short. Funnily enough, phages were first discovered by two different scientists, in two different countries, around the same time! But considering that we now know that there exist more bacteriophages on Earth than stars in the galaxy, maybe it isn’t so astounding that two minds would stumble upon them simultaneously!

So, what exactly is this mysterious “bacteria-eater?”

A bacteriophage is simply a virus that infects bacteria. And just like our other favorite microbial “undead,” a bacteriophage is acellular, and thus not considered alive.

Photo by Drew March.

 But bacteriophages are not nearly as scary as zombies (save for the fact that some resemble microscopic spiders!) Rather, phages just boil down to a handful of proteins and your choice of nucleic acid for the assembly instructions. The DNA or RNA is kept within a hardy protein covering, studded with different surface proteins for some bling (and to perform important biological functions, of course! Talk about a two-for-one deal!) This is called the capsid or head of the virus.

Phages largely also have a slim protein tube or tunnel that nucleic acid dashes through to wiggle its way into a bacterium during infection. And in more complex phages, this tail sheath can be decked out with tail fibers: long, threadlike protein filaments that resemble the lanky, spindly legs of a daddy-longlegs!

Bacteriophages have breathtaking diversity! Some may be teeny-tiny, plain-Jane RNA phages with nothing more than a simple capsid and a hunk of RNA, while others may have gizmos and doodads such as baseplates, tail fibers, and an array of surface proteins sprucing up their already intricate capsid, out the wazoo!

But phages can be picky eaters (a phenomenon almost unheard of among college students!) For a phage to be able to grab onto a bacterium, there must be a painstakingly precise molecular interaction between a surface protein in the bacterial cell wall and the tail of the virus. Since this attachment is so tightly under lock and key, a given phage typically has an exclusive VIP list of hosts it can party with. Just look at “coliphages” like T2 and T4 that selectively infect E. coli.

 

Photo courtesy of  MicrobiologyBytes.

But once a phage has hitched itself a ride on a bacterium, it injects its DNA or RNA into the cell and right into a “choose your own adventure” book. If the environment is good to go, the nucleic acid launches its sneak attack and hijacks the cell to copy itself and use itself as a blueprint for new infant viruses. But the virus also has genes for the ace up its sleeve: lysosome. This enzyme is essentially a wrecking ball to a bacterial cell wall, all but obliterating it, to allow fledgling phages to burst free and infect nearby hosts. Since this option demolishes or “lyses” the host bacterium, it is fondly named the lytic cycle.

But the flip scenario is in an environment with a red flag, a bacteriophage will instead initiate stealth mode. In this undercover state, that is: the lysogenic cycle, the phage slips its DNA into the DNA of the bacterium so that when the bacterium divides future generations also get the bonus phage DNA. But if the environment were to somehow shift, it can activate the phage DNA, throwing the unsuspecting bacteria right into the midst of the lytic cycle! Espionage at its finest, if I do say so! But not all phages have these sneaky spy skills; rather, these tricksters get a special code name: temperate phages.

Although we can thank phages for a multitude of scientific discoveries and our comprehensive understanding of molecular biology, since their discovery was followed closely by that of Penicillin and thus the advent of antibiotics; we have rarely seen them in therapeutic use, especially in the western scientific community. But as more and more bacterial strains acquire handy-dandy antibiotic resistance, some scientists have begun turning to our friendly neighborhood bacteriophages!

Not only do bacteriophages mutate and evolve with bacteria, but there exist literally countless phages capable of lysing a single strain of bacteria.

Promising, no? Maybe the natural predators of bacteria should take the wheel!

Beware the Escape Artist!

MRSA, the marvelous Houdini of bacteria, has taken the stage yet again! 

For its debut stunt, staph aureus faced down the fearsome antibiotic, penicillin, and miraculously, it managed to evade this formidable foe! But how, you might ask? Staph aureus had an ace up its sleeve: penicillinase! This enzyme breaks the chemical bonds in penicillin, rendering it inept. So, scientists drew up a new challenge for the master illusionist. When bulky side chains were added to a penicillin molecule, turning it into methicillin, it befuddled penicillinase. But staph aureus still had a few more tricks up its sleeve.

Antibiotics such as methicillin and penicillin bind to proteins called PBPs or penicillin binding proteins. Staph aureus has four of these PBPs that happen to be critical in building new cell wall. When penicillin latches onto these proteins, it leaves them useless, causing cell wall upkeep and growth to plummet.

But staph aureus refused to be outsmarted. Not only has it pulled “methicillin-hydrolyzing beta lactamase,” a novel form of penicillinase that disrupts the bonds in methicillin, seemingly out of thin air, but it also has come up with a never-before-seen version of its second PBP! PBP2a is far less receptive to binding methicillin, so when methicillin stops the other PBPs in their tracks, PBP2a can pick up the slack and keep cell wall construction humming along!

It is simply astounding how staph aureus, the modest round bacterium behind many skin infections, has tamed the impossible and come to be the infamous methicillin resistant staph aureus (MRSA)!

Photo courtesy of NIAID. 

In fact, nearly one-third of us carry staph aureus in our nose or on our skin without harm. It is only able to cause more severe infections along the lines of pneumonia or even life-threatening sepsis, if it finagles its way inside, such as via a cut or surgical incision.

And as its name implies, MRSA can no longer be subdued with methicillin. But this just scratches the surface. The magician is resistant to a plethora of other antibiotics including penicillin, amoxicillin, oxacillin, and on and on! And it just keeps doing the impossible and finding ways to dodge any antibiotics we throw at it!

Recall me citing antibiotics as saving the day in last week’s post about pneumonia? Well, superbugs like MRSA have become our antibiotics’ kryptonite.

On the bright side, however, through much research, we have come to understand the tricks and sleight of hand behind antibiotic resistance.

Bacteria reproduce extraordinarily quickly, “doubling every 4 to 20 minutes” according to PNNL. This means that bacteria can evolve new genes with a breathtaking velocity. All it takes is a single mistake in copying the cell’s DNA, generating a slightly different protein. Just look to PBP2a. This penicillin-binding protein is a barely distinct form of PBP2, but it is different enough to keep from binding methicillin!

And once these resistant proteins have come to be, their blueprint DNA is often kept in small circles of DNA, called plasmids, that float around in a bacterial cell. These “DNA bubbles” can be copied and shared with other bacteria, spreading resistance in a flash.

Antibiotic resistance is an enormous issue for medicine and consequently a vast field of research in microbiology right now, especially since MRSA and other resistant bacteria can be spread through contact so effortlessly!

But MRSA does not only affect hospital patients; rather, it can sweep through a community through shared equipment and spaces such as gyms. In fact, the average age of a patient with community-associated MRSA is 23 years old.

Image by Arlington County. 

Harrowing isn’t it? Just remember to be diligent about washing your hands, covering open cuts and scrapes, and keeping your clothes clean. And while you are at it, check out some of the cool research going on with combating resistance and finding antibiotic alternatives!

Mission Impossible IV: Covert Alveoli Infiltration!

“And the closing act for tonight’s show “Winter Fun” is the one and only: pneumonia! A talented performer who typically stars in films with his colleagues the cold and the flu, pneumonia has been known to make rare solo appearances every so often.” 

In tiny air sacs in our lungs, called alveoli, oxygen from the air we breathe moves into the bloodstream as carbon dioxide is flushed out. Pneumonia strikes when these alveoli fill with fluid or pus thanks to an infection courtesy of one of our friendly neighborhood microbes. 

Pneumonia can be caused by any of microbiology’s big three: fungi, bacteria, or viruses! But since fungal and viral forms tend to be less common and less severe, the real showstopper here is bacteria, specifically Streptococcus pneumoniae. 

Image of S. pneumoniae provided by AJC1. 

Hence its classification as a microbe, a bacterium is just one cell, and this cell is typically 10-20 times smaller than any of our own 30-some trillion cells. But in the “smallest splash” competition, viruses still have bacteria beat by a factor of 10-100 times! But unlike “zombie” viruses, since a bacterium is cellular (and doesn’t eat brains, of course), it is considered alive. 

And bacteria are also independent (setting them apart from both viruses and teenagers)! Not only can a bacterium turn its food into something edible, namely ATP, and carry out other metabolic tasks to take care of itself, but it can also copy its own DNA and make its own proteins without mooching off a host cell. 

Of course, having to do so many chores means you have to be a bit more complex than the one-gene rhinovirus! In fact, the circular DNA molecule of Strep. pneumoniae codes for more than 2,000 different proteins. 

So, when bacteria can take care of themselves, why and how do they cause disease? 

Photo provided by Yale Rosen.

A bacterium is an extracellular pathogen. In other words, bacteria just hang around, rather than going behind enemy lines and infiltrating our cells.

 Strep. pneumoniae specifically, has decked its capsule out with different proteins that help it grab onto the mucous membranes in our throats. It is also bejeweled with pili, or what is basically a forest of stubby hairs for sticking to membranes. And it can be a quiet, or even suave companion, hanging out in your throat without causing any mischief. But don’t let your guard down; S. pneumoniae is up to no good! 

Just as soon as your immune system gets worn-out (since we’re a bunch of overly stressed, sleep-deprived college students), these bacteria launch their covert mission to finagle their way into your lungs, eventually dropping anchor and setting up shop in the skin cells lining the alveoli. Here S. pneumoniae comes out of hiding and begins a coup d'état, replicating en masse, and giving our immune system a run for its money! 

Not only do our immune defenses inflame our tissues, but the proteins, sugars, and fat molecules in the bacterial cell wall and membrane also antagonize our cells. And to make matters even worse, S. pneumoniae secrete enormous volumes of hydrogen peroxide and different toxins. Its like the itchy sweater on top of the blistering sunburn and extreme poison ivy! The cells in our alveoli don’t stand a chance! 

That is, without the help of our handy-dandy antibiotics! Luckily, these beauties can typically clear pneumonia up in a jiffy, so be sure to see a doctor if you think you might have pneumonia. Otherwise, this not-so-friendly bacteria could bring even nastier acts to the stage! 

For a complete list of symptoms associated with pneumonia see Mayo Clinic or WebMD’s webpages. 

And as always, best of luck staying healthy this winter!

Epidemic!

WARNING: The United States is in the midst of an epidemic! This outbreak has been cited as the cause of more than 9% of deaths during the first week of the new year. Nearly all fifty states have reported widespread infection and hospitalization rates have spiked. But in the words of CDC Influenza Division Director Dr. Dan Jernigan, “yes, [we’re] definitely in an epidemic, but that happens every year in the United States and in the Northern Hemisphere with influenza.” 

Yes, that’s right. This epidemic that America is struggling with just so happens to be the same one we that face year after year: the flu. 

Yet again, we come to the question: how is something no more than 120 nanometers across able to wreak so much havoc? Our culprit is another small RNA virus: influenza! 

Image courtesy of Kat Masback.

But influenza is certainly not the shrimpiest kid on the block.  Instead of having just a single gene like a rhinovirus, it has upgraded to a whopping 10 genes, and it has a bonus feature: an envelope! Much like the plasma membrane of our own cells, a viral envelope resembles a bubble of fatty molecules and serves as another defense for the virus. 

The influenza envelope has two surface proteins embedded into it. Known as H and N or hemagglutinin and neuraminidase respectively, these proteins play crucial roles in helping the virus grab onto cells in our airways and in defining our immune response. In fact, they are so important that we name strains or forms of influenza according to them! 

For example, the strain we have seen this winter is H3N2, aka. a form of the influenza virus with the third type of H and the second form of N. 

But more broadly, the classification of the human influenza virus is as simple as A, B, C! Influenza A is broken down into the H and N subtypes we discussed above, and it, along with its accomplice Influenza B, causes the seasonal outbreaks we look forward to each and every winter. 

But it seems that after more than 50 years of fighting this virus, we should have figured it out by now! 

But, influenza A and B are fickle and indecisive, making it difficult for us to pinpoint them. These viruses just can’t stand still, continuously shifting via a process called antigenic drift. 

Antigenic drift is a gradual change where small mistakes in copying the viral genes cause minuscule tweaks in the identity of the new virus particles produced. These mutations might not make immediate drastic transformation, but with time, they stack up. 

Antigenic shift is the big brother to antigenic drift and the big bad behind the Swine Flu (H1N1) panic and pandemic of 2009. Remember way back to elementary school when H1N1 came from nowhere? All of the sudden, everyone had to get a swine flu shot, and school halls were riddled with rumors about how swine flu killed people! A titanic change had occurred in the flu virus, creating entirely new types of H and N that we had never seen before. Antigenic shift may be rare, but it is undoubtedly terrifying! 

Either way, since influenza can’t seem to make up its mind about what surface proteins will be in style this winter, we just have to wager an educated guess about what to include in the annual vaccine. As a consequence, vaccines might not always be entirely effective. (This is not to say that you shouldn’t get the flu shot; rather it is an essential preventative measure required to stay healthy!) 

This flu season, in particular, is the most intense since the Swine Flu in 2009. But, why is the flu so severe this year? 

Image courtesy of Agência Brasília. 

The specific strain of influenza A that is widespread throughout North America right now is known as H3N2. And according to Live Science, H3 strains of influenza tend to cause more serious cases of the flu. Vaccines have also been shown to be only 30% effective against H3 strains of the virus, relative to the typical 50-60% efficacy against other forms of influenza. 

In other words, this year especially, you must be sure to get a flu shot – its not too late – and to see a doctor within 48-hours of seeing symptoms of the flu. Although flu symptoms do tend to resemble those of a cold, the flu comes on more suddenly and often involves a high fever (above 101°F). 

Taking precautions similar to those for avoiding the common cold (check out last week's post), can also help keep the flu away! As always, best of luck staying healthy.

The Most Wonderful Time of the Year!

Not quite sleigh bells and mistletoe anymore.

Soprano sneezes blend with the deep, rattling timber of chest coughs as the frantic staccato of sniffling echoes through the tin can that my 300-student chemistry lecture has been crammed into like sardines. Some glumly clutch tissues while others cling to XL bottles of hand sanitizer, eyes wide and paranoid, knowing that there is no escape. Soon they too will join in this miserable melody: this symphony of sickness.

But this big bad is nothing more than a smidgen of protein and a dash of genetic material: the rhinovirus!

This image is provided by Welcome Images. 

Yes, the culprit of this doom and gloom is none other than a virus, one of the tiniest and simplest microbes around. In fact, most scientists don’t even consider them alive. But be careful not to underestimate them!

Sometimes less is more. For viruses, to be pragmatic and efficient is to thrive. Rhinoviruses, for one, have only one gene in the form of single-stranded RNA. This single gene contains instructions for assembly of 11 different proteins: four for the body of the virus, and the remainder for use in replication.

But packing light has its downfalls, such as hoarding the hotel shampoo and “borrowing” that one item you forgot, but just can’t survive without from the front desk. And viruses are no different. In fact, they’re some of the finest moochers around (second only to us starving college students, of course).

To cause a cold, a rhinovirus first hitches a ride on a receptor on the cells in our throat and nose, before finagling its way inside. There, the virus sweet talks the cell into making copies of and making proteins from the virus RNA rather than the cell’s own DNA. The new viruses created ultimately burst free to attack other nearby cells.

Ironically enough, however, the actual symptoms and feelings of illness and fatigue that complement a cold come from our own immune system rather than the virus itself. As the immune system digs the trenches, calls for reinforcements, and settles in to fight it out with the virus, it also drastically saps our energy and inflames the linings of our throat and nose.

Viruses clearly subscribe to the “strength in numbers” mentality. We have identified more than 200 different types of cold-causing viruses, but rhinoviruses, just one of these varieties, accounts for roughly half of cold cases each year. Unfortunately, due to their vast numbers, we will never be able to build up immunity to all of these viruses. According to Medical News Today, adults should anticipate suffering through 2-3 colds each year.

And contrary to the timeless warnings against sauntering outdoors in Wintertime because “you’ll catch cold,” it is actually our mass migration indoors and into closer confines with others during winter months that gets colds on the rise.

So how do you keep the cold at bay in college – the perfect recipe for illness?

The cold virus is transmitted either via direct contact with a contagious person, by inhaling droplets in the air from coughing or sneezing, or by touching an infected surface. But how is it possible to never contact an infected surface on a campus of more than 40,000 students?!

This photo is provided by Ethan Gruber. 

And to be honest, it’s probably not possible. But it is possible to keep anything from an infected surface from contacting your nose and mouth and causing an infection. Keeping your hands away from your face and sanitizing them before eating is a key to staving off the cold.

And as much as it has already been said, the legitimacy of bolstering our immune systems by eating vitamins, specifically vitamin C (can’t forget your OJ) and getting plenty of sleep, cannot be overstated. But another pointer is to avoid the gym if you do come down with a cold. While it is imperative to stay healthy in order to be able to deal with illness, exercise can actually weaken the immune system and exhausts even more energy when we need it most.

And this seems unfeasible for us caffeine-driven college students, but keep the stress under control! Stress puts a damper on our immune system and viruses take advantage. If left unattended cold viruses can sometimes advance into bronchitis or pneumonia. Remember it is just as important to take care of yourself as it is to get the grade!

For information on when to cave and talk to a doctor see this article from Mayo Clinic.

Good luck staying healthy!