C3.2 Defence against disease

A pathogen is an organism or virus that causes an infectious disease: one that can be passed from one host to another. Humans can be infected by a very wide range of pathogens, but most belong to four groups.

The other prokaryotic domain, the archaea, includes many species that live in and on the human body, but no archaea are known to cause human disease.

Careful observation led to disease control

• Childbed fever in Vienna (1840s). Ignaz Semmelweis noticed that many more mothers died of fever after childbirth on the ward where doctors came straight from dissecting corpses than on the ward run by midwives. He concluded that doctors were carrying “cadaverous particles” on their hands. When he made them wash in chlorinated lime solution, deaths fell sharply. This was before anyone knew that bacteria cause disease.
• Cholera in London (1854). John Snow mapped the cases in an outbreak in Soho and found that they clustered round one public water pump in Broad Street. People who drew water elsewhere were mostly spared. Removing the pump handle helped stop the outbreak and showed that cholera spreads in contaminated water, not through “bad air”.

Skin and mucous membranes: the primary defence

Most pathogens never get inside the body, because the skin and mucous membranes keep them out.

• The skin is a physical barrier: its outer layer is made of tough, dead, keratin-filled cells that are constantly shed, so pathogens cannot easily attach or pass through.
• It is also a chemical barrier: sebaceous glands secrete sebum containing fatty acids, and lactic acid in sweat keeps the surface acidic, which inhibits the growth of many bacteria and fungi.
• Mucous membranes line the airways, gut and urinogenital tract. They are thinner and moist, but the mucus they secrete traps microorganisms and contains lysozyme, an enzyme that breaks down bacterial cell walls. In the airways, cilia sweep the mucus away.

A cut in the skin breaks the primary barrier and the walls of blood vessels. Blood loss must be stopped quickly, and the gap must be closed before pathogens enter. Both are achieved by blood clotting.

1. Platelets, small cell fragments in the blood plasma, stick to the damaged tissue at the cut and release clotting factors.
2. The clotting factors set off a cascade: a series of reactions in which the product of each reaction activates the next. Near the end, an inactive plasma protein, prothrombin, is converted into the active enzyme thrombin.
3. Thrombin converts fibrinogen, a soluble plasma protein, into fibrin, which is insoluble. Fibrin forms long fibres that join into a mesh across the wound.
4. Red blood cells (erythrocytes) are trapped in the mesh, forming a clot that seals the cut. Exposed to air, it dries into a scab.

The cascade has two advantages. Because each step activates many molecules of the next, a small trigger is amplified into a rapid response. And because several steps must happen in turn, clotting only starts where a vessel is damaged, not in the circulating blood.

Pathogens that get past the skin and mucous membranes meet the immune system, which has two parts.

Phagocytes

Phagocytes are white blood cells that ingest and destroy pathogens. Macrophages and neutrophils are examples. They circulate in the blood, but many of them leave it at sites of infection.

1. Amoeboid movement: a phagocyte squeezes out between the cells of a capillary wall and crawls through the tissue towards the infection by extending its cytoplasm.
2. Recognition: receptors on its surface recognize molecules that are common to many pathogens but absent from body cells.
3. Engulfing by endocytosis: the plasma membrane extends around the pathogen and fuses, enclosing it in a vacuole (phagocytosis is a form of endocytosis; see B2.1 Membranes and membrane transport).
4. Digestion: lysosomes fuse with the vacuole and their hydrolytic enzymes digest the pathogen.

Pus at an infected wound is mainly dead phagocytes, together with bacteria and tissue fluid.

Phagocytes also link the two systems. A macrophage that has digested a pathogen displays fragments of its antigens on its surface, which starts the adaptive response (see the 3D model below).

Lymphocytes

Lymphocytes are small white blood cells with a large, rounded nucleus. They circulate in the blood, but large numbers are also contained in the lymph nodes: small swellings along the lymphatic vessels that drain tissue fluid. Pathogens carried in the lymph are filtered out there, where lymphocytes meet them.

A person has an enormous number of different B-lymphocytes (B-cells). Each B-cell can make one specific type of antibody, and displays copies of it on its surface as receptors. Because there are so many different B-cells, the body can make antibodies against almost any antigen, but only a small number of B-cells match any one antigen.

Antigens

An antigen is any molecule that the immune system recognizes as foreign and that triggers the production of antibodies. Most antigens are proteins or glycoproteins, usually on the outer surface of pathogens, such as the spike proteins of viruses or proteins in bacterial cell walls and flagella.

Our own cells also carry surface markers. MHC proteins, which differ between people, mark cells as “self”; this is why transplanted organs must be closely matched in tissue type. The ABO blood group antigens are glycoproteins and glycolipids on red blood cells.

If red cells are transfused into someone with a different blood group, their surface antigens act as foreign antigens: antibodies in the recipient bind them, clumping (agglutinating) and destroying the cells. Antigens such as the Rhesus (D) antigen can also stimulate the recipient to start making new antibodies against them.

Antibodies

Switch the 3D model below to Antibody structure. An antibody is a protein made of two heavy and two light polypeptide chains held together by disulfide bonds. The tips of the arms are variable regions that form two identical antigen-binding sites; the rest is the constant region. Binding is specific, like a substrate in an enzyme’s active site, but the antigen is not chemically changed.

Activation of B-cells by helper T-cells

There are antigen-specific B-cells and antigen-specific helper T-cells (helper T-lymphocytes). A B-cell produces antibodies, and memory cells, only after it has been activated. Activation needs two things:

1. Direct binding of the specific antigen to the receptors on the B-cell.
2. Contact with a helper T-cell that has been activated by the same antigen. Helper T-cells are activated when their receptors bind the antigen presented by a macrophage. The activated helper T-cell binds to the matching B-cell and releases signalling proteins.

This double check helps prevent the immune system from attacking the body’s own cells.

Clonal expansion

Because only a few B-cells match an antigen, they could not make enough antibody on their own. So an activated B-cell first divides repeatedly by mitosis, producing a clone of genetically identical cells that can all make the same antibody (clonal selection: the antigen selects which B-cell is cloned). Most cells of the clone differentiate into plasma cells: larger cells with extensive rough endoplasmic reticulum and Golgi apparatus, which synthesize and secrete large amounts of antibody. Antibodies help to destroy pathogens by making them clump together (agglutination), by neutralizing them or their toxins, and by making them easier for phagocytes to engulf.

Memory cells and immunity

Immunity is the ability to eliminate a particular infectious disease from the body. After an infection, antibodies and plasma cells gradually disappear, but some cells of the clone survive for years as memory cells. If the same antigen enters again, memory cells divide and produce plasma cells rapidly, so antibody is made sooner, in larger amounts and for longer. This secondary response usually clears the pathogen before symptoms develop.

HIV (human immunodeficiency virus) is a retrovirus (see A2.3 Viruses). It does not survive long outside the body, and it is transmitted only when body fluids from an infected person enter another person’s body. Blood, semen, vaginal and rectal fluids and breast milk can contain the virus. Examples of transmission:

• sexual intercourse without a condom, vaginal or anal;
• sharing hypodermic needles, for example among people who inject drugs, or needlestick injuries;
• transfusion of infected blood or blood products (now prevented in most countries by screening donated blood);
• from mother to baby during pregnancy, at birth or through breastfeeding.

HIV is not passed on by touching, sharing cups, coughing, saliva or insect bites.

From HIV infection to AIDS

HIV infects and kills only certain types of lymphocyte, mainly helper T-cells, which carry the CD4 receptor protein that the virus binds to. At first the immune system controls the infection and makes antibodies against HIV (a person with these is “HIV-positive”). Over several years without treatment, the number of helper T-cells falls. Without helper T-cells, B-cells cannot be activated, so the body loses the ability to produce antibodies against new pathogens.

The person then develops opportunistic infections: diseases caused by pathogens that a healthy immune system would control, such as tuberculosis, a pneumonia caused by the fungus Pneumocystis, and Kaposi’s sarcoma, a cancer caused by a herpesvirus. This collection of diseases is AIDS (acquired immunodeficiency syndrome). Antiretroviral drugs block viral enzymes such as reverse transcriptase; they cannot cure the infection but keep the virus at very low levels, so treated people can expect a near-normal lifespan and are much less likely to transmit the virus.

An antibiotic is a chemical that inhibits or kills microorganisms. Antibacterial antibiotics work because they block processes that occur in bacteria but not in eukaryotic cells, so they can be used inside the body without harming our cells.

Why antibiotics do not work against viruses

Viruses are not cells. They have no metabolism, no cell wall and no ribosomes of their own; they reproduce inside host cells using the host’s ribosomes, enzymes and ATP. There is therefore nothing for an antibacterial antibiotic to act on, and blocking the host’s own processes would harm the host cells. Viral infections are treated with antiviral drugs that target viral enzymes, or prevented by vaccines.

Evolution of resistance

Resistance evolves by natural selection (see D4.1 Natural selection):

1. Variation: a few bacteria in a population carry a gene for resistance, from a random mutation or by gene transfer from other bacteria, often on a plasmid.
2. Selection: the antibiotic kills the susceptible bacteria. The resistant ones survive.
3. Reproduction: survivors multiply rapidly, so the resistance gene becomes common. It can spread to other species by gene transfer.

Repeated use of different antibiotics selects for strains with multiple resistance, such as MRSA (methicillin-resistant Staphylococcus aureus), which infects wounds and blood of hospital patients and resists many antibiotics.

To slow the emergence of multiresistant bacteria: prescribe antibiotics only for bacterial infections and take them as directed; keep hospital hygiene high to stop cross-infection; avoid routine use in livestock to promote growth; and develop new antibiotics. A new technique is helping: computers screen chemical libraries of millions of compounds to find molecules likely to kill bacteria, which are then tested. Halicin, found this way in 2020, is one example.

A zoonosis is an infectious disease that can be transmitted from other animal species to humans in natural conditions. Zoonoses are very common: around 60% of known human infectious diseases, and most new (emerging) ones, come from animals. They reach humans by many routes.

Most human TB is now caused by M. tuberculosis and spreads between people, but bovine TB shows how a pathogen of cattle can infect humans. Rabies is almost always fatal once symptoms start, but a vaccine given soon after a bite prevents it.

COVID-19 shows the profound consequences when a zoonosis can also spread efficiently between humans. Within months SARS-CoV-2 had spread worldwide: the pandemic killed millions of people, overloaded health systems and disrupted economies and education, until vaccines and immunity from infection reduced deaths.

Immunization is the use of a vaccine to make a person immune to a specific pathogen. A vaccine contains antigens, or nucleic acid (DNA or RNA) with a sequence that codes for an antigen, so that the body’s own cells make the antigen. It stimulates the development of immunity without causing the disease.

The vaccine triggers a primary response: helper T-cells and B-cells are activated, plasma cells make antibodies and memory cells are produced. If the real pathogen later enters, the secondary response destroys it before it can cause disease. Some vaccines need booster doses.

Herd immunity

If a high enough proportion of a population is immune, an infected person mostly meets immune people, so the pathogen cannot spread. This is herd immunity. It also protects people who cannot be vaccinated, such as newborn babies and people with weakened immune systems, so members of a population depend on each other. The proportion needed depends on the basic reproduction number, R₀, the average number of people one case infects in a population with no immunity:

herd immunity threshold ≈ 1 − 1/R₀

For measles, R₀ is about 12–18, so about 92–94% of people must be immune. A vaccine that is not 100% effective raises the coverage needed.

Huge amounts of data were collected during the COVID-19 pandemic. Two calculations are especially useful.

Percentage change compares the same quantity at two times:

percentage change = (final value − initial value) ÷ initial value × 100

Percentage difference compares two groups (or places) at the same time, relative to a stated reference value:

percentage difference = (value A − value B) ÷ value A × 100, where A is the reference group

Always say which group is the reference, because the answer depends on it. If a question defines percentage difference differently, use its definition.

Worked example

The table shows illustrative weekly death rates from COVID-19 in one age group, in the pattern reported by many countries in 2021–2022 (not real figures).

• Percentage difference in period 1, with the unvaccinated as reference: (40.0 − 6.0) ÷ 40.0 × 100 = 85% lower in vaccinated people.
• Percentage change for unvaccinated people from period 1 to period 2: (25.0 − 40.0) ÷ 40.0 × 100 = −37.5%, a 37.5% decrease.

When evaluating such data, consider: are the groups comparable (age, health)? How were deaths attributed to COVID-19? Did testing rates change? Rates per 100 000 are needed because the groups are of different sizes, and correlation alone does not prove cause.