In this new article series, we will be taking a look at the role that microbial pathogenesis has played in human health and history. Here, we will first identify what defines pathogenesis and how microbes are able to instigate the disease pathway.
Written by: Shreya
It may be difficult to comprehend how organisms as minute as 20 nanometers long, or about ten times the diameter of our very DNA, can wreak havoc throughout our bodies and take millions of lives every year. To understand this seeming enigma, we must realize that we truly operate at the molecular level, our shared domain with the microscopic. This new article series will take a look at pathogenesis and the human body, considering everything from historic diseases such as Black Death to novel pathways towards curing currently untreatable diseases. To begin, let’s take a look at what exactly constitutes pathogenesis and how the body responds to disease.
Pathogenesis is the development of a disease, and microbe-mediated pathogenesis can arise from five sources: viruses, protozoa, helminths/worms, fungi, and bacteria (4). Each of these sources aims to utilize the host’s nutrients to multiply and grow, classifying them as “parasitic organisms”, and their impacts on the body are as extensive as they are in number, with 1,400 pathogens currently known to infect humans. Three virulence factors classifying a successful pathogen include (1) host entry, (2) disease onset, and (3) the evasion of host defenses. Let’s take a look at some examples of each:
Host Entry
Adherence Factors: Pathogens colonizing mucosal sites along the gastrointestinal sites use short, hair-like structures across their cell membranes called pili or fimbriae to adhere to cells. Adherence in the GI tract is crucial to virulence since the mucosa regularly cleanses the track with layers of mucus and the flow of gut contents across the epithelium. Bacteria that have successfully attached to the body can begin to reproduce and form mature biofilms, which keep the bacteria safe from host defenses and enable strong signaling between microbes within their community. Aggregates of cells from the biofilm can break off and enter the bloodstream to travel elsewhere in the body. Bacteria within the biofilm secrete EPS, or extracellular polymeric substances, which is a composition of macromolecules that helps retain water within the community and acts as a protective barrier (1).
Invasion Factors: Microbes can have surface proteins that enable their entry into host cells and bypass security measures. Once inside, they are free to proliferate and hasten the disease pathway. The specific proteins used by individual species are widely unknown, making them a difficult target when designing disease treatment, but one known example is that of Shigella bacilli. This pathogen uses the Type III secretion system to inject bacterial effector proteins into the host’s cytoplasm in order to evade the issue of traversing through the armored cell membrane.
Consumption/Inhalation: Several microbes gain access into the body through consumption or inhalation; in fact, all five sources of the pathogen types mentioned earlier have developed pathways through this mode of infection. Contaminated food or water is a prominent source of infectious protozoa, bacteria, and helminths/worms, while viruses and fungal spores are more often inhaled (3). Once inside the body, worm eggs hatch, fungal spores proliferate, bacteria form biofilms, viral genetics incorporate into the body, and protozoa multiply. Some worms take an alternate route into the stomach: once in the body, they travel through the bloodstream to get to the lungs, where they are coughed up and swallowed to be taken to the GI tract where they can grow.
Water contamination from sewage leakage is a substantial source of gastrointestinal infections.
Bodily Fluids: Some viruses and bacteria spread person-to-person through bodily fluids such as saliva, amniotic fluid, semen, vaginal secretions, blood, and cerebrospinal fluid (although there are several more). One prominent example is HIV, or Human Immunodeficiency Virus, which can be transmitted from one person to another through unprotected sexual activity, birth, breastfeeding, or the sharing of unsanitized needles. Several sexually transmitted diseases are transmitted through this mode of infection (eg. gonorrhea, syphilis, chlamydia).
Other: The list of infection modes could go on with the sheer diversity of microbial life observed on our planet. Some common methods not listed above include transmission through a vector, or a vehicle such as a mosquito, fly, or mouse that is used to transfer viral or plasmid DNA to a host. Once in the host, the DNA is expressed to create more infectious bodies that can replicate within infected cells. The protozoal disease malaria, the Zika virus, and dengue are examples of microbes that necessitate vectors (and specifically, mosquitos). Some diseases must be transmitted by direct contact with the infectious substance. For example, anthrax bacilli are almost always contracted through directly touching discharge from disease sores (although aerosolized spores can sometimes also be inhaled). Spores inside the body begin dividing rapidly and generate black sores where tissue has begun to die. Inhaled anthrax is much more lethal than spores directly touched since inhalation leads to tissue damage within internal organs where the bacilli produce deadly toxins.
Disease Onset:
Endotoxins: Endotoxins are toxins on the surfaces of cells that can break off and are composed of lipopolysaccharides. Endotoxins have been generally characterized by three regions: oligosaccharide side chains, the genus-specific core polysaccharide, and the toxic Lipid A. While mild exposures to endotoxins can be beneficial to the host in prompting greater resistance to future toxin attacks, endotoxins can also become lethal in the right concentration. They can elicit an impact on several cell types including platelets, lymphocytes, macrophages, and granulocytes by binding to the host’s CS14 cell surface receptor, which can trigger sepsis, the clotting system, fibrinolytic (anti-clotting) pathways, and inflammatory reactions (1).
Exotoxins: Exotoxins are toxins pumped out of microbes rather than those adhering to the cell surface. Another difference between the two is that exotoxins are much more specific than endotoxins, with each very particular in the response it generates and the cell type(s) it is able to affect. Some microbes are able to directly inject their exotoxins into host cells through projections called a pilus, in which case the toxins are called effectors. In the case of anthrax, for instance, exotoxins bind to the host cell’s surface cell receptors, triggering the endocytosis of the bacilli inside where they can now disturb kinase and cyclic AMP activity (which, as aforementioned, causes necrosis or cell death, leading to swollen black sores). Due to their specificity, exotoxins can be classified into categories, including (but not limited to) neurotoxins, cytotoxins, and enterotoxins. Neurotoxins, for instance, hinder the reception and transmission of signaling molecules, such as the botulinum produced by C. botulinum, which blocks acetylcholine release at neuromuscular joints and thereby prevents muscular excitation (1).
Siderophores: Siderophores are small, iron-chelating molecules (molecules with a high affinity for iron) that microbes can release to sequester nutrients from the host for their own metabolism. However, many host organisms have their own defenses to protect their essential iron reservoirs. In the bloodstream, iron is tethered to hemoglobin, inaccessible for uptake without specialized receptors from the microbe (2).
Host Defense Evasion:
Capsules and Other Mechanisms: In order to prevent phagocytic opsonization (or elimination), many bacteria have a protective outer capsule. Viral and bacterial capsule proteins are easily alterable, enabling them to evade detection by the immune system since their key identification markers mutate between generations. Certain bacterial species can also replicate and remain sheltered inside the phagocytes themselves by deactivating the immune cells’ hydrolytic lysosome activity. Helminths are able to endure long periods in the GI tract by inducing apoptosis in immune cells, suppressing the activity of cytokines that would alert the immune system of a foreign presence, and blocking phagocytosis.
Clearly, the diverse array of virulent microbes that demonstrate parasitic behavior in humans comes with just as varying an assembly of virulence factors and behavior. Understanding these virulence factors enables us to treat infections more effectively. These microbes are able to evade our immune systems and gain access to our bodies’ nutrients by instigating toxic chemical reactions that deregulate our cellular systems. In future articles, we will continue to look at the role pathogenesis has played in human health and history as well as introduce particularly devastating strains and means of staying safe.
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