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Pathogens, and the defences that never ask who you are

Four kinds of organism cause almost every infectious disease you can name, and they damage you in a small number of ways. Against all of them your body runs the same opening defence: barriers that keep them out, chemistry that kills them at the entrances, and phagocytes that engulf anything that is not you.

Before this Cell-surface membranes and membrane proteins · Lysosomes and enzyme hydrolysis · Water potential and osmosis

Before you start

White blood cells fight infection by recognising the germ and producing the right antibody for it. Most of that becomes true after a few days, and none of it is true at the start. The first cell to reach a splinter or a mouthful of Salmonella has no idea what it has found and does not need one: it engulfs anything carrying surface molecules it does not recognise as yours. Recognition of a particular pathogen comes later, and it comes because that first cell put the pathogen's antigens on display where a lymphocyte could find them.

What you should be able to do

Name the four groups of pathogen and give a disease caused by each.
Explain how a pathogen damages its host, using toxins and cell lysis as the two main routes.
Distinguish a physical barrier from a chemical one, with named examples of both.
Describe phagocytosis as an ordered sequence, ending with antigen presentation.
Explain why an antibiotic that cures tuberculosis does nothing whatever for influenza.

What counts as a pathogen

A pathogen is an organism that causes disease in its host. That is a job description rather than a group on a family tree. The four kinds below are not close relatives of one another, and one of them is arguably not alive at all.

Four groups, four diseases, four routes to damage. The line at the bottom is the one that gets tested most often: an antibiotic has nothing to bind to in a virus.

Bacteria are prokaryotes: no nucleus, a peptidoglycan cell wall, 70S ribosomes, and a metabolism of their own. Mycobacterium tuberculosis causes tuberculosis, Vibrio cholerae causes cholera, and various staphylococci turn an ordinary wound into an infected one. Because bacteria have structures and enzymes that your cells do not, they can be attacked selectively — which is exactly what an antibiotic does.

Viruses have no cytoplasm, no ribosomes and no metabolism. A virus is nucleic acid in a protein coat, and it can do nothing at all until it is inside a host cell whose machinery it can use. Influenza, measles and HIV are viruses. Be careful with the last one: HIV is the virus, and AIDS is the condition that develops years later when the infection has destroyed enough T-helper cells that the specific immune response can no longer be co-ordinated.

Fungi that infect humans are usually superficial. Athlete's foot and ringworm are both caused by Tinea, the group of fungi that grows in the keratin of skin and nails, digesting tissue outside its own cells and absorbing the products. In plants the fungal diseases are far more destructive, and black sigatoka in banana crops is the standard example.

Protoctista are eukaryotic and single-celled. Plasmodium, carried between people by female Anopheles mosquitoes, causes malaria; Phytophthora infestans caused the potato blight of the 1840s. Both are eukaryotes, which is precisely why drugs against them are harder to design than antibiotics: their cells work much the way yours do.

Pathogen: An organism that causes disease in its host.
Antigen: A molecule, usually a protein or glycoprotein on a cell surface, that the immune system can recognise as self or non-self and that can trigger an immune response.
Non-specific defence: A defence that acts against any pathogen, without recognising which one it is, and acts at the same speed every time.

Most microorganisms are not pathogens. The bacteria living on your skin and in your large intestine occupy space and consume nutrients that a pathogen would otherwise get, which makes them part of your defences rather than a threat to them. A course of broad-spectrum antibiotics kills a good many of those too, and the digestive upset that follows is the consequence.

How a pathogen actually makes you ill

Exam questions rarely ask you to list pathogens. They ask how one causes damage, and there are two answers worth having ready.

The first is toxins. Many bacteria release proteins that interfere with a host process. Cholera toxin binds to the cells lining the small intestine and locks open a channel protein, so chloride ions pour into the gut lumen. That lowers the water potential of the lumen below that of the cells, water follows by osmosis, and the resulting diarrhoea can remove several litres a day. Nobody dies of Vibrio cholerae as such; they die of dehydration, which is why oral rehydration salts save so many lives so cheaply. Tetanus toxin does something different again, blocking the signals that would normally stop a motor neurone firing, so muscles contract and cannot relax.

The second is cell lysis. A virus enters a host cell, its nucleic acid is transcribed and translated using the host's ribosomes, enzymes and nucleotides, and hundreds of new virus particles are assembled. When they are released the cell is destroyed. Repeat that across an epithelium and you have a sore throat; repeat it in the T-helper cells of an untreated HIV infection and, over years, you have AIDS. Plasmodium does the same thing to red blood cells, and the bursting of infected cells in synchrony is why the fever of malaria comes in waves rather than continuously.

Fungi work a third way, secreting hydrolytic enzymes onto living tissue and absorbing what dissolves, which is why athlete's foot itches and flakes. And some of what you feel during an infection is not the pathogen at all. Fever, swelling, aching and tiredness are your own response, and a question that asks you to explain a symptom will sometimes want that answer rather than a description of the microbe.

Reading a toxin question properly

Cholera toxin causes chloride ions to be secreted from intestinal epithelial cells into the lumen of the gut. Explain how this leads to severe diarrhoea, and suggest why oral rehydration solution contains both salts and glucose.

Start with the water potential. Chloride ions accumulating in the lumen lower the water potential there, so it becomes more negative than the water potential of the epithelial cells and the tissue fluid behind them.

Water therefore moves out of the cells and into the lumen down a water potential gradient, by osmosis, through the partially permeable cell-surface membranes. Large volumes of watery faeces follow, and the patient loses both water and ions.

The glucose is the part candidates miss. Sodium ions are absorbed from the gut by co-transport with glucose, so putting glucose in the solution drives sodium uptake, which raises the water potential in the lumen relative to the cells and lets water be absorbed again. Salts alone are absorbed far more slowly.

Notice that nothing in that answer required you to know anything about the bacterium. The mark scheme wanted osmosis and co-transport, and named the toxin only to set the scene.

Keeping them out, and killing them at the door

Before any of the immune system proper is involved, a pathogen has to get past defences that work on everything equally. These are worth sorting into two kinds, because questions ask for one or the other by name.

Each layer removes most of what reaches it, so very little arrives at the bottom. Nothing above the last band recognises a particular pathogen — the whole stack works on anything.

Physical barriers keep pathogens out by being in the way. Skin is the obvious one: its outer layer is dead, dry, and packed with keratin, which almost nothing can digest. Where the body has to be moist and permeable — airways, gut, reproductive tract — it uses mucous membranes instead. Goblet cells secrete sticky mucus that traps particles, and the ciliated epithelium beneath beats the mucus upwards to the throat, where it is swallowed. Damage that cilia layer, as cigarette smoke does, and the trapped material stays put. A wound is a hole in the barrier, so blood clots to seal it within minutes.

Chemical barriers destroy pathogens rather than blocking them. Stomach acid holds the gut contents near pH 2, which denatures the enzymes and other proteins of most swallowed bacteria. That is where the mucus you have just cleared from your lungs arrives, and the trapped bacteria arrive with it: the two defences work as a chain, one sweeping upwards and the other waiting at the bottom of the oesophagus. Lysozyme, an enzyme in tears, saliva and mucus, hydrolyses bonds in bacterial cell walls so the cell bursts. Sebum makes the skin surface slightly acidic and inhospitable.

Defence	Kind	How it works	Where
Skin	Physical	Keratinised, dry, impermeable	Body surface
Mucus and cilia	Physical	Traps particles and sweeps them out	Airways, gut
Blood clotting	Physical	Seals a break in the barrier	Any wound
Stomach acid	Chemical	pH near 2 denatures enzymes and proteins	Stomach
Lysozyme	Chemical	Hydrolyses bacterial cell walls	Tears, saliva, mucus
Gut and skin flora	Chemical/competitive	Out-competes pathogens for space and nutrients	Gut, skin

If a pathogen does get through, the response at the site of damage is inflammation. Mast cells in the damaged tissue release histamine, which dilates arterioles and makes capillary walls more permeable. More blood arrives, so the area is red and warm, and more tissue fluid leaks out, so it swells. That fluid carries phagocytes and antibodies to exactly the place they are needed. The soreness is a real cost, but the swelling is not an accident.

A raised body temperature helps in two ways worth stating precisely: most pathogens reproduce more slowly above about 37 °C, and the specific immune response works faster at the higher temperature. Very high fevers are dangerous for the same reason boiling an egg works — human enzymes denature too.

Phagocytosis, stage by stage

Phagocytes are white blood cells that engulf and digest pathogens. Neutrophils are the short-lived ones that arrive first and die in large numbers, which is what pus is; macrophages are larger, live longer, and are the ones that matter for what comes next. The process is the same in both, and it is marked as a sequence, so learn it in order.

Six stages. Stages three to five are the ones students remember and stage six is the one that earns the mark, because it is the only stage that leads anywhere.

Phagocytosis: The engulfing and hydrolysis of a pathogen or other foreign material by a phagocyte, forming a phagosome that fuses with a lysosome.
Phagosome: The vesicle formed when a phagocyte's cell-surface membrane closes around an engulfed pathogen.
Lysosome: An organelle containing hydrolytic enzymes, including lysozymes, kept separate from the cytoplasm.
Antigen-presenting cell: A cell displaying antigens from a pathogen it has destroyed on its own cell-surface membrane.

In words: the phagocyte moves towards the pathogen along a concentration gradient of chemicals released by the pathogen itself or by damaged tissue, which is chemotaxis. Receptors on the phagocyte's membrane attach to antigens on the pathogen's surface. The membrane then folds around it, and the two edges fuse to enclose the pathogen in a vesicle — the phagosome. Lysosomes move to the phagosome and fuse with it, emptying hydrolytic enzymes inside. Those enzymes hydrolyse the pathogen, and the soluble products are absorbed into the cytoplasm.

Two details are worth getting right. The enzymes stay inside a membrane throughout, so the phagocyte does not digest itself. And engulfing is endocytosis: it needs ATP and a flexible membrane, which is why it is not something a plant cell with a rigid cell wall could do.

The stage everyone forgets

After hydrolysis, the phagocyte moves some of the pathogen's antigens to its own cell-surface membrane and displays them there. That is antigen presentation, and it turns the phagocyte into an antigen-presenting cell.

It matters because of what a lymphocyte can and cannot find. There are millions of different T cells circulating, each with a differently shaped receptor, and the chance of the right one bumping into a free pathogen in the middle of a lung is small. Presented antigen, concentrated on the surface of a cell that then travels to a lymph node full of lymphocytes, makes the meeting far more likely. Nothing specific — no clonal selection, no antibody, no memory cell — begins until this has happened.

So phagocytosis is doing two jobs at once. It removes pathogens immediately, at the same speed on the first exposure as on the fiftieth, and it starts the response that will not be the same speed next time. If a question asks how a non-specific response leads to a specific one, the answer is this stage and no other.

TRY IT — Two defences, two speeds

A person is infected with the same strain of a bacterium twice, six months apart. Phagocytosis begins within hours on both occasions, but detectable antibody appears after about eight days the first time and about two days the second. Explain both observations.

Check your answer

Phagocytosis is non-specific. Phagocytes attach to antigens on anything they do not recognise as self, and nothing about that process improves with practice, so it happens just as quickly the second time as the first.

Antibody production is specific. The first time, a phagocyte had to present the antigen, the one lymphocyte with a complementary receptor had to be found and selected, and it had to divide repeatedly before enough cells existed to secrete measurable antibody — hence roughly eight days.

The second time, memory cells specific to that antigen were already present in far greater numbers than the original single lymphocyte. The selection and much of the division had already happened, so antibody appears in about two days.

The full explanation is in the next lesson, but you can already say the useful half of it: the non-specific response has no memory, and the specific one does.

In the exam

Name the organism, not the disease, when a question asks what causes an illness. 'A bacterium' scores; 'tuberculosis' does not, because that is what you were told.
If you write about antibiotics and viruses in the same sentence, say why they fail: no cell wall, no ribosomes and no metabolism of its own means nothing for the drug to disrupt. 'Viruses are too small' scores nothing.
Phagocytosis questions are marked as a sequence. Engulfing before lysosome fusion, lysosome fusion before hydrolysis, and antigen presentation last. Getting two stages the wrong way round loses the mark even if every stage is mentioned.
Use 'hydrolyse', not 'break down' or 'destroy', when lysosomal enzymes act on a pathogen. It is a specific chemical claim and it is worth a mark.
Physical against chemical barriers: skin, mucus, cilia and clotting are physical; stomach acid, lysozyme and sebum are chemical. Questions ask for one kind and reject the other.

Check yourself

A long-term smoker has destroyed much of the ciliated epithelium lining her airways, and she also takes a drug that greatly reduces the secretion of stomach acid. She suffers repeated chest infections, and a sample of her sputum is found to contain very large numbers of dead neutrophils. Explain how each of the two changes makes infection more likely, and explain what the neutrophils show about the defences that are still working.

Answer

Losing the cilia breaks a physical defence in the middle. Goblet cells are still secreting mucus, and that mucus still traps bacteria and virus particles as it always did, so the trapping half of the barrier is intact. What has gone is the removal. Cilia normally beat the mucus upwards to the throat, where it is swallowed; with the ciliated epithelium damaged, the mucus and everything caught in it stays in the airways, warm and undisturbed, which is a good place for bacteria to reproduce. A defence that traps without clearing has become somewhere for pathogens to accumulate.

Reducing stomach acid breaks a chemical defence at the other end of the same chain. Acid normally holds the gut contents near pH 2, which denatures the enzymes and other proteins of most swallowed bacteria and kills them. Raise that pH and swallowed pathogens survive — including the ones in whatever mucus she does still clear from her lungs, which are swallowed rather than coughed out. Both defences are non-specific: they act on any pathogen at all, and they act at the same speed every time, so neither is improved by how often she has been infected before.

The dead neutrophils show that phagocytosis is running hard. Neutrophils are the short-lived phagocytes that arrive first, drawn to the infected tissue by chemotaxis along a gradient of chemicals from the bacteria and the damaged cells. Receptors on the neutrophil attach to antigens on the bacterial surface, the membrane folds round the bacterium to enclose it in a phagosome, lysosomes fuse with the phagosome and empty hydrolytic enzymes into it, and the bacterium is hydrolysed. Neutrophils die in the process in very large numbers, which is what pus and that sputum sample are.

So the phagocytes are doing the work the barriers are no longer doing, and they are doing it without needing to know what the pathogen is. They are also doing the one thing that leads anywhere: macrophages at the site present the bacterial antigens on their own cell-surface membranes, which is the only route by which a specific response — clonal selection, antibody, memory cells — can begin at all. A question that asks how a non-specific response leads to a specific one is asking about that stage and no other.

Questions

Written to the command words the boards use. Try them on paper before opening a scheme: the marks go to points made, not to length.

Question 15 marks

Describe the stages of phagocytosis, in order, from the phagocyte approaching a bacterium to the display of its antigens.

Mark scheme

B1 the phagocyte moves towards the bacterium along a concentration gradient of chemicals released by the pathogen or by damaged tissue, which is chemotaxis
B1 receptors on the phagocyte's cell-surface membrane attach to antigens on the bacterium's surface
B1 the membrane folds around the bacterium and the edges fuse, enclosing it in a vesicle called a phagosome
B1 lysosomes move to the phagosome and fuse with it, emptying hydrolytic enzymes inside, and those enzymes hydrolyse the bacterium
B1 the phagocyte moves some of the bacterium's antigens to its own cell-surface membrane and displays them, becoming an antigen-presenting cell

Question 24 marks

Compare physical barriers with chemical barriers as defences against infection, using a named example of each.

Mark scheme

B1 both act against any pathogen without recognising which one it is, and both act at the same speed on every exposure
B1 a physical barrier blocks or removes pathogens, whereas a chemical barrier destroys them
B1 a named physical barrier with how it works, for example skin, which is dry, dead and keratinised, or mucus which traps particles while cilia sweep it to the throat
B1 a named chemical barrier with how it works, for example stomach acid near pH 2, which denatures the enzymes and other proteins of swallowed bacteria, or lysozyme, which hydrolyses bacterial cell walls

Question 34 marks

A drug prevents lysosomes from fusing with phagosomes inside a phagocyte. Suggest how this would affect a patient's response to a bacterial infection.

Mark scheme

B1 bacteria are still engulfed, because chemotaxis, attachment and the forming of the phagosome are unaffected
B1 hydrolytic enzymes are not emptied into the phagosome, so the bacteria are not hydrolysed and may survive inside the phagocyte
B1 fewer antigens become available to be moved to the phagocyte's cell-surface membrane, so antigen presentation is reduced
B1 the specific response is therefore slow to begin, since clonal selection cannot start until antigen is presented, and the infection is likely to be more severe and to last longer

Question 43 marks

Explain why an antibiotic that cures tuberculosis has no effect whatever on influenza.

Mark scheme

B1 tuberculosis is caused by a bacterium while influenza is caused by a virus
B1 antibiotics work by disrupting structures or processes that bacteria have and human cells do not, such as the peptidoglycan cell wall or the 70S ribosomes
B1 a virus has no cell wall, no ribosomes and no metabolism of its own, so there is nothing for the drug to disrupt

Question 53 marks

Explain how inflammation at the site of an infection helps the body to clear the pathogen.

Mark scheme

B1 mast cells in the damaged tissue release histamine
B1 histamine dilates the arterioles and makes capillary walls more permeable, so more blood arrives and more tissue fluid leaks out into the tissue
B1 that tissue fluid carries phagocytes and antibodies to the site where they are needed, and the increased blood flow makes the area red and warm

Question 62 marks

Give one named human disease caused by a bacterium and one named human disease caused by a protoctistan.

Mark scheme

B1 a bacterial disease named, for example tuberculosis caused by Mycobacterium tuberculosis, or cholera caused by Vibrio cholerae
B1 a protoctistan disease named, for example malaria caused by Plasmodium

Worth remembering

Four groups of pathogen: bacteria, viruses, fungi, protoctista. Learn one named disease for each.
Pathogens damage the host mainly by releasing toxins or by destroying the cells they reproduce inside.
Physical barriers block; chemical barriers destroy. Both act on any pathogen at all.
Phagocytosis in order: chemotaxis, attachment, engulfing into a phagosome, lysosome fusion, hydrolysis, antigen presentation.
Antigen presentation is the handover from the non-specific response to the specific one.

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