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!