Diseases: Communicable and Chronic
As previously mentioned, students seem to have difficulty differentiating between communicable diseases and diseases that originate from ‘self’ tissues. For this reason, it is important to address the idea of disease itself. The first part of this unit discusses what constitutes disease, a small primer on the immune system, and how disease can originate from a foreign agent or from a fault in our own tissues.
Look up the list of diseases and conditions hosted by the Center of Disease Control and you can find every malady imaginable from chronic kidney disease to Ebola. So what exactly qualifies as a disease? One could argue that a disease is any condition that disrupts the body’s normal optimum conditions, homeostasis, outside of physical trauma or injury. However, for the purpose of this paper, a disease or a disorder will refer to any ailment that causes damage or interferes with the body’s ability to function resulting in a failure of a part of or the whole body.
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It is important for students to understand the distinction between disease and injury. Take, for example, the symptoms of an allergy sufferer in early spring and compare it to a person who is cleaning and stirs up dust. Both might exhibit sneezing, watery eyes, and general tissue irritation, however only the person who suffers allergies has a condition that could be qualified as a disease. Diseases and injuries can both causes long lasting damage to the body, may have similar symptoms, or may share identical treatments. The body responds atypically to the allergen, responding by releasing histamines and setting off the chemical cascades that correspond to an allergy attack. This is a defined change that disrupts the normal physiological conditions of the body. Unlike diseases, injuries usually occur from an outside source of trauma, accident, unexpected event. They can be enduring—a person who is in a car accident may have damage that lasts years—but usually occur because of a single event.
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This curriculum unit further breaks down diseases into several categories to allow for an easier understanding. While the majority of this paper will delve into chronic conditions that develop from within the body, I will also provide a brief refresher on communicable diseases, particularly those of bacterial and viral origin. For a more in depth review of these concepts, and a survey of current emerging infectious diseases, please reference
Emerging and Reemerging Infectious Diseases
, a curriculum unit written in 2014.
Communicable Diseases
A communicable disease is one that can, if given the opportunity, pass from one unfortunate host to another in an act called transmission. In recent years, news of bacterial and viral infections has taken center stage in the infectious disease world. On any given day, a quick visit to the Office of Infectious Diseases hosted by the Center for Disease Control can quickly provide a running list of current epidemics and outbreaks in the United States and internationally.
Bacterial and viral infections are not quite as simple as common media would have them pictured. Transmissions are often highly specific-- Ebola can only spread through infected fluid like blood and semen, not by air or water-- and the body has a built in surveillance system constantly on the lookout for anything that could qualify as “not self”.
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Regardless of the mode of transmission, bacterial and viral particles cause disease through several common methods.
Once inside the host body, bacteria and viruses both continue their lifecycle by undergoing replication. Bacterial cells replicate by splitting through a process called binary fission. As bacteria grow and replicate, they may directly damage tissues through the release of cytotoxins and other dangerous compounds. For example,
Streptococcus pyogenes,
releases a hyaluronidases and proteases that cause soft tissue inflammation of the throat in a disease known as strep throat.
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In other species, the actual act of destroying the bacteria may be responsible for releasing toxins into the host tissues.
Viruses also use their hosts as a tool for replication. The virus life cycle can go via two routes. The more immediate route involves replication through the lytic cycle where the virus hijacks the host cell’s machinery as a tool for creating many viral particles before lysing (breaking out) or otherwise leaving the host cell. The lysogenic life cycle is similar in that it does eventually result in the lysis of infected cells, the main difference being that prior to this stage the virus acts as a sleeper agent hiding among its host’s DNA and slowly replicating every time the host divides.
The lysogenic cycle, while taking longer to complete, can produce many more viral particles for this reason. This particular life cycle may also cause many problems in addition to the viral infection. Many viruses do not have a specific part of the host DNA that they insert themselves into. As a result, a virus may insert their DNA into a part of the DNA that is responsible for maintaining the healthy condition of the cell. In human papilloma virus infections, the virus might insert its DNA into a region that disrupts a gene that codes for proteins responsible for suppressing tumors.
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More information about HPV is found in below when we discuss instances where surveillance is turned off or broken.
Non-Communicable Diseases
A portion of this unit will focus on non-communicable diseases caused by surveillance errors. A non-communicable disease (NCD) is any ailment that is unable to be transmitted from one person to another via direct or indirect contact. Non-communicable diseases progress slowly over the lifespan, as seen in cases like arthritis and chronic pulmonary obstructive disorder (COPD). These diseases often require long term treatment plans to mitigate any symptoms as they appear.
Other NCDs have a rapid onset, and may cause a quick fatality depending on the type of disease. For example, an allergy sufferer may have a sudden “attack” during peak seasons. In this instance, the disease has rapid onset and the person usually recovers in a matter of hours. Some cancers, on the other hand, can present quickly in a patient and cause rapid degeneration and eventual death. According to the WHO, NCDs kill about 38 million people annually with nearly half of those deaths due to cardiovascular diseases.
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There are some connections between communicable and non-communicable diseases. Scientists are discovering more connections between communicable pathogens and what were traditionally believed to be chronic diseases. For example, there are a number of diseases, like cancers and Type 1 Diabetes, which have connections to viruses. As previously mentioned, viruses DNA insertions into the host DNA may turn deactivate genes that are responsible for surveillance. A few examples of autoimmune surveillance errors and their connection to viruses are discussed in the section about what happens when surveillance makes a mistake.
Our Body’s Surveillance and Regulation
Before we can start discussing NCDs specifically, it is important to understand how the human body maintains homeostasis. Homeostasis is the body’s ability regulate the internal conditions of the body despite change. For example, your body maintains a constant temperature, pH, and O
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saturation level that is vital to keeping tissues healthy. In addition to the systems that are responsible for maintaining physiological conditions in the body, the body is constantly being sampled to identify problems that are happening inside the body. The second portion of this unit will be dedicated to demonstrating the various ways that the body is able to recognize mistakes in DNA, proteins, and microorganisms.
DNA Replication Self Editing
DNA replication is crucial in the replication of cells. All proteins in the body are derived from the genes found in the body’s cells and each cell contains identical copies of DNA. It is important for DNA to have the ability to self-edit and catch replication errors as these can lead to malformation of important proteins. If the error is not caught, it will be passed along through mitosis to all subsequent generations of daughter cells.
If DNA errors are present, they can cause mutations in the formation of proteins that are essential for maintaining homeostasis. For example, an insertion or a deletion in a gene may cause a frame shift mutation, rendering the protein that it codes for. This sort of mutation is seen in familial hypocholesteremia, where a frameshift mutation alters the structure of the LDL receptor proteins.
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Point mutations, where the wrong nucleotide is inserted into the DNA instead of the complimentary nucleotide base, can also be devastating. One type of basal breast cancer is caused by a point mutation in the PIK3CA gene which alters its function. A single error is enough to activate this oncogene.
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Using these techniques described below, DNA fidelity is very high, with only one error per every 10
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bases.
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A high fidelity rate in DNA synthesis is important because errors in replication are inherited by daughter cells.
DNA replication has several built in checkpoints. First, DNA base pairs are complementary only to another specific nucleic acid-- adenosine pairing with thymine and cytosine pairing with guanine. As the DNA strand unwinds and unzips for replication, DNA polymerase attaches at the strand at the 5’ end at a primer. This enzyme attaches to the old DNA strand joins new amino acids together as it forms the complementary strand. This process is efficient because complementary base pairs have a higher affinity to one another than other nucleic acid residues. As the correct nucleic acid enters the DNA polymerase and binds with the complementary nucleotide, a conformational change occurs within the enzyme, allowing it to move forward on the chain. If an incorrect nucleotide were to enter into the sequence, it is unlikely that the conformational change in the enzyme would occur before the nucleotide is covalently bonded into the chain.ix This process acts as a way to check the complementary DNA strand as it is being formed.
If an incorrect nucleotide is bonded into the forming complementary DNA chain, a secondary check takes place using a proofreading exonuclease. When a non-complementary nucleotide attaches, it disrupts the -OH end of the primer strand, shifting the conformation of the DNA strand and inhibiting the addition of new nucleotides.
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Essentially, this ends up dislodging the polymerase which prevents additional nucleotides from being added to the strand. When this happens, the cell takes time to correct the nucleotide mistake. A special molecule called a 3’ to 5’ exonuclease breaks the covalent bond and removes the incorrect nucleotide. Once this step occur, DNA polymerase is able to continue strand elongation.9
If a mistake is overlooked by either of the two processes previously mentioned, a third system is in place called strand directed mismatch repair.
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This process works by identifying distortions in the sugar-phosphate backbone of DNA caused by non-complementary base pairs. Usually, an incorrectly selected nucleotide will cause the backbone to bow out or to pull in. This irregularity in the width of the double helix can be identified by the cell. Once a distortion has been identified, the backbone is nicked by an enzyme. At the same time, MutS, a protein that travels along the DNA strand checking for errors, binds to the incorrect base pair that is causing the distortion. MutS binds to MutL which causes MutH recruitment.
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This in turn causes the helix to fold like a hair pin as MutH cuts the backbone. One this occurs, the piece of DNA with the incorrect nucleotide can undergo degradation. After, the gap can be filled in using DNA polymerase III, correcting the error. This process is only able to occur within a very narrow window of time while the newly synthesized strand is unmethylated.
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At this point, the DNA double helix is considered to be hemi-methylated. After methylization has occurred on the newly formed strand, these control proteins are no longer able to recognize which is the original template.
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DNA Double Strand Break Repair
There are many things that can cause DNA strands to break, including mechanical stress and ionizing radiation from x-rays. Once a DNA strand is broken, there are repair mechanisms in place to help reassemble damaged strands. It is important that damaged DNA be repaired in order to prevent the loss of the chromosome, recombination that trigger oncogene activation, or creating critical errors that will cause the cell to me marked for destruction.
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There are two main mechanisms for strand break repair in eukaryotic cells: homologous recombination of DNA strands and non-homologous DNA end joining.
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In homologous recombination, the damaged strand of DNA will form a bond with a comparable DNA.
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Sticky ends of the damaged strand will invade a full strand of DNA looking for homologous sites forming connections called Holliday Junctions.12
Once the damaged DNA strands are connected with the template DNA strands at these sites, DNA synthesis can occur. DNA polymerases will use the template strand to fill in the damaged strand, resulting in repaired DNA.
In non-homologous DNA end joining, the protein Ku binds to the break site. At this point, a nuclease is able to attract nuclease attachment.
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These nucleases cut a sticky end overhang in the DNA where polymerases can bind. Once bound, this forms a full complex that the ligase can bind to. At this point, the ligase can rejoin the strands of DNA, and complete the template.13 While the integrity of the DNA is repaired, this method of repair damages the sequence of the original strand which may cause harm later.
Protein Misfolding and Degradation
In addition to checking the DNA of an organism, it is also important to look for errors that are found in the products that the DNA is producing. Proteins can also have errors that reduce their function or cause entirely new problems to occur as a result of how it interacts with a substrate. In order to reduce the amount of non-functioning or mis-functioning proteins, there are several checkpoints that collect these products and dispose of them through degradation.
Proteins are created through the translation process by ribosomes. Ribosomes are responsible for reading the codons of mRNA and constructing proteins. In order to ensure that the proteins being created are able to function correctly, there are multiple forms of control that are used during translation of new proteins. One example of quality control that occurs during translation is the kinetic favorability of anti-codons that match the correct mRNA codon. Non-cognate anticodon pairings, i.e. those that do not match, inhibit GTP hydrolysis and A site entry—two necessary steps to adding an amino acid to a growing peptide chain.
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After the initial stringing of the protein’s amino acid chain, secondary, tertiary, and even quaternary structures start to form. One of the key quality control points used in the surveillance of proteins is recognition of which proteins are and which are not folded. Folded proteins have a high affinity for a carrier protein that will pick them up and transport them for packaging, leaving unfolded or misfolded proteins where they are tagged by another protein for removal.
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In the endoplasmic reticulum, the targeted protein is transported to the Sec61 translocon where it is degraded.
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Other protein machinery exists to differentiate between correctly folded proteins and those that must be targeted for and degradation. Chaperone proteins, also know as heat shock proteins, assist with the folding of complex amino acid chains into their tertiary and quaternary forms. When a cell undergoes stress, the products that they make might be damaged. Excessive heat is able to cause proteins to unfold or to fold incorrectly, denaturing them.15 One chaperone protein—HSP70— assists proteins with folding and refolding denatured proteins. After HSP70 attaches to a protein that is folding correctly, HSP70 recruits two co-chaperones which in turn, recruits additional proteins like HSP90 that further facilitate folding.15 If the protein takes too long to refold, HSP70 recruits two other chaperones which ubiquinate the misfolded protein thereby targeting it for degradation.15
The Immune System: Self vs. Non-self
In many diseases, especially those involving a foreign agent such as a bacteria or a virus, the ability of the body to recognize which cells belong and which are intruders is crucial in maintaining health. This concept is often tied into immune surveillance, as this is the primary tool for dealing with potential outside threats.
Cells carry special marker proteins embedded in their membranes that allow for communication and identification within the body. The cells of our immune system are able to recognize these specific marker molecules and will leave them alone. When a foreign molecule enters into the environment, the lymphocytes are unable to recognize the epitopes on the surfaces of the invading cell membrane. The presence of these unknown epitopes acts as an antigenic trigger, which can stimulate the immune system into responding.
It is for this reason that blood transfusions are only possible between compatible donor-recipient pairs. Blood cells also carry epitopes on the surface of their membranes: A, B, O and Rhesus polypeptide factors. The erythrocytes in a person carry special sugar markers on their cell surface. These markers, or antigens, have two forms A or B. The presentation of these marks on the surface of the cell is what grants a person A, B, or AB blood type. If a person lacks these markers altogether, then they are type O blood.
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If A positive blood was introduced into the body of a B negative recipient, the immune system would quickly recognize the antigens related to the A blood phenotype as well as the presence of the Rhesus polypeptide. As such, their body would launch an immune attack on the foreign blood, causing coagulation, hemolysis, and ultimately rejection of the transfused tissue.28
This same principle explains why organ donors must be matched to a recipient before a transplant. The cells of our tissues have special markers that indicate that they are self. These markers are called HLA markers. The specific structure of these proteins is different for every person, depending on the alleles that they possess
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. As T-cells patrol the tissues, they are able to identify cells that are coated in specific HLA markers. If other major histocompatibility complexes are present that do not belong, then the immune system will react.18 HLA proteins interact with specific receptors on T cells. If these two receptors are able to interact appropriately, then the T cell continues on its way.
HLA proteins also present, or hold onto, proteins from within the cell. This allows T cells to monitor what is going on within the cell.18 If the protein is normal, then the T cells do not react. However, if a foreign antigen is presented by autosomal HLA cells, then the small differences in the interaction between the two receptors triggers an immune response.18
In order for organ donation to be successful, doctors identify candidates with similar major histocompatibity complex profiles to their patient.18 Highly similar profiles are less likely to trigger an immune response from the T cells, forcing rejection of the organ.
