How are other living organisms threatening to human beings? We could be mauled by bears, poisoned by mushrooms, or stung by wasps. However, what if that organism was small—microscopically small? These tiny organisms can sometimes make us sick with infectious diseases and, when they do, we call them pathogens. This article explores what these pathogens are, where they come from, how we recover from infections, and their effects on human populations.
It was September 1854, and something was terribly wrong in London. In just ten days, 500 people became ill and died within 250 yards of the intersection of Broad and Cambridge Street. Most believed that disease was caused and spread by “miasma,” or impure air. However, one physician, John Snow, did not subscribe to the miasma theory of disease. After interviewing residents and creating a map  of cholera deaths, he found that most deaths came from households that drew drinking water from the Broad Street pump. He organized removal of the pump handle, which helped slow and eventually stop the outbreak [2, 3].
Today, we know that John Snow was dealing with cholera, an infectious disease caused by the bacterium Vibrio cholerae. People can develop cholera from contaminated food and water, which leads to symptoms including vomiting and diarrhea. In 19th century London, outbreaks were relatively common because human waste was often thrown into rivers and onto streets. Today, cholera is not a problem in developed countries due to improved hygiene and sewage systems. However, infectious diseases are still the source of most epidemics and outbreaks. For example, the most recent outbreaks compiled by the Center for Disease Control (CDC) were caused by the bacteria Salmonella and Listeria in sprouts and cheese, as well as the parasite Cyclospora cayetanesis in cilantro . Infectious diseases are caused by microorganisms too small to be seen by the naked human eye. In contrast, other diseases – such as cancer and heart disease – are caused by some combination of genetics, environmental factors, and lifestyle. In the following sections, we will discuss the microorganisms that cause disease, how we recover from infectious disease, and how we transfer microorganisms to one another.
Who is making you sick?
Microorganisms can be classified into bacteria, viruses, fungi, and parasites. Those that can cause disease are collectively known as pathogens. These microorganisms vary in size and position in the tree of life . Viruses are the smallest, followed by bacteria, fungi, and parasites. Viruses are technically not included in the tree of life; since they cannot reproduce independently, they are not considered living organisms by most scientists. Bacteria are distinct from fungi and parasites in that they are considered prokaryotes, while the latter two are considered eukaryotes. The difference between prokaryotic and eukaryotic cells is in the way they organize their DNA (deoxyribonucleic acid), the primary genetic material in the cell. This organization can change how cells grow, replicate, and function.
Figure 1 On the left is a scale that ranges from the size of an atom to the size of a child (one meter). From this, we can see how tiny viruses are relative to bacteria, as well as how small bacteria are relative to parasites and fungi. From the microscope images on the right, we can see how diverse pathogens are structurally. This diversity originally made microorganisms very difficult to classify. Today, they are primarily classified by differences in their genetic material (DNA vs. RNA), as well as morphological features.
Some pathogens are from the human microbiota, which consists of the microbes that live on and within the human body. Most of these microbes are beneficial or commensal (causing no harm) to humans, but some may become pathogenic in the face of disturbances such as dietary changes, stress, and antibiotic use. Other pathogens may come from our surrounding environment – in the air, soil, and surfaces we touch, as well as from other organisms, including livestock, wild animals, and humans.
How do they make you sick?
In order to cause disease, these microorganisms must enter the human body, stick to specific human cells and tissues, and grow and replicate. This first step is important for pathogens from the outside environment. They can enter through breaks in the skin, as well as through the mouth, nose, and urogenital tract. This means that infectious diseases can affect our skin (e.g., acne and eczema), digestive system (food poisoning and cholera), lungs (tuberculosis and flu), urinary tract (UTIs), and sexual organs (most sexually transmitted diseases (STDs)).
Many of these microorganisms only invade specific parts of the body. For example, Vibrio cholerae specifically affects the digestive tract; it does not infect the skin or the lungs. This is because pathogens will only adhere to the human cells and tissues by which they grow best. To do this, they often use cell surface receptors, which are proteins on the cell surface. This is comparable to gluing puzzle pieces together: specific pathogen cell surface receptors only fit and stick to certain human cell surface receptors. Some parasites will not use receptors, but instead use “hooks” to attach to the small intestine.
Once bound, these microorganisms will begin growing and replicating. Some pathogens will simply steal nutrients from the surrounding environment. Other pathogens will invade the host cell and hijack the host cells’ nutrients or cellular machinery. This may cause host cells to die or malfunction, making us sick. Furthermore, some pathogens produce toxins as they grow, which can also make us ill.
How do we get better?
We can fight infectious diseases through our immune system and modern medication. Our immune system consists of barrier immunity, innate immunity, and adaptive immunity. Barrier immunity is built into the human body. Examples of this include our skin, which keeps invading microorganisms out, as well as the low pH in our stomachs, which kills pathogens trying to enter the intestines. Innate immunity is mediated by specific immune cells that immediately respond and work to seal lacerations and remove damaged cells. An example of this would be the blood clotting and inflammation that occurs after getting a paper cut. While innate immunity is a general response, meaning that it recognizes nonspecific, well-conserved patterns in pathogens, adaptive immunity is a response specifically targeted to the pathogen currently in the body. It is primarily controlled by special immune cells called B and T cells, and can take up to two weeks to activate. This is why it sometimes takes up to 14 days to recover from a cold. B cells make antibodies, which will specifically stick to the cell surface to the invading pathogen, preventing them from attaching to host cells and tissues and targeting them for destruction. If we envision cell surfaces as Velcro strips, antibodies would be akin to lint, hair, and fuzz that fill the Velcro loops on pathogens and make them “unsticky.” T cells have many functions: some help activate these B cells, while others directly kill pathogens and infected cells. Some of these B and T cells further go on to form memory cells, which will immediately reactivate if the same or similar pathogen returns. This is the basis by which vaccines work.
Figure 2 The Human Immune System: Defending Against Pathogens (A) Barrier immunity prevents outside pathogens from entering the body. Examples of this include the mucus that lines the nose and lungs, the skin, and the acidity of your urine. (B) However, sometimes pathogens may find a way in. In this case, a pathogen has entered through a cut on the arm. Innate immunity immediately responds with special immune cells. These cells will seal the cut, as well as remove foreign debris and pathogens that may have made it through. (C) If innate immunity is not enough, the adaptive immune system will activate. This is primarily mediated through T and B cells. The T cells can go and kill the pathogen, or they may activate B cells to make antibodies. The antibodies will cover the pathogens and make them easier to kill and less likely to infect other cells.
If the immune system is not enough, we may turn to medication. Currently, treatments tend to take three general strategies. The first strategy requires that we kill pathogens without killing our own cells. Fortunately, bacteria, viruses, fungi, and parasites are distantly related to humans. By creating drugs that target pathogen-specific cellular processes, we can kill pathogens without killing human cells. This is also why most antibiotics, which are specific to bacterial cellular processes, do not work on viral, fungal, or parasitic infections.
The second medication strategy is to prevent infection, primarily through the use of vaccines. This process involves training the adaptive immune system to recognize the pathogen without actually having an infection. Thus, most vaccines are made up of heat-killed pathogen, protein pieces of the pathogen, or a similar but less deadly variant of the pathogen. For example, the flu vaccine is made up of three strains of inactivated influenza virus . The adaptive immune system creates antibodies based on these harmless versions of the flu, enabling it to quickly recognize and neutralize the live versions if a person becomes infected. This is often the most effective strategy for pathogens that are especially difficult to treat or have no treatment after infection. In addition, it can also provide herd immunity. If there are fewer people who can be infected, the disease cannot spread as quickly through the population .
The third strategy involves treating symptoms until the pathogen is cleared by the immune system or expelled. This is actually how cholera is currently treated. Rather than using antibiotics, patients can recover if they stay hydrated until the bacteria are expelled from the body. Another example is over-the-counter medications such as Tylenol and Nyquil: these medications will not help kill the pathogen, but will alleviate symptoms such as stuffy nose, sore throat, and cough until our immune system clears the infection.
What if there’s an outbreak?
In the previous sections, we have seen how infectious diseases can invade and be cleared by a single person. However, because infectious diseases are caused by living organisms, they pose two problems to medicine and public health. First, pathogens can grow and replicate, allowing them to evolve drug resistance or change just enough to be unrecognized by our memory immune cells. Second, they are contagious and potentially lead to outbreaks. Human-to-human transmission is outlined in more detail in the figure below. There is even human-to-animal transmission.
Figure 3 Modes of Infectious Disease Transmission (A) Pathogens can be transferred by environmental factors, such as wind and water. They can also be transferred between humans, as well as from humans to animal vectors. Animal vectors can further spread the disease through migration (if carried by birds or fish) or trade. (B) Human-to-human transmission has been classified into five main modes . These five modes are not mutually exclusive; for example, the Ebola virus can be spread through direct contact and, potentially, through droplet transmission. How pathogens can be transmitted mostly depends on how “hardy” they are outside a human body. Some cannot survive for long periods of time, so they require direct contact, droplet transmission, or transmission through an animal vector. Others, such as flu, can survive for long periods of time on surfaces – making them extremely contagious. Fecal-oral pathogens are a large problem in developing countries, but not in developed countries such as the US.
In order to control outbreaks, we often call upon epidemiologists. Epidemiologists observe how health-related events are distributed in the population and use that information to determine their causes and control their spread. In fact, John Snow (described in the first paragraph) is celebrated as one of the fathers of epidemiology. Drawing from John Snow’s example, we can see that the solution to fighting epidemics requires coordination between multiple agencies, including citizens, scientists, physicians, and government officials. In the US, this job often falls to the CDC, and internationally, the World Health Organization (WHO).
In conclusion, infectious diseases are caused by microorganisms that can hijack the nutrients and cellular machinery in our bodies. Fortunately, our immune system and current therapies can keep us healthy. In fact, according to the WHO, infectious, maternal, neonatal, and nutritional-related diseases combined caused about 23% of deaths around the world in 2000 . However, the recent Ebola outbreak has shown us that infectious diseases are still a major threat. This is especially important with an increasing amount of global travel and a lack of new drugs . We can do our part by taking sick leave or avoiding travel when ill, taking antimicrobial drugs properly (finishing the course), getting the appropriate vaccinations to protect those vulnerable in the population (through herd immunity), and asking scientists and politicians to make infectious diseases a priority.
Tiffany Hsu is a 3rd year graduate student in the Biological and Biomedical Sciences (BBS) PhD program at Harvard University.
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