1The idea in one paragraph

A pathogen is an organism that causes disease, and the body has three lines of defence against it. First, barriers: skin and mucous membranes keep most pathogens out, and a clot seals a cut. Second, the innate immune system: phagocytes engulf anything they recognise as foreign, the same way every time. Third, the adaptive immune system: lymphocytes make antibodies that fit one particular pathogen, and they remember it, so a second infection is beaten before it causes illness. That memory is immunity, and vaccines create it without the disease. Medicine adds antibiotics, which kill bacteria but not viruses, and which select for resistant bacteria when overused. In a population, enough immune people stop a pathogen spreading at all.

2Pathogens, and how careful observation changed medicine

An infectious disease is one caused by a pathogen that can spread from one host to another. A broad range of organisms can infect humans, from viruses to worms, but the word pathogen is usually reserved for four groups: viruses, bacteria, fungi and protists. Some examples: the influenza virus; Mycobacterium tuberculosis, a bacterium; Candida, the fungus that causes thrush; and Plasmodium, the protist that causes malaria. One whole domain of life, the Archaea, is not known to cause any human disease.

That diseases are caused by pathogens was not always known, and two 19th-century cases show how careful observation moved the science forward before anyone could see the microbes responsible.

• In Vienna in the 1840s, the physician Ignaz Semmelweis noticed that far more mothers died of childbed fever (an infection after giving birth) on the ward run by doctors than on the ward run by midwives. The doctors came to the ward from dissecting corpses. When he made them wash their hands in a chlorinated solution, deaths on their ward fell sharply.
• In London in 1854, John Snow mapped the deaths in a cholera outbreak and found them clustered around one public water pump on Broad Street. When the pump handle was removed, the outbreak subsided. The pattern pointed to contaminated water, not bad air.

Neither man knew what the pathogen was. Both found the cause by recording what happened, to whom and where, and comparing.

3Skin and mucous membranes: the primary defence

Most pathogens never get in. The skin is both a physical barrier and a chemical barrier. Its outer layer is made of tough, dead, tightly packed cells that pathogens cannot easily penetrate, and it is constantly shed, taking microbes with it. Its surface is dry and slightly acidic, and secretions from sebaceous and sweat glands contain chemicals that inhibit bacteria and fungi.

Where the body must be open to the outside, in the airways, gut and urinary and reproductive tracts, it is lined by mucous membranes. These secrete mucus, which is sticky and traps pathogens; in the airways, cilia sweep the mucus up and out. Mucous secretions also contain antimicrobial enzymes such as lysozyme, which breaks down bacterial cell walls. Figure 1 places these barriers as the first of three lines of defence.

4Sealing cuts: blood clotting

A cut breaches the skin barrier. Blood clotting seals it quickly, stopping blood loss and closing the entry route. Figure 2 shows the sequence the guide requires.

1. At the damaged vessel, platelets (cell fragments in the blood) release clotting factors.
2. The clotting factors set off a cascade: a chain of reactions in which each activated protein activates many molecules of the next, so the response is amplified and very fast.
3. The cascade converts an inactive plasma protein, prothrombin, into the active enzyme thrombin.
4. Thrombin rapidly converts fibrinogen, a soluble plasma protein, into fibrin, which is insoluble and forms long threads.
5. The fibrin threads form a mesh that traps erythrocytes (red blood cells). This is the clot, which dries into a scab.

Platelets release clotting factors → cascade → thrombin → fibrinogen converted to fibrin → fibrin mesh traps erythrocytes.

5The innate and the adaptive immune systems

Pathogens that get past the barriers meet the immune system, which has two parts. Learn the difference as a comparison.

You do not need to know any part of the innate system other than phagocytes.

6Phagocytes

Phagocytes are white blood cells that ingest and destroy pathogens. They circulate in the blood, and when tissue is infected they leave it, squeezing between the cells of capillary walls by amoeboid movement, to reach the site of infection. Figure 3 follows what happens there.

1. The phagocyte recognises the pathogen as foreign, by molecules on its surface.
2. It engulfs it by endocytosis: the membrane flows round the pathogen and encloses it in a vesicle.
3. Lysosomes fuse with the vesicle and release hydrolytic enzymes that digest the pathogen.
4. The pathogen is destroyed.

Pus in an infected wound is largely dead phagocytes and the debris of the pathogens they have destroyed.

7Antigens and lymphocytes

An antigen is a recognition molecule that triggers the production of antibodies. Most antigens are glycoproteins or other proteins, usually on the outer surface of pathogens: the proteins of a virus coat, or the glycoproteins of a bacterial cell wall. Each kind of pathogen carries its own antigens, and the adaptive immune system recognises it by them.

Antigens are not only on pathogens. Erythrocytes carry antigens on their surface that differ between blood groups. If blood is transfused into a person with a different blood group, the donor's red-cell antigens can be recognised as foreign and stimulate antibody production, and the antibodies make the transfused cells clump. That is why blood is matched before transfusion.

Lymphocytes are the white blood cells of the adaptive immune system. They circulate in the blood and are also held in large numbers in the lymph nodes, where they meet antigens brought from the tissues. There are two kinds that matter here: B-lymphocytes (B-cells), which produce antibodies, and helper T-lymphocytes (helper T-cells), which activate them.

An antibody is a protein that binds specifically to one antigen. Binding marks the pathogen for destruction, for example by making it easier for phagocytes to engulf, or by clumping pathogens together.

The key fact: each B-cell makes only one type of antibody, and a person has a very large number of different B-cells, millions of kinds, each specific to a different antigen. Whatever pathogen arrives, a few B-cells somewhere already make an antibody that fits it. The problem is that there are only a few of them.

8Activation of B-cells, and clones of plasma cells

Figure 4 shows how the right B-cells are found and multiplied.

1. B-cells meet the antigen. Only the B-cells whose antibodies fit that antigen bind it. These are antigen-specific B-cells.
2. Helper T-cells are activated by the same antigen. Helper T-cells are also antigen-specific, and the ones that recognise this antigen become activated.
3. Activation of the B-cell needs both. A B-cell is activated only after direct interaction with its specific antigen and contact with a helper T-cell that has been activated by the same antigen. The double requirement is a safeguard against attacking the body's own cells by mistake.
4. Clonal expansion. Relatively few B-cells respond to any one antigen, far too few to make enough antibody. So the activated B-cell divides repeatedly by mitosis, producing a clone of identical cells, all making the same antibody.
5. Plasma cells. Most cells of the clone become plasma cells, which secrete large quantities of that one antibody into the blood and tissue fluid.
6. Memory cells. Some of the clone become memory cells (section 9).

Only activated B-cells produce antibodies and become memory cells. An unactivated B-cell does neither.

9Immunity: memory cells

Immunity is the ability to eliminate an infectious disease from the body before it causes illness. It is due to the long-term survival of memory cells: lymphocytes, formed during the first infection, that can make the specific antibody needed, and that persist for years or decades. Figure 5 shows what they change.

On first exposure, the primary response is slow: it takes days to find, activate and multiply the few matching B-cells, and meanwhile the pathogen multiplies and the person may be ill. On a second exposure, memory cells are already present in large numbers and are activated quickly. The secondary response is faster, much larger and lasts longer, and the pathogen is usually destroyed before any symptoms appear. That person is immune.

10HIV and AIDS

HIV (human immunodeficiency virus) is transmitted in body fluids: blood, semen, vaginal fluid and breast milk. The mechanisms of transmission are:

• unprotected sexual intercourse;
• sharing hypodermic needles, for example among people who inject drugs;
• transfusion of infected blood or blood products, which screening of donated blood now prevents in most countries;
• from mother to child during pregnancy, at birth or through breastfeeding.

It is not transmitted by touching, sharing cups, or insect bites.

HIV infects and kills only certain types of lymphocyte, above all helper T-cells. Figure 6 shows the long course of an untreated infection.

For years there may be few symptoms, but the number of helper T-cells falls steadily. Without helper T-cells, B-cells cannot be activated (section 8), so the body's ability to produce antibodies is lost. The person develops AIDS (acquired immune deficiency syndrome) and becomes vulnerable to opportunistic infections: diseases, such as some forms of pneumonia and tuberculosis, that a healthy immune system would easily control. It is these infections, not HIV directly, that kill. Antiretroviral drugs, taken continuously, keep the virus suppressed and prevent the progression to AIDS.

11Antibiotics, and why they fail against viruses

An antibiotic is a chemical that blocks processes occurring in bacteria but not in eukaryotic cells, so it kills bacteria or stops their growth without harming the host's cells. Examples of the targets:

• Bacterial cell wall synthesis: penicillin blocks the building of the peptidoglycan wall, which human cells do not have.
• Protein synthesis on 70S ribosomes: antibiotics such as streptomycin and tetracycline bind bacterial ribosomes and not the 80S ribosomes in human cytoplasm.
• Other bacterial enzymes, such as those that copy bacterial DNA.

Why antibiotics do not work on viruses. A virus has no metabolism of its own, no cell wall and no ribosomes. It reproduces inside a host cell using the host cell's enzymes and ribosomes. There is nothing for an antibiotic to block that is not also part of the host's own cells. Antibiotics taken for a cold or flu do nothing to the virus, and they select for resistant bacteria elsewhere in the body.

12Resistance to antibiotics

Strains of pathogenic bacteria have evolved resistance to several antibiotics at once: multiresistant bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus). The mechanism is natural selection, and Figure 7 shows it.

1. Variation. In a large population of bacteria, a few carry a gene that gives resistance, arising by random mutation, or acquired from another bacterium by gene transfer (often on a plasmid).
2. Selection. When the antibiotic is used, susceptible bacteria are killed; resistant ones survive.
3. Reproduction. The survivors multiply, passing on the resistance gene. With no competition from susceptible bacteria, the resistant strain becomes the population.
4. Repeat. Exposure to several antibiotics in turn selects for bacteria carrying several resistance genes.

Bacteria reproduce very fast, some dividing every half an hour, and can swap genes between species, so resistance spreads quickly. Careful use of antibiotics is needed to slow the emergence of multiresistant bacteria: prescribing them only for bacterial infections, taking them as prescribed, not using them routinely in livestock, and good hygiene in hospitals so resistant strains do not spread.

New techniques, new research. New antibiotics are hard to find. Researchers now screen large libraries of chemicals, hundreds of thousands of compounds, testing each for activity against bacteria, often with computers helping to pick the likely candidates. This technique has opened a new line of research and is yielding new antibiotic candidates.

13Zoonoses

A zoonosis is an infectious disease that can transfer from other species to humans. Zoonoses are very common: US public health estimates put them at around six in ten of known human infectious diseases, and around three in four of newly emerging ones. The guide's examples show how varied the routes are.

COVID-19 is the recent case with profound consequences. A virus that crossed from another species into humans spread worldwide within months, causing millions of deaths, overwhelming health services and disrupting economies and education across the world. It showed how quickly a new zoonosis can become a pandemic once it can pass directly between people.

14Vaccines and immunization

A vaccine contains antigens of a pathogen, or nucleic acids (DNA or RNA) with sequences that code for those antigens. The antigens may be in a killed or weakened pathogen, or in a purified part of it. In an mRNA vaccine, such as several used against COVID-19, the recipient's own cells read the mRNA and make the antigen for a short time.

Either way, the immune system meets the antigen and makes a primary response: matching B-cells are activated, clones form, antibodies are made, and memory cells are left behind. The vaccine stimulates immunity to a specific pathogen without causing the disease, because the antigen alone cannot cause illness. If the real pathogen later arrives, the fast secondary response destroys it. Immunization is the process of making a person immune this way. Some vaccines need booster doses to raise the number of memory cells.

15Herd immunity

Members of a population are interdependent: whether you catch a disease depends partly on whether the people you meet can pass it to you. Herd immunity is the protection of a whole population, including people who are not immune, that happens when a high enough percentage of it is immune. Figure 8 shows why.

Each infected person can only pass the pathogen on to people who are susceptible. If most of their contacts are immune, the chain of transmission is broken again and again, the pathogen reaches dead ends, and an epidemic cannot start. That protects babies too young to be vaccinated and people whose immune systems cannot respond to vaccines. The more contagious the disease, the higher the percentage of the population that must be immune: for measles, one of the most contagious, it is over 90%.

Science, the media and certainty. Scientists publish their research so that other scientists can evaluate it. The media often report research while that evaluation is still going on, and readers need to know that a single new study is not yet a settled conclusion. Vaccines are tested rigorously before and after approval. Their risks of side effects are minimal but not nil, and no honest scientist will claim zero risk. Science deals in pragmatic truths, conclusions well enough supported to act on, rather than absolute certainty; the demand for certainty, and the misunderstanding of that difference, is behind much public distrust of vaccines.

16Evaluating pandemic data: percentage change and percentage difference

The guide asks you to calculate two different percentages from COVID-19 data, and to know which is which. Figure 9 gives invented data for two districts.

Percentage change compares one quantity at two times: how much it went up or down relative to where it started.

Percentage change = (new value − original value) ÷ original value × 100

Percentage difference compares two values measured at the same time, neither of which is "the original". The usual method divides the difference by the mean of the two values.

Notice that "A is 50% higher than B" ((1800 − 1200) ÷ 1200) is also true: that is a percentage change taking B as the reference. The two calculations answer different questions, so write down which one you are doing. If a question tells you which value is the reference, divide by that value.

Evaluating the data. Numbers of reported cases are not the same as numbers of infections. When judging data like this, ask:

• Testing: did the amount of testing change over time, or differ between the districts? More tests find more cases.
• Population size: 1800 cases in a district of 2 million is a lower rate than 1200 in a district of 500 000. Compare cases per 100 000 people.
• Definitions and delays: cases may be recorded by date of test or date of report, and deaths lag behind cases by weeks.
• Other variables: vaccination rates, age structure and control measures differ between places, so a difference is not automatically caused by the one factor you are interested in.