Microbiology and the Immune System

A microorganism, or microbe, is any living thing too small to see clearly without a microscope. The word covers very different kinds of life. Bacteria (and the similar-looking archaea) are prokaryotes: single cells with no nucleus. Fungi such as yeasts and molds, and protists such as amoebas and algae, are eukaryotes, with a nucleus and other membrane-bound organelles, like your own cells. The difference between the two cell types is covered in The Cell. Viruses are studied alongside microbes but are not cells at all.

Sizes span a huge range. A typical virus is about 100 nanometers across, roughly ten times smaller than a typical bacterium at about 1 micrometer, which is itself at least ten times smaller than a typical plant or animal cell at 10 to 100 micrometers. Your eye can make out objects only from about 100 micrometers up (see OpenStax Microbiology 1.3).

A bacterium is a complete living cell, just a simple one. Its DNA is a single circular chromosome sitting in a region called the nucleoid, not wrapped in a nucleus. Many bacteria also carry small extra rings of DNA called plasmids, which can be passed from one bacterium to another; plasmids often carry genes for antibiotic resistance, which comes up again in section 8.

Binary fission. Bacteria reproduce by copying their chromosome, growing, and splitting into two identical cells. In good conditions this can be startlingly fast: E. coli can double in as little as 20 minutes in the lab, while the tuberculosis bacterium takes 15 to 20 hours (see OpenStax Microbiology 9.1). Fast doubling, plus occasional mutations, means bacterial populations can evolve quickly.

Helpful and harmful. Most bacteria do not harm us. Gut bacteria help break down fiber and make some vitamins, soil bacteria recycle dead matter, and nitrogen-fixing bacteria make nitrogen usable by plants, which is part of the nitrogen cycle covered in Ecology and Ecosystems. Pathogenic bacteria cause diseases such as tuberculosis, strep throat, cholera and some food poisoning. Some damage tissue directly; many release toxins.

A virus particle, or virion, is genetic material (DNA or RNA) packed inside a protein coat called a capsid. Some viruses, like influenza and the coronaviruses, also have an outer envelope of membrane taken from the cell they left. Virions vary from about 20 nanometers for small viruses up to about 900 nanometers (see OpenStax Microbiology 6.1).

Are viruses alive? Most biologists say not quite. A virus has genes and can evolve, but it has no metabolism, no ribosomes and no way to copy itself on its own. Outside a cell it is an inert particle. Only inside a host cell, using that cell's machinery, does it reproduce. That is why viruses are usually described as being on the edge of life rather than as organisms. Each kind of virus can infect only certain cells, depending on whether its surface proteins can attach to receptors on them.

Viruses that infect bacteria, called bacteriophages (phages for short), show two strategies clearly (see OpenStax Microbiology 6.2).

Animal viruses can behave in similar ways. HIV inserts a DNA copy of its genes into the chromosomes of the white blood cells it infects, and the virus behind chickenpox can hide in nerve cells for decades before returning as shingles.

Fungi include single-celled yeasts and many-celled molds and mushrooms. They absorb food from their surroundings after breaking it down with enzymes, which makes them important decomposers. A few cause human disease, usually on the skin or in people whose immune systems are weakened: athlete's foot and thrush are fungal infections. Because fungi are eukaryotes like us, drugs that kill them tend to have more side effects than antibiotics do.

Protists are a catch-all group of eukaryotes that are not plants, animals or fungi. Most are harmless, and algae among them make a large share of the world's oxygen. The best-known pathogen is Plasmodium, the parasite that causes malaria. A female Anopheles mosquito injects it while feeding. It multiplies first in the liver and then inside red blood cells, which burst in waves, causing cycles of fever and chills. Here the mosquito is a vector, an animal that carries a pathogen between hosts.

The germ theory of disease, the idea that specific microbes cause specific infectious diseases, only became widely accepted in the late 1800s. Before that, illness was blamed on bad air or imbalanced body fluids. The timeline in section 9 shows how evidence piled up in the 1800s.

Pathogens travel between hosts in a few main ways (see OpenStax Microbiology 16.3):

• Direct contact: touching, kissing, sexual contact, or from mother to baby.
• Droplets: large droplets from coughs and sneezes that land on someone nearby, within about a meter. Some pathogens can also travel in smaller particles that stay in the air longer.
• Indirect contact: objects such as door handles that pick up germs, called fomites.
• Vehicles: contaminated food or water, as with cholera.
• Vectors: animals, usually insects, such as the mosquitoes that spread malaria.

Epidemiologists summarize how contagious a disease is with its basic reproduction number, R0 ("R-nought"): the average number of people one infected person infects in a population where everyone is susceptible. If R0 is above 1, each case leads to more than one new case and an outbreak can grow. Below 1, it dies out. R0 is not a fixed property of a germ: it also depends on how people live and mix.

A classic way to model an outbreak, going back to Kermack and McKendrick in 1927, splits a population into three groups: Susceptible, Infected and Recovered (or removed) (see Kermack & McKendrick). People move from S to I to R. As immune people build up, each case finds fewer susceptible people to infect, and the outbreak slows. Vaccination moves people straight into the immune group before the outbreak begins.

If a fraction of people are immune, each case infects on average R0 times the fraction who are still susceptible. Spread stalls once that falls below 1, which gives a rough herd immunity threshold of 1 − 1/R0 (see Fine et al.). For R0 = 4 the arithmetic gives 1 − 1/4 = 75%. Real thresholds are higher if a vaccine does not fully protect everyone, and they change when people mix unevenly (see Fine et al.).

The Human Body introduced the two branches of immunity. Here is how they work together during an infection.

Barriers

Most microbes never get in. Skin is a tough, dry, slightly acidic wall. Mucus in the airways traps particles, and tiny hairs called cilia sweep it up to be swallowed. Tears and saliva contain an enzyme, lysozyme, that attacks bacterial cell walls. Stomach acid kills many swallowed microbes, and harmless bacteria on the skin and in the gut crowd out newcomers.

Innate defenses: fast and general

When something does get through, say via a cut, the innate system responds within minutes to hours, in the same way every time.

• Phagocytes (neutrophils and macrophages) recognize features shared by many microbes and engulf them, digesting them inside.
• Inflammation: damaged cells and immune cells release chemical signals that widen local blood vessels and make them leaky. More blood and white blood cells reach the site, causing redness, heat, swelling and pain.
• Fever: signals from immune cells reset the brain's thermostat higher, which slows some pathogens and speeds up some immune reactions.
• Virus-infected cells release interferons, which warn nearby cells to resist infection.

Adaptive defenses: slow to start, precise, and with memory

The adaptive system is built from lymphocytes: B cells and T cells (see OpenStax Biology 42.2). Each lymphocyte carries receptors that fit one particular antigen, a molecule (usually part of a protein) that the immune system can recognize. Across the body there are millions of different receptor shapes, made by shuffling gene segments, so whatever germ arrives, a few cells will already fit it.

1. Antigen presentation. A phagocyte, often a dendritic cell, engulfs the invader, chops it up and displays fragments on its surface. It travels to a lymph node to show them to T cells.
2. Helper T cells whose receptors match become activated. They release signals that switch on the right B cells and cytotoxic T cells.
3. Clonal selection. Only the lymphocytes that match the antigen are activated, and they divide again and again, making a large clone of identical cells. This takes days, which is why you feel ill for a while during a first infection.
4. B cells turn into plasma cells that pour out antibodies. Antibodies bind the antigen, blocking viruses from entering cells, clumping bacteria and tagging them for phagocytes (see OpenStax Biology 42.3).
5. Cytotoxic T cells hunt down body cells displaying the matching fragment, a sign that they are infected, and make them self-destruct, stopping the virus being copied.
6. Memory. When the infection clears, most of the clone dies off, but long-lived memory B and T cells remain.

First and second exposure

The memory cells are why you rarely catch measles or chickenpox twice. Meeting the same antigen again triggers a secondary response that is faster and stronger than the first, often stopping the infection before you notice symptoms (see OpenStax Microbiology 18.1).

A vaccine gives the adaptive immune system a preview of a pathogen's antigens without the danger of the real disease. Antigen-presenting cells, helper T cells and B cells go through the same steps as in a real infection, leaving memory cells behind, so a later real infection meets a secondary response (see OpenStax Microbiology 18.5). Some vaccines need booster doses to build or refresh that memory.

Vaccines protect the person who gets one, and by cutting the number of susceptible people, they also slow spread to people who cannot be vaccinated, such as newborns. Smallpox was eradicated this way, the only human disease so far (see WHO).

Antibiotics are drugs that kill bacteria or stop them multiplying. They work by hitting structures bacteria have and our cells do not, or have in a different form: penicillin blocks the building of bacterial cell walls, while others jam bacterial ribosomes. Viruses have no cell wall and no ribosomes of their own, so antibiotics do nothing against viruses such as colds and flu. Viral infections are treated with rest, sometimes antiviral drugs, and prevented with vaccines.

Resistance is natural selection. In a large population of bacteria, a few may carry a mutation, or a gene picked up on a plasmid, that helps them survive a drug. When the antibiotic kills the rest, those survivors have less competition and multiply, and resistance becomes common. The drug does not create resistance; it selects for it. This is the same process described in Evolution, happening fast enough to watch. Overuse of antibiotics in people and farm animals speeds it up.

What about finishing the course? Patients have long been told to finish every antibiotic course to avoid resistance. Some doctors now argue that this advice has little evidence behind it for many infections, since longer use also exposes the bacteria in your gut and on your skin to the drug, selecting for resistance there; for many infections shorter courses work as well (see Llewelyn et al.). Others point out that for some infections, such as tuberculosis, stopping early is dangerous. The safe rule is to take antibiotics exactly as prescribed and talk to the prescriber before stopping. The model below shows the selection idea, not a dosing rule.

Germ theory was not obvious. It took two centuries of microscopes, careful experiments and arguments to move from "little animals" in a drop of water to vaccines designed on a computer.