Figure 1. Major classes of pathogen. Very few potentially infectious agents are pathogenic. A pathogen invades a host to gain shelter, feed or reproduce , and so that it can survive to infect other hosts. (1) The smallest pathogens are viruses, which use the machinery of the host's cells to reproduce. (2‐‐4) Next in size are bacteria, fungi and single‐celled protozoa; some live outside cells, others preferentially live inside cells. (5) The largest parasites are multi‐cellular metazoans which are too big to invade cells, but which can live in body cavities, such as intestinal worms. All these can trigger immune responses. Not surprisingly different types of immunity are needed to deal with these different infectious agents.

Figure 2. Transmission of infectious diseases. Infectious agents are transmitted to their host from reservoirs, which may include the host itself. The vectors of transmission can be physical (e.g. droplets) or other biological species. Infectious agents can enter the host by different routes, usually by ingestion, inhalation or injection (sexual transmission is also frequent).

Figure 3. Life cycles of pathogenic viruses. Following transmission, viruses bind to specific molecules expressed by the host cell (this determines the cells that can be infected i.e. the tropism of the virus) and are then internalized by endocytosis or by direct fusion with a cell membrane. The viral nucleic acid is released and viral proteins are synthesized. Some proteins are involved in replication of the viral nucleic acid and others are used for assembly of new viral particles. Viruses can then be released from the cell either by budding from the membrane or by killing the cell.

Figure 4. Life cycles of pathogenic bacteria. Different types of bacteria cause very different types of diseases. Some pyogenic (pus‐forming) bacteria such as Streptococcus can live and replicate extracellularly and may spread destructive infections to a variety of tissues. If not treated they can cause acute inflammation that resolves within a few days or can cause death, again in a few days. Other bacteria such as Mycobacterium tuberculosis which causes tuberculosis can only survive and replicate intracellularly. The immune response against the infected cells often causes chronic inflammation that typically lasts for months or years if not treated successfully.

Figure 5. Generalized life cycles of parasites. Parasites display a huge variety of life cycles. In many cases there is an animal reservoir and a different animal vector. Often, as in schistosomiasis, the parasite exists in different forms in the reservoir, the vector and the human host. Schistosomes are metazoan parasites that live in water snails and are transmitted by their cerceriae forms that penetrate the skin of humans in the water. They migrate to the lungs, mature and adult sexual forms live in blood vessels in different sites. Some species live in blood vessels around the bladder and the eggs may then enter the bladder, and re‐enter water via urine, to infect more snails.

Figure 6. Clinical and subclinical infection. Most microbes that enter the body do not cause any symptoms: they are dealt with by the immune system silently so the infection is subclinical. Other microbes when they infect will almost always cause symptoms: the infection is clinically evident. Some organisms such as the fungus Pneumocystis jirovecii do not cause clinical infection in normal humans, but can do so if the immune system is defective, as in AIDS; these infections are opportunistic. Opportunistic infections tell us that in normal individuals the immune system is working continually to eliminate or control many microbes.

Figure 7. Gene‐targeted, knock‐out mice. Embryonic stem (ES) cells from the blastocyst (an early stage of embryogenesis) have the potential to develop into any cell or tissue of the body. Techniques have been developed to maintain these cells indefinitely in culture. DNA containing a gene whose sequence has been disrupted can then be inserted (transfected) into ES cells. In tissue culture the stem cells divide and, on rare occasions, the inserted gene will replace the normal gene through the process of homologous recombination. The altered ES cell can then be injected into an early mouse embryo, inserted into a “pseudo‐pregnant” female, and may enter the germline. One copy of the defective gene may then be expressed in the progeny of the resulting mouse. By interbreeding mice expressing one copy of the defective gene, mice homozygous for the defective gene may be selected. These mice will not express the protein encoded by the normal gene because that gene has now been “knocked out”.

Figure 8. The principle of adoptive transfer of immunity. If an animal is vaccinated against a pathogenic microbe (or has recovered from an infection) it is usually resistant to re‐infection with the same microbe. To find out which part of the immune system is mediating this resistance, different immune components such as antibodies in serum or T cells isolated from lymphoid tissues can be transferred to a normal animal; this procedure is known as adoptive transfer. The recipient can then tested for resistance to the microbe. In the case shown, T cells, but not antibodies, are needed for defence against this particular pathogen.

Figure 9. Endocytosis and phagocytosis. All cells can sample their extracellular milieu through the process of endocytosis. All can take up molecules in the fluid‐phase by pinocytosis or through receptor‐mediated endocytosis, into endosomes. Specialized cells such as neutrophils and macrophages can also internalize particles by phagocytosis. During phagocytosis, sequential interactions of cell surface receptors and ligands on the particle may result in a zippering process involving the actin cytoskeleton that leads to the particle being enclosed within the cell in a phagosome. Some cells (especially some DCs) can extend large sheets of cytoplasm that fuse to enclose large volumes of fluid; this is macropinocytosis. The internalized vesicles may then fuse with lysosomes that contain degradative enzymes. As the endolysosomes mature they become increasingly acidified, resulting in activation of the degradative enzymes (e.g. acid proteases) that degrade their contents. Sometimes internalized receptors are recycled back to the surface to be re‐utilized (not shown).

Figure 10. Opsonization. Opsonization prepares a particle for phagocytosis by coating it with molecules for which phagocytes have receptors that can mediate internalization. For example, some bacteria can be phagocytosed directly via PRRs (not shown) and are often non‐pathogenic. Pathogenic bacteria may have developed capsules to protect themselves from uptake in this way, but can be taken up after they have been opsonized. The main opsonins are antibodies and certain complement components that are bound directly to the surface of microbes, or to antibodies that are attached to them (mainly IgM and some classes of IgG). A variety of different Fc and complement receptors can mediate internalization of antibody‐ and complement‐opsonized particles, respectively.

Figure 11. Complement activation and production of opsonins. Complement comprises a large group of proteins, some of which can be activated sequentially in a cascade. Three main pathways are involved in activation. The classical pathway typically starts with C1q binding to antibodies on the surface of a particle. The lectin pathway often involves mannose‐binding lectin (MBL) binding to carbohydrates on a particle. The alternative pathway utilizes the continual activation of C3 on particle surfaces and serves to amplify the other pathways. These pathways all come together with the activation of component C3. Its products C3b, and particularly iC3b, act as potent opsonins through binding to complement receptors such as CR3 and CR1.

Figure 12. Neutrophil microbicidal mechanisms. Phagocytosed bacteria are subjected to a variety of potential killing mechanisms within the phagosome. These include reactive oxygen intermediates, anti‐microbial proteins and peptides, and lysosomal enzymes. Neutrophils may also be able to secrete or release anti‐microbial mechanisms that act extracellularly. These include anti‐microbial proteins and peptides such as defensins, and NETS consisting of extruded sheets of nuclear material that may serve to trap bacteria, facilitating their killing.

Figure 13. Microbial macrophage evasion mechanisms. Many pathogens have evolved mechanisms to help them avoid being killed by macrophages. Some general mechanisms used by three different types of bacteria are shown for Listeria, Mycobacterium tuberculosis and Legionella (the causative agents of diseases such as listeriosis, tuberculosis and Legionnaire's disease respectively); the relevance of the coiling mechanism of phagocytosis that is induced by the latter is not known. Many other evasion mechanisms have been discovered; for example, some bacteria may interfere with signalling pathways such as that stimulated by IFN‐γ, thus inhibiting macrophage activation (not shown). Many others are probably yet to be discovered.

Figure 14. Some functions of natural killer cells. NK cells are developmentally related to lymphocytes but are considered as belonging to the innate arm of immunity. Two main types of function are highlighted. Immune regulation. NK cells can regulate the functions of other cell types. For example, a feedback loop triggered by IL‐12 secretion from macrophages can stimulate IFN‐γ production by NK cells which in turns helps macrophage activation. Cellular cytotoxicity. NK cells can kill other cells. Different recognition systems enable NK cells to deliver pre‐formed granule contents or to ligate “death‐inducing” receptors and induce apoptosis (e.g. in cells infected with certain types of virus).

Figure 15. Mast cell activation, degranulation and secretion. Mast cells reside in connective tissues and can be activated in several ways. They express receptors for complement components C3a and C5a, and a selection of PRRs such as Toll‐like receptors (TLRs) that recognize microbial pathogen‐associated molecular patterns (PAMPs). They can also be activated by cross‐linking pre‐formed IgE bound to FcRs on their surface. Activation results in very rapid degranulation with the release of pre‐formed granule components such as histamine and cytokines. Mast cells can then synthesize and secrete other pro‐inflammatory molecules such as lipid mediators (leukotrienes, prostaglandins) and more cytokines. Mechanical damage to mast cells can also lead to the release of histamine.

Figure 16. Eosinophil properties and functions. The functions of eosinophils are not fully understood. They are recruited into inflammatory sites such as those associated with parasitic infections and asthma. They express TLRs, and respond to cytokines such as IL‐4, the chemokine eotaxin and some leukotrienes, for example. When activated they can secrete several cytokines including IL‐4 and IL‐13, and major basic protein which may be involved in defence against parasites. They can also mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC) against some IgE‐ or IgA‐coated parasites.

Figure 17. Functions of T _h1 CD4 T cells. T _h1 cells secrete IFN‐γ which activates macrophages and is involved in B cell differentiation into plasma cells that secrete opsonizing antibodies (e.g. those that can bind to FcRs of activated macrophages). They also secrete IL‐2 which may be important in the activation and clonal expansion of CD8 cytotoxic T cells at sites of infection. T _h1 cells express the T‐bet transcription factor (not shown).

Figure 18. Functions of T _h2 CD4 T cells. T _h2 cells secrete IL‐4, IL‐5 and IL‐13 which are involved in helping B cells to develop into plasma cells that secrete IgE (and some subclasses of IgG). They are also involved in mast cell activation, and eosinophil and basophil production or recruitment (all of which have FcRs for IgE). These cytokines are also involved in alternative activation of macrophages that may be important in helping tissue repair. T _h2 cells express the transcription factor GATA‐3.

Figure 19. Functions of T _h17 CD4 T cells. T _h2 cells secrete IL‐17 that acts on stromal cells to stimulate secretion of IL‐6, which is involved in neutrophil recruitment to sites of acute inflammation, particularly in pyogenic bacterial and some fungal infections. T _h17 cells express the transcription factor RORyt.

Figure 20. Functions of regulatory CD4 T cells. Some “natural” CD4 regulatory T cells (T _reg) are formed in the thymus. They generally express CD25 on one of the high‐affinity IL‐2 receptor chains. Naïve CD4 T cells activated with insufficient co‐stimulation, and perhaps also in the presence of transforming growth factor (TGF)‐β, may become T _reg in peripheral tissues. Other populations of T _reg also exist, but generally all seem to regulate immune responses by acting on other T cells or on different cells such as DCs. Natural T _reg express the FoxP3 transcription factor (not shown).

Figure 21. Functions of CD8 T cells. Activated CD8 T cells can express Fas ligand on their surface; Fas ligand can bind to Fas on another cell and this may initiate apoptosis. Activated CD8 T cells are also potent secretors of IFN‐γ. It is possible for naïve CD8 T cells to be activated in a manner analogous to T _h2 differentiation in CD4 T cells, but the functions of these cells are unclear. Activated CD8T cells can also acquire conspicuous cytoplasmic granules. These contain molecules involved in cell killing (cellular cytotoxicity) such as perforin and the granzymes. When such a CTL binds to its target, the granule contents are secreted into the immunological synapse between the two cells. Perforin monomers polymerize in membranes of the other cell forming a pore though which granzymes enter the cytoplasm and also initiate the apoptotic sequence.

Figure 22. Functions of IgM. Pentameric IgM is recruited to sites of inflammation. IgM is usually of low affinity but its multiple antigen‐binding sites give it high avidity for microbes expressing multiple copies of an epitope. Hence, it is a potent neutralizing antibody for bacteria and viruses. It cannot opsonize microbes directly, but is a potent complement activator, and this permits it to act indirectly as an opsonin and to trigger acute inflammation.

Figure 23. Functions of IgG. IgG is made later than IgM and in small quantities in primary immune responses, but is made rapidly in large quantities in secondary responses. IgG can enter non‐inflamed extravascular tissues. It can also cross the human placenta and confer resistance to infection on the foetus and early neonate. IgG can neutralize pathogens and opsonize them directly or indirectly after activating complement; by activating complement it can also initiate acute inflammation. IgG can also mediate antibody‐dependent, cell‐mediated cytotoxicity (ADCC e.g. by monocytes; not shown).

Figure 24. Functions of IgA. Plasma cells in mucosal tissues typically secrete dimeric IgA. This binds to a specific receptor that transports it across mucosal epithelial cells. On the luminal surfaces of mucosal tissues it acts as a neutralizing antibody, blocking attachment of pathogens and toxins to the epithelial cells.

Figure 25. Functions of IgE. IgE, secreted by plasma cells in connective tissues, binds to high‐affinity FcRs on mast cells in the absence of antigen. It is present at very low levels in the blood of normal individuals, but its levels are raised in parasitic infections, particularly with helminths. IgE may play a role in defence against these parasitic infection by helping to maintain epithelial barriers, assisting expulsion of worms (e.g. because histamine triggers smooth muscle contraction in the gut) and in some cases may kill larval parasites by ADCC. IgE is also responsible for allergic responses: cross‐linking of IgE on mast cells leads to the release of many inflammatory mediators.

Figure 26. Koch's postulates. Koch defined conditions that needed to be fulfilled to show that a particular microbe is the cause of a particular disease. The microbe must be able to be isolated from all cases of the disease and grown as a pure culture in vitro. The isolated microbe must cause a similar disease in a suitable experimental model. It must also be able to be re‐isolated and cultured from the infected animal. Tuberculosis is shown as one example.

Figure 27. Helicobacter pylori and peptic ulcers. Stomach (peptic) ulcers were not thought to have an infectious origin. Australian workers, however, isolated a novel bacterium, Helicobacter pylori, from the stomachs of ulcer patients. They could grow it in pure culture but they did not have an animal in which it would grow and cause disease. To convince the sceptics, one of the workers swallowed a pure culture of the bacterium and developed stomach inflammation, gastritis. He, and subsequently other patients with peptic ulcers, were cured by antibiotic treatment.

Figure 28. Pathogenesis of cholera. If water containing Vibrio cholerae, the cause of cholera, is drunk, it is likely the bacteria will adhere to intestinal epithelial cells. The bacteria secrete toxin composed of two parts. CTB binds to a ganglioside on the cell surface, facilitating the internalization of CTA. The latter induces the intracellular synthesis of large amounts of cyclic AMP, resulting in massive chloride secretion into the intestinal lumen. Water and other electrolytes follow the chloride ions, causing profuse diarrhoea. In immune individuals, IgA antibodies block the binding of both the toxin and of the bacteria to the intestinal cells.

Figure 29. Pathogenesis and immunity in tetanus. Tetanus spores germinate in the anaerobic environment of dead tissue. The bacteria secrete a toxin which, in non‐immune individuals, diffuses to a nearby peripheral nerve, binds to receptors and is internalized. It travels by retrograde axonal transport to the cell body of the nerve in the CNS, where it blocks secretion of inhibitory neurotransmitters, leading to uncontrolled activation and spastic paralysis. Individuals who been vaccinated against tetanus have pre‐formed antibodies that can bind the toxin and prevent its binding to the nerve.

Figure 30. Lobar pneumonia. (1) The bacterium Streptococcus pneumoniae is inhaled and travels to the lung alveoli. (2) It multiplies in the alveolar air spaces and release toxins that cause acute inflammation. (3) The inflammation recruits neutrophils to the alveolar spaces, but they cannot phagocytose the bacteria because it has a polysaccharide capsule. (4) Bacterial antigens are carried to secondary lymphoid organs where they initiate an adaptive immune response to the capsular polysaccharide. (5) IgM is synthesized and travels in the blood to the inflamed area. Here it can enter the alveoli because of the increased venule permeability consequent to the inflammation. (6) IgM binds to the bacteria, but cannot act directly as an opsonin since neutrophils do not express FcRs for IgM. However, complement also enters the alveoli and is activated and binds to the IgM on the bacteria. Neutrophils have receptors for complement components C3b and iC3b, permitting phagocytosis and killing of the bacteria. The inflammatory exudate containing bacteria, neutrophils and other molecules is coughed up, often leading to complete recovery of lung function.

Figure 31. Pathogenesis of tuberculosis. (1) Mycobacterium tuberculosis enters the body by inhalation. (2) In the lung alveoli it infects and kills alveolar macrophages, leading to local inflammation (3). Mycobacterial antigens are transported to the draining lymph nodes, probably by DCs which have been activated in the lung via PRRs. (4) The DCs activate CD4 and CD8 T cells, which migrate to the inflamed lung tissues (5). (6) The local inflammation also recruits blood monocytes, and IFN‐γ activates these macrophages, increasing their ability to kill the bacteria, most probably by hydrogen peroxide and reactive nitrogen intermediates. (7) The bacteria, however, possess many mechanisms that help them to avoid being killed, and the infection becomes chronic. (8) The macrophages are also secreting tissue‐damaging enzymes that result in the breakdown of connective tissues, leading to chronic inflammation (collateral damage). (9) When the infection is controlled, the resulting repair is likely to cause much fibrosis and scarring. Some bacteria are, however, likely to remain in the tissues in a dormant state.

Figure 32. Bacterial Type III secretory systems. After binding to an intestinal epithelial cell, Gram‐negative bacteria such as Salmonella construct hollow needles which insert into the cytoplasm of the host cell. Bacterial proteins are injected into the host cell, inducing changes that help the bacteria to infect and maintain itself in the host. One example is that the intestinal cell can become phagocytic, now enabling the bacteria to enter the cell where they are able to survive by interfering with phagolysosomal function.

Figure 33. Initial resistance to viral infection. Viruses need to evade or subvert a series of defence mechanisms if they are to set up an infection. Natural barriers such as stomach acid can inactivate many viruses. If they pass these barriers, the viruses activate the innate immune system via PRRs expressed by alarm cells such as macrophages, pDCs and other cell types. The most important effect of this activation is the synthesis of Type I IFNs e.g. IFN‐α and IFN‐β, which act on other cells to make them resistant to viral replication. The infected cells may also produce Type I IFNs to help protect other cells in the vicinity.

Figure 34. Recovery from viral infection. In most cases of viral infection an adaptive response is needed to bring about recovery. This response involves both CD4 and CD8 T cells. CD8 T cells are often essential and generate two main effector mechanisms. Activated CD8 T cells can kill infected cells, and if this happens before new, infectious virus has been made, the spread of infection can be stopped (Section 4.5.2). Activated CD8 T cells can also secrete IFN‐γ, which is a weak anti‐viral agent but more importantly activates macrophages which are potent secretors of Type I IFNs. CD4 T cells may provide help in the activation of CD8 T cells and also help B cells to make antibodies – these may play some role in recovery, but are crucial in resistance to re‐infection. In some cases, NK cells may also kill virally infected cells, aiding recovery from infection (Section 4.4).

Figure 35. Immunity to polio virus infection. Polio vaccines consist of either attenuated (weakened) live virus (Sabin) or inactivated virus (Salk). The live, Sabin vaccine is given orally (often on a sugar lump). The virus infects intestinal epithelial cells, mimicking the natural infection, and induces a local IgA response. This prevents virulent virus from attaching to the epithelial cells and replicating, and virulent virus is not excreted. There is, however, a small risk that the vaccine virus will revert to virulence. The Salk vaccine is given by injection and induces an antibody response that is mainly IgG. This prevents the spread of the virus beyond the intestine by opsonization and neutralization, but does not prevent infection of intestinal epithelial cells and the subsequent excretion of live, virulent virus. In practice both are very effective vaccines at both individual and population levels.

Figure 36. Life cycle of the influenza virus. HA on the viral envelope binds to sialic acid on the host cell. The virus is internalized by endocytosis and the low endosomal pH (increased acidity) alters the HA so that it can mediate fusion of the envelope with the endosomal membrane. The viral RNA (eight discrete segments) is released, and induces synthesis of early proteins, involved in RNA replication, and late proteins that are assembled into new viral particles. The virus buds from the plasma membrane of the infected cell, incorporating some of the membrane as its envelope. The viral NA is involved in releasing the virus from the cell. Different forms of HA and NA give different strains of influenza viruses their characteristic names (H1N1, H5N1, etc.).

Figure 37. Immunity to influenza I: recovery. (1) Influenza virus infects and replicates in respiratory epithelial cells and is released by budding. (2) Viral PAMPs and or cytokines released by the epithelial cells stimulate pDCs, which make large amounts of Type I IFNs. (3) Type I IFNs, which can also be produced by the infected epithelial cells, induce resistance to viral infection in other cells. (4) PAMPs also activate classical DCs which acquire viral antigens either from viral debris or by taking up apoptotic infected cells. (5) These DCs migrate to lymph nodes where they activate CD4 and CD8 T cells. (6) The activated CD8 T cells migrate to the inflamed epithelium (7) and are able to kill infected cells, hopefully before new virus is assembled. They may also secrete IFN‐γ, which is weakly anti‐viral, but also activates macrophages which may then secrete Type I IFNs.

Figure 38. Immunity to influenza II: resistance to re‐infection. Antibodies, particularly of the IgA class and specific for HA, prevent the virus binding to epithelial cells. Additionally, but later, DCs may acquire viral antigens, travel to lymph nodes and activate CD8 memory T cells. The latter may become activated effector cells that may kill epithelial cells that are infected by any viruses that escape neutralization, thus preventing further release of live virus.

Figure 39. Hepatitis C. Hepatitis C is usually transmitted by infected blood. The virus infects hepatocytes and induces an adaptive immune response. In many cases this response does not clear the infection and the virus persists in the liver. The virus continues to stimulate the immune response, which itself stimulates, as part of chronic inflammation, a healing and repair response. This leads to excessive deposition of collagen (cirrhosis), which over a long period can lead to liver failure.

Figure 40. Virally induced tumours. If a tumour causing virus (an oncogenic virus) infects a cell it may insert its own genes or induce abnormal activation or suppression of host genes that regulate growth of the cells (oncogenes and tumour suppressor genes respectively). This results in a clone of cells becoming able to divide indefinitely (immortality) and independently of external growth factors, and lack control of proliferation through cell–cell contacts. A tumour starting to develop may also induce angiogenesis, helping to support its growth. Tumour cells may invade into normal tissues, and escape into blood or lymph to seed more distant sites, leading to metastasis.

Figure 41. Prevention of cervical carcinoma by vaccination. Carcinoma of the uterine cervix is very strongly associated with genital infection with sexually transmitted strains of HPV. Young women are immunized (prophylactically, before they have become infected) with an anti HPV virus vaccine which induces an immune response, mainly antibody, that prevents the virus infecting cervical epithelial cells. This is proving very effective in preventing subsequent tumour development. It must be emphasized that the immunization prevents infection: it is not an immunization against the tumour itself. Since the virus is typically transmitted through sexual intercourse there may be some value in vaccinating young men as well.

Figure 42. Viral events in human immunodeficiency virus infection. (1) Viral infection usually occurs via mucosal surfaces. (2) Often a single viral particle crosses the epithelium and infects submucosal memory (CCR5) CD4 T cells and DCs. (3) There is an eclipse phase of 5–10 days after infection when virus cannot be detected in the blood. During this phase virus has entered the draining lymph nodes as either free particles or transported by CD4 T cells or DCs. The virus replicates in the node, killing many CD4 T cells, forming viral reservoirs and destroying the architecture of the node. (4) The virus now disseminates widely via the blood (a viraemia can be detected) to secondary lymphoid organs. (5) Here, it continues to replicate, destroying many CD4 T cells directly and inducing bystander apoptosis in many other non‐infected CD4 T cells. Eventually CD4 T cell numbers decline to a level where opportunistic infections can occur.

Figure 43. Immunological events in human immunodeficiency virus infection. Early after infection, innate immune activation leads to the appearance of acute phase reactants and pro‐inflammatory cytokines in the blood. The first adaptive immune response leads to the appearance of non‐neutralizing antibodies which do not select for escape mutant virus. Soon after, a CD8 T cell response starts, which does select for escape mutants. Repeated cycles of CD8 activation occur in response to appearance of many different escape mutants. It is only after around 70–80 days that neutralizing antibodies appear, again selecting for escape mutants. The processes of immune selection of escape mutants continues for years, until CD4 T cell numbers have declined sufficiently to permit opportunistic infection to occur, with the onset of AIDS. At this point the viraemia increases substantially (not shown).

Figure 44. Malaria parasite life cycle. The Plasmodium protozoan is acquired by an Anopheline mosquito from an infected person. It reproduces in the mosquito intestine and migrates to the salivary glands. (1) When a new subject is bitten, the parasite enters the blood and infects and reproduces in hepatocytes. (2) It is released from the hepatocytes and (3) infects RBCs, where it again reproduces and is released to infect other RBCs when the infected RBCs lyse. This cycle may recur many times and, should a mosquito bite the infected individual, the parasite starts the cycle over again. (4) The parasite changes form and divides asexually or sexually at different stages of its life cycle. Some points at which potential preventative measures might be introduced, to control transmission or induce immunity by vaccination, are indicated (green text).