TL;DR: What makes a microbe a pathogen is the damage it does, not its species or its numbers — and the host meets it with four layers of defence that differ mainly in how fast they act and how precisely they aim.
The microbes living on you right now
Trillions of microorganisms are on you at this moment: on the skin, in the mouth, across the surface of the eye, and in very large numbers in the gut. Almost none of them are trying to harm you. The episode starts from that fact and asks the obvious follow-up: what makes the rare one dangerous?
Four kinds of pathogen, and how each causes damage
Disease-causing microbes fall into four groups: viruses, bacteria and archaea, fungi, and parasites, the last ranging from single-celled organisms to multicellular worms. Each group damages tissue in a different way, and going from smallest to largest makes the differences clear.
- Viruses are the smallest, from about five nanometres to a few hundred. A virus cannot live on its own. It is an obligate intracellular pathogen: it enters a cell, takes over the cell’s machinery, and bursts the cell as it replicates.
- Intracellular bacteria and mycobacteria kill a cell directly or poison it with toxins. Some single-celled parasites act the same way; Plasmodium, the cause of malaria, destroys the cells it infects.
- Extracellular bacteria and fungi never enter cells. They grow in the spaces between them and release toxins into tissue and blood, which is the route to shock and sepsis.
- Helminths are parasitic worms, far too large to hide inside a cell. They migrate through tissue and form cysts, and much of the damage they cause comes from the host’s own response to them.
That last point is flagged as an idea to keep hold of, because it recurs through the series: the immune response can itself be the source of injury.
Where commensals end and pathogens begin
The organisms on the skin, oral mucosa, conjunctiva and gastrointestinal tract together make up the microbiome: archaea, bacteria and fungi that live on the host without causing damage. They are called commensal organisms, and the relationship is often symbiotic, with some commensals genuinely benefiting the host.
So the dividing line between commensal and pathogen is not the species, and it is not the number of organisms. It is damage. The gut illustrates this well. It carries an enormous bacterial population, held inside the lumen behind a layer of mucus. A pathogen is the organism that breaks through that layer, injures the epithelial cells, and spreads into the tissue beneath.
Avoidance, resistance and tolerance
A host has three broad strategies against microbes:
- Avoidance: never being exposed in the first place, through anatomic barriers and through behaviour.
- Resistance: once infection is established, reducing or eliminating the pathogen. Most of immunology concerns these tools, the effector mechanisms.
- Tolerance: not preventing infection, but strengthening the tissue’s ability to withstand the damage it causes.
Two meanings of “tolerance”
The episode adds a deliberate warning here. “Tolerance” in this sense comes from plant biology, and it is not the same as immunological tolerance, which is the set of mechanisms that stop the immune system attacking the body’s own tissues. When those mechanisms fail the result is autoimmune disease. It is the same word for two entirely different ideas, so it is worth keeping them separate from the start.
The four layers of defence
Defence is arranged in layers.
- Anatomic barriers: skin, oral mucosa, respiratory epithelium and intestine. This is pure avoidance, keeping the inside and the outside apart.
- Chemical defence: mucosal surfaces secrete antimicrobial proteins, natural antibiotics such as the defensins and RegIII gamma. In plasma, complement is a cascade of around thirty proteins, discovered by Jules Bordet. It works alongside antibody but can also mark a foreign organism on its own, so it belongs to both halves of immunity.
- Innate immune cells: macrophages, granulocytes, natural killer cells and epithelial cells, providing a rapid, coordinated, cell-mediated defence.
- Adaptive immunity: B cells and antibody, and T cells. This is the slowest layer and by far the most precise.
Minutes versus days: the speed problem
The difference between the layers matters most in time. The innate response begins within minutes and runs for days. The adaptive response takes days to weeks to build, but it ends with something innate immunity cannot offer: memory that can last a lifetime.
The next episode in the series covers the cells that do the fighting.
Based on Janeway’s Immunobiology.