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An Overview of Infectious Diseases, Part I
In many cases, disease is due to a secreted form of toxin, called an exotoxin, which can produce a wide variety of symptoms. Why do bacteria produce these substances? Usually, the bacterium itself is confined to a wound site, as it probably doesn’t grow well in the body. Nonetheless, the exotoxin can spread well beyond the site of infection, and aid in the spread of the organism, perhaps by inducing diarrhea (sorry to be blunt).
Have you ever thought that bacteria, viruses, and other infectious diseases might be the only human predators left on earth? I would argue that not only is this true, but that they are by far the most successful! Bacteria, in particular. However, of the 10’s of hundreds of thousands of bacteria in existence, only a handful are able to survive in a human, and only a subset of those are able to cause us any harm. I am intending this post to be an overview, part I of II, of bacterial infectious diseases or pathogens, and the danger they pose to the human race.
THE DEFINITION OF A PATHOGEN
First, we need to define the word “pathogen”. The word itself frightens us – we associate a pathogen with nothing less than a world epidemic – but it is defined merely as an organism that can cause disease. To cause disease, the organism must successfully perform several steps:
- Enter a host organism (for our purposes, the host will be a human).
- Attach or adhere to an organ tissue, such as the lungs, or the intestine. Human hosts go to a great deal of trouble to avoid the intimate association that bacteria or other invading pathogens seek with these organs. For example, the human lung has a number of defenses, such as cilia (small fingerlike projections that serve to catch and eject foreign particles), scavenger cells that engulf bacteria and other invaders, and the ability to cough.
- Enter a cell within the tissue.
- Grow to a significant number.
- Cause tissue destruction and disease, a task often accomplished by the production of toxins.
All bacteria want to do is eat, grow, and produce offspring.
One of the ways in which bacteria infect cells is via the type III secretory apparatus. This is a recently identified organelle of virulence (meaning that it is a structure that is necessary for the bacteria to enter, survive, or grow in a host), present in gram negative bacteria. Gram negative simply me ands that the bacteria have a cell envelope containing two membrane leaflets with a cell wall made of something called peptidoglycan in between.
The apparatus is composed of a series of plates that sit in the envelope, and a needle-like projection that punctures a host cell, injecting factors that reprogram the cell and cause it to engulf the bacterium.
Despite the adaptations that allow bacteria to survive and propagate in a human host...
...we've designed a number of drugs and therapies that compromise the bacteria's basic needs. For instance, several classes of molecules must be produced prior to division, or rather, the production of offspring:
- DNA – Replication of DNA in bacteria is accomplished by several cellular machines, many of which are the targets of antimicrobials. The drugs novobiocin and synthethic quinolones inhibit DNA gyrase, a protein which unknots the DNA to be replicated. Humans also require that their DNA be unknotted, in order for replication to occur, so in order to be clinically effective, such drugs must attack only the bacteria component. Luckily, the gyrase is different enough between humans and bacteria that this is indeed the case!
- Protein – The ribosome is a cellular organelle responsible for making protein, and it too is the target of a very large group of antibiotics, such as erythromycin, tetracycline’s, and streptomycin.
- Peptidoglycan – This cell envelope component is synthesized in three different cellular compartments: subunits in the cytoplasm are transferred across the membrane by a carrier molecule, and are cross-linked to the existing peptidoglycan.
For a resistant bacterium to become significant, it must have the opportunity to increase it’s numbers – when a drug dose is too low, the opportunity for a stepwise acquisition of resistance arises. This is, however, unlikely with proper treatment.
THE PROBLEM: ANTIBIOTIC-RESISTANT BACTERIA
Unfortunately, bacteria are emerging that will greatly challenge our treatment protocols. In fact, it is likely that many of our commonly used drugs will fail in the near future due to this phenomenon.
There are several reasons that pathogens seem to be emerging at this point in time:
- Human demographics (population increase).
- Technology and industry have contributed to the misuse of antibiotics in livestock.
- Economic development and land use, war and social unrest.
- International travel and commerce (see image below).
- Microbial adaptation.
- The breakdown of public health measures.
THE SPREAD OF INFECTIOUS DISEASES
Virtually every place on earth is connected to every other place on earth by no more than a day or two of travel.
Of course, the limiting factor here is the acquisition of mutations that confer resistance.
When a bacterium has acquired such a mutation, somewhere in the body will be its “sweet spot”, much like a basketball player has. This can be due to three things:
- Variation in drug concentration throughout the patient.
- Variation in tissue damage due to disease.
- Variation in levels of competing bacteria.
These conditions maximize the chance that the resistant bacteria will survive and divide.
In order to understand resistance, we need to know how bacteria disseminate antibiotic resistance.
DOWN TO THE MOLECULAR LEVEL
First of all, fun fact: Amoeba have the largest genomes – 1012 bases! Ours is about 100X smaller!
Likewise, some bacteria have simple genomes, while others have complex genomes. They can contain one or more of these elements:
- Chromosome – The typical bacterial genome, called the nucleoid, resides on one or more haploid chromosomes without a membrane surrounding it, which can be circular or linear, contrary to the dogma. The average bacterial chromosome consists of about 4,000 genes.
- Plasmid – This genome is composed of double-stranded DNA, is self-replicating, and can range from a few thousand bases to hundreds of thousands. These are often a problem clinically, because the encode virulence factors and antibiotic resistance genes. In addition, some, called F and R plasmids, can transfer themselves from one bacterial host to another, thereby passing antibiotic resistance. These are, essentially, molecular parasites.
- Bacteriophage – Believe it or not, this is a virus genome that lives within a bacterium. In fact, Cholera would not be a problem if the bacterium were not infected with a virus – it is the virus that produces the Cholera toxin, causing the disease.
Now that we’ve seen how the bacterial genomes are organized, what do you think is the probability that a cell will acquire three independent mutations? A mutation arises within any given gene, on average, in one bacterium out of one million every generation (10-6). The probability that three independent mutations occur is the product of each event, or 10-18. This is an incredibly small number – however, cells do acquire resistance.
They do so by acquiring large pieces of DNA from other bacteria, via transformation (the release of naked DNA into the environment by cell lysis), conjugation (cell-cell contact, or mating), and transduction (mediated by a bacteriophage). All involve the one-way transfer of DNA from a donor to a recipient cell.
WHAT CAN YOU DO?
The answer is, not much. Resistance is unavoidable, but you can ask your doctor about the proper dosage of antibiotics, should you need them. Make sure that you take the full course, and at the correct time of day, because there is a scenario in which you could be the reason that resistant bacteria survive another day!