11 Host and Microbial Factors Influencing Susceptibility 379 America. The case fatality approaches 10%, and in severe famines reaches the tragic figure of 50%. The severe form of measles is seen in unvaccinated children in tropical Africa, and it was also seen in chil- dren in European cities in the nineteenth century. The virus ('seed') has not altered, but changes in the 'soil' (host) dramatically enhance the severity of the disease. Increased susceptibility to herpes simplex and P. carinii (see Glossary) infection, and to Gram-negative septi- caemia is also seen in protein deficiency. Because of the effect on CMI, there is greater susceptibility to tuberculosis. Tuberculosis has often been noted to increase in frequency in times of famine, and this has also been observed in the inmates of concentration camps. On the other hand, it looks as if certain infections are less severe in malnourished individuals. Typhus, for instance, is said to cause a higher mortality in well-fed than in malnourished individuals, and clinical malaria was suppressed in Somali nomads during the 1970s' famines, only to be reactivated 5 days after refeeding. A 4-year study of 100 000 prisoners in the UK in the 1830s showed that those given the most food (costing 3 shillings per week) had a 23% mortality, presum- ably largely due to infection, whereas those given least food (costing 10 pence per week) had a 3% mortality. It is not known why malnourished individuals are sometimes less susceptible to infection. A decrease in the vigour of host inflammatory and hypersensitivity responses would be expected, and perhaps there are adverse effects on the nutrition of the infectious agent itself, with depressed replication in the malnour- ished host. Vitamin A, B and C deficiencies are known to lead to impaired integrity of mucosal surfaces, which in turn causes increased suscepti- bility to infection, and adds to the complexity of the picture. In devel- oping countries the severity of measles is greatly reduced when children are given vitamin A supplements. There may be a pre-existing vitamin A deficiency, but measles itself causes reduced vitamin A levels. Mortality is lowered and ocular damage, in particular, is less severe. The effect is not only on the integrity of epithelial surfaces. Children given these supplements show less depletion of Th lympho- cytes and increased production of measles-specific IgG antibody, compared with untreated children with measles. Children in Papua New Guinea suffered much less from malaria when given vitamin A supplements. The commonest mineral deficiency is iron and, by affecting certain enzyme systems, this can increase susceptibility to infection. For example, it causes reduced myeloperoxidase activity in phagocytes, with less hydroxyl radical formation, and this means defective killing of bacteria (see Ch. 4). Zinc, selenium, and vitamin E deficiency, espe- cially in the elderly, can reduce immune and phagocytic function. Chronic diarrhoea leads to zinc deficiency, and by giving zinc supple- ments to children in New Delhi, Brazil and China, the incidence of cough, pneumonia and diarrhoea was reduced. 380 Mims" Pathogenesis of Infectious Disease Hormonal Factors and Stress Hormones have an important role in maintaining homoeostasis and in regulating many physiological functions in the body. The hormones with a pronounced effect on infectious diseases are the corticosteroids. This is largely because corticosteroids are vital for the bodily response to stress (see Glossary), and infection, like injury or starvation, is a stress (see Fig. 11.2). It has long been known that the adrenal glands are needed for resistance to infection and trauma. Corticosteroids of various types have a complex and wide range of actions; the most important for infectious diseases are the glucocorticosteroids, which inhibit inflammation and depress immune responses. These cortico- Mental stresses Threatened bodily stresses Actual bodily stresses halamus 0 P~u~ Autonomic nerves Adrenal medulla Catecho~mines ACTH \ Cortisol / Adrenal cortex Blood vessels, Muscles, Inhibition of bronchi, metabolic inflammation and heart, etc. changes, immune responses. Fig. 11.2 Diagrammatic representation of stress mechanism in man. Various cytokines (IL-1, IL-6 and tumour necrosis factor) act on the hypothalamus, and IL-1 and IL-2 on the pituitary gland. 11 Host and Microbial Factors Influencing Susceptibility 381 steroids also stabilise cell membranes and lysosomes, giving cells some protection against damage or destruction. There is, moreover, a great deal of interaction between the neuroendocrine and the immune system which is not included in Fig. 11.2. Not only are immune cells influenced by corticosteroids (see below) and by other mediators gener- ated via the hypothalamic-adrenal axis, but the immune cells them- selves (B cells, T cells and macrophages) produce endorphins, adrenocorticotrophic hormone (ACTH), growth hormone and other hormones. Indeed the brain, the endocrine and the immune systems tend to use the same cytokines, peptide hormones and neurotransmit- ters. For instance, lymphocytes produce growth hormone when cultured in vitro. If this is prevented, the lymphocytes stop synthe- sising DNA, but start again when growth hormone is added. Again, neural cells have receptors for interferons and for interleukin (IL-1), IL-2, IL-3 and IL-6. It seems that discoveries are providing us with more and more mechanisms by which the mind can influence health and disease! Inflammation makes an important contribution to tissue damage and pathology in infectious disease (see Ch. 8) and injected corticos- teroids (or ACTH) have a pronounced anti-inflammatory effect, their therapeutic use in infectious diseases depending on a reduction in the inflammatory pathological components at sites of infection. At the same time they tend to inhibit immune responses. This last action is not completely understood. There is an ill-defined effect on lympho- cytes, some of which have receptors for corticosteroids, and inhibition of production and action of immune mediators, such as IL-1 and IL-2. Corticosteroids also prevent the inflammatory expression of the immune response in tissues by blocking the movement of plasma and leucocytes from blood vessels, and this is partly due to inhibition of prostaglandin production. The inflammatory and immune responses, although on the one hand contributing to pathological changes and disease, are also powerful antimicrobial forces (see Ch. 9). This dual role is reflected in the results of giving corticosteroids in infectious disease. Herpes simplex kerato- conjunctivitis or encephalitis, for instance, is temporarily improved by corticosteroids because of the reduction in inflammation, but the simultaneous weakening of antimicrobial forces means that the infec- tion progresses more readily. The net effect is to make the disease worse. For the same reasons a large number of different experimental infections in animals are made more severe by corticosteroid adminis- tration. All the above remarks apply to corticosteroids administered artifi- cially, often in large doses. It is perhaps more relevant to ask what effect the individual's own corticosteroids have on the course of an infectious disease. It is first necessary to say something about the func- tion of the corticosteroid response to stress. Small areas of tissue injury give rise to quite severe but nevertheless locally useful inflammation, 382 Mires' Pathogenesis of Infectious Disease mediated by various inflammatory factors. If exactly the same response took place in multiple sites of infection in the body or in response to more extensive tissue injury, the immediate overall result in terms of vasodilation and loss of fluid into tissues would be harmful. An individual who is infected or wounded may need to retain bodily functions for running or fighting, and the effect of multiple unmodified local inflammatory responses might well be incapacitating. When inflammation occurs on a large scale, therefore, it is an advantage to make an overall reduction in its severity, so that the general impact on the host is lessened. This is a teleological way of looking at the function of corticosteroid hormones, which also makes sense of their metabolic function in mobilising energy sources. The response to stress of the autonomic nervous system, involving arenalin-mediated changes in preparation for bodily action (fight or flight) is more obviously inter- preted in these terms. During an infection there is an increase in the rate of corticosteroid secretion, just as in response to other bodily stresses such as hunger, injury or exposure to cold. Rises in urinary 17- ketosteroids are seen, for instance, in Q fever and sandfly fever infec- tions in man. There is also an increased rate of utilisation of corticosteroids by tissues. Inflammatory and immune responses thus take place against the dampening and modifying background of increased corticosteroid levels, which ensure that continued bodily function and balance (homoeostatis) is maintained. When the corticos- teroid response is depressed, as in Addison's disease (see Glossary), the consequences of infection or tissue injury are very severe, and affected patients therefore have to be given increased doses of corticosteroids during infections.* Bilaterally adrenalectomised animals usually show greatly increased susceptibility to tissue damage and death in experi- mental infectious diseases. It can be concluded therefore that increased circulating levels of corticosteroid hormones are necessary for a successful host response to infectious disease. Administering additional amounts of corticosteroids is not necessarily of value unless the host's own corticosteroid response is known to be subnormal, or if it is for the moment more important to reduce inflammation than to control infection. Otherwise, additional corticosteroids tend to promote the infection by decreasing the effec- tiveness of antimicrobial forces, as discussed above. When corticosteroids are given, they not only make any infection that happens to occur at the time more severe, but also favour the lighting up of persistent infections that are normally held in check by immune forces. Tuberculosis in man is often activated or made worse by corticosteroid administration. Stress tends to act in the same way, * It may be noted that in Cushing's syndrome there is also a greatly increased suscepti- bility to infection because of excessive production of corticosteroids from the adrenal cortex. Abnormally high corticosteroid levels promote infection for reasons referred to above, and bacterial infections have been leading causes of death in these patients. 11 Host and Microbial Factors Influencing Susceptibility 383 probably because of increased secretion of corticosteroids. One classical example in animals is psittacosis, a chlamydial infection of parrots and budgerigars. These birds normally carry the microorganism as a persistent and harmless infection, localised in the spleen. Following the stress of transport in cages, exposure to strange surroundings or inadequate diet, the infection is activated in the bird, and the micro- organism begins to be excreted in the faeces. Human infection can then take place by inhalation of particles of dried droppings from the cage, causing the troublesome disease psittacosis, with pneumonia as a common feature. In humans, mental stress in the form of anxiety calls into action the same physiological changes which were designed to deal with physical stresses (see Fig. 11.2). For instance, in a university boat race the crew had increases in corticosteroid production that enabled them to sustain the physical stress of the race, but the coxswain was found to have an increase of equal magnitude. The evidence for mental stress acting on infection is not impressive, and for the most part involves immune responses. For example, a study of a symptomatic human immunodeficiency virus (HIV)-infected individuals showed that those judged to be stressed had lower counts of cytotoxic T cells and NK cells. In another study, 48 students were given three doses of hepatitis B vaccine during examination periods over the course of 6 months, and those who had seroconverted after the first injection were less likely to have been stressed and anxious. Standard stress and anxiety assess- ment scales were used. It is possible but not proven that sustained mental stress, by causing persistent rises in circulating corticos- teroids, lowers resistance to persistent infections and other infections that occur during the period of stress (see illness clustering, below). Stress appears to influence the recurrence (reactivation) of oral and genital herpes. Infections are sometimes more severe when the host animal lives under crowded conditions. Increased transmission as well as stress responses, can play a part. Intestinal coccidiosis in domestic animals is generally asymptomatic, but clinical disease is seen when a heavy parasite load is carried. This is favoured under crowded conditions because of increased transmission. The increased rate of meningo- coccal and streptococcal disease when people are crowded together is due to increased transmission. The adrenal cortex itself is not often involved in infectious diseases but, if it is, the infection in the cortex tends to be extensive. Examples include tuberculosis and histoplasmosis in man and various viral, bacterial, fungal and protozoal infections in experimental animals. Infectious agents localising in the adrenal cortex encounter a high concentration of corticosteroid hormones originating from cortical cells. Antimicrobial forces are therefore weakened locally, and the infection is exacerbated. Active adrenal foci of infection are often seen at a time when foci elsewhere in the body are healing. 384 Mims' Pathogenesis of Infectious Disease There is usually a change in susceptibility to infection during preg- nancy, as discussed earlier in this chapter, and this is due to hor- monal changes. The relative importance of oestrogens, progesterone and corticosteroids is not clear. Oestrogens are necessary for main- taining the resistance of the adult vagina to most bacterial infections, as described on pp. 44-45. The male sex hormones responsible for the changes in the testicle at puberty can be regarded as causing this organ's susceptibility to mumps virus infection. Insulin is also worth mentioning because the metabolic changes in poorly controlled dia- betes in some way increase susceptibility to staphylococcal, fungal and tubercular infections (see pp. 50-51). Clearly there are hormones that control the health and well-being of cells and tissues in all parts of the body and, in this sense, serious hormonal disturbances could always affect the course of infectious diseases. It would be surprising for instance if untreated cretins showed a completely normal response to infections. Such effects would scarcely be worth mention- ing were it not for the existence of this category called 'hormonal factors'. Stress proteins So far, the word stress has been used to describe the response of the infected host. It can also refer to the response of the individual host cell, or to the response of the infecting microorganism or parasite. In other words, infecting bacteria, etc. and host cells have their own stress responses, elicited during infection, heat or other stimuli. Stress proteins are recognised in most living organisms. They help protect cells from harmful effects of stress, and often function by helping with the correct folding, translocation and assembly of other proteins, acting as 'molecular chaperones'. They are present under normal circumstances but are produced in much larger amounts in response to stress. There are families of heat shock proteins (hsp), and hsps 60, 70 and 90 are well-studied examples. S. aureus has four classes of heat shock genes, and hsps are often dominant antigens of microbes. For instance, in human mycobacterial infection, up to 40% of the total T-cell response is to bacterial hsp 65. The fact that the human equivalent, also produced in the infection, is hsp 60, and shows considerable sequence similarity with hsp 65, gives opportuni- ties for cross-reactive autoimmune responses by the host. However, the importance of such responses in mycobacterial or other infections has not been established. Viruses do not have their own stress proteins, but there are indications that they make use of those produced in the infected cell. In the adenovirus-infected cell, the adenovirus E1A gene product itself causes increased synthesis of host hsp 70, which seems to have a role in the handling of viral proteins and the assembly of virus particles. 11 Host and Microbial Factors Influencing Susceptibility 385 Other Factors A host of miscellaneous factors influence the course of infectious diseases, and some of them merit particular mention. Certain lung conditions resulting from the inhalation of particles have an important effect on respiratory infection. Silicosis is a disease due to the continued inhalation of fine particles of free silica. It occurs in coal miners and in various industries where sandstone and similar mate- rials are used. There is a great increase in susceptibility to tubercu- losis, which is more likely to cause serious or fatal disease. This is because lung macrophages, which play a central role in resistance to respiratory tuberculosis, become damaged or destroyed following the phagocytosis of the free silica particle. When intact macrophages containing nonlethal amounts of silica phagocytose tubercle bacilli, the bacteria grow faster, the cell dies, and the progeny bacteria are released sooner. Nowadays, most people spend 90% of their lives indoors, and air exchange with the outside world is much less than it used to be, but some exposure to atmospheric pollutants is inevitable. The air is polluted in many towns and cities, especially with substances derived from the combustion of commercial, domestic and automobile fuels. These include SO2, nitrogen oxides, CO, ozone, benzene, acid aerosols, and also particles. Although these particles form a small proportion of the total mass of particles suspended in air, they are important because they include small (<2 pm diameter) particles, which are stable, pene- trate deep into the lungs and may bear acidic gases or contain toxic elements such as lead. In many countries, pollutants (but not CO2!) have been reduced by clean air laws, catalytic converters, and the use of lead-free fuels. The commonly measured pollutants are SO2 and particulates (smoke). For both, the upper limit (24 h mean) recom- mended by the World Health Organisation (WHO) is 100-150 pg m -3, but these values are commonly exceeded. Can atmospheric pollution increase the severity of respiratory infections? It has been reported that people with chronic bronchitis produce larger volumes of morning sputum and note a worsening of symptoms when SO2 values in air reach 250 pg m -3, and there is an increase in respiratory mortality when levels exceed 750 pg m -3. In the great London smog of 1952, before the Clean Air Bill greatly improved the quality of London air, SO2 levels reached 8000 pg m -3, and there were 4000 excess respira- tory deaths. The morbidity and mortality, however, is seen in the respi- ratory cripples (chronic bronchitis, etc.), in the very old and in other susceptible individuals.* One feels that atmospheric pollution must also be having a long-term harmful effect on the lungs of normal * The same vulnerable groups also experience increased mortality in influenza epidemics. 386 Mires' Pathogenesis of Infectious Disease people, but what about respiratory infections? Although exacerbations of asthma and of cardiopulmonary disease are well established, there is no convincing evidence that normal people exposed to atmospheric pollution experience an increase in the severity of acute respiratory infections. A careful study of 20000 children and adults in four geographical areas of the USA has shown that high levels of SO2 and suspended sulphates are significantly associated with excess acute respiratory disease, much of which can be assumed to be infectious. The effect was most marked after more than 3 years' exposure, and it was independent of cigarette smoking and socioeconomic status, two of the factors that had always been difficult to dissociate from atmos- pheric pollution in previous studies. Cigarette smoking can be regarded as self-induced atmospheric pollution, and many interesting observations have been made. For instance, cigarette smoke inhibits ciliary activity, the debris-laden alveolar macrophages of smokers show less bactericidal activity, and lung pathogens, such as pneumococci and Haemophilus influenzae, attach more readily to pharyngeal cells from smokers. Cigarette smoking is certainly associated with chronic bron- chitis, but the evidence linking cigarette smoking with susceptibility to acute respiratory disease in otherwise healthy individuals is con- flicting. For instance, one study of 1800 students at a military college in the USA during the Hong Kong 'flu epidemic showed that those who smoked 21 cigarettes a day had a 21% higher incidence of clinical influenza, but other studies have failed to show an effect. On the other hand, a recent (2000) study of 228 smokers and 301 nonsmokers showed that smokers were four times as likely (and passive smokers 2.5 times as likely) to develop pneumococcal disease as nonsmokers. The subjects were immunocompetent, otherwise healthy people aged 18-64 years. It is a widespread popular belief that people are less resistant to infectious diseases when they are in a poor mental state, and there is in fact some evidence that psychological factors influence suscepti- bility. This is seen in the phenomenon of illness clustering. In two studies in the USA, the illnesses and significant life events of several thousand people were recorded over a period of about 20 years. It was found that in a given individual, illnesses of all kinds, not only psycho- somatic conditions such as peptic ulcers but also bacterial infections and tumours, tended to occur in clusters. There was a significant asso- ciation of these illness clusters with stressful life situations, such as the death or serious illness of a close relative, personal injury, career crises, etc. It can be difficult to interpret results and, indeed, not all studies have given the same results. Little is known of the mechanism by which such events influence infectious diseases. Presumably it involves the stress response and the known effects of the nervous system on immune responses (see p. 380). Simple fatigue generally has little effect on susceptibility to infec- tion, but violent exercise in the early stages of poliomyelitis is known 11 Host and Microbial Factors Influencing Susceptibility 387 to predispose to paralysis in the exercised muscles. The exercise must be done during the preparalytic stages of infection, when virus is spreading from the alimentary canal to the central nervous system. It is associated with dilation of capillary blood vessels supplying the spinal cord neurons that innervate the exercised muscles. Perhaps circulating virus is more likely to invade such regions of the spinal cord. Paralytic poliomyelitis also tends to involve muscles that receive injections during the preparalytic stages of the infection, especially with materials such as pertussis vaccine. In this case too, the injec- tion causes capillary dilation in the appropriate region of the spinal cord. Exposure to changes in temperature and sitting in draughts are traditionally regarded as influencing infectious diseases. Careful studies with common cold viruses have not provided any evidence for this. Volunteers infected intranasally with a standard dose of virus were exposed to cold, but failed to show detectable changes in the inci- dence or severity of infection even after standing naked in draughty corridors. The effect of changes in relative humidity has been less care- fully studied. Experimentally, ciliary activity in segments of respira- tory epithelium is impaired by reductions in the relative humidity of the overlying air. Increases in air temperature in heated buildings lead to substantial reductions in relative humidity unless the air is humid- ified. The lower respiratory tract would tend to be protected because of humidification of inhaled air by the turbinate mucosa, but the nasal mucosa would be exposed to the dry air, and an effect on ciliary activity and thus on respiratory infection might be expected. The local concentrations of key elements sometimes determine microbial growth in tissues. For instance, nearly all bacteria require iron, but the body fluids of the host contain iron-binding proteins, such as lactoferrin and transferrin, which limit the amount of free iron available. Hence certain bacteria show greatly increased virulence after administration of iron to the host, and patients with excess iron in the blood may show increased susceptibility to infection. The lethality for mice ofPseudomonas aeruginosa is increased 1000-fold by the injection of iron compounds to saturate the iron-binding capacity of serum transferrin. The ability of bacteria to compete with the host for iron can be an important factor, and virulent bacteria such as patho- genic Neisseria and enteric bacilli that produce their own iron-binding compounds (collectively called siderophores), are able to circumvent the host restriction on the availability of iron (see also Ch. 8).* Oxygen is a key element for other bacteria. It is essential for many, such as the tubercle bacillus, but Clostridium perfringens, for instance, is strictly anaerobic and multiplies best in tissues that are anoxic as a result of * Malaria parasites induce the formation of transferrin receptors on the surface of infected red blood cells. 388 Mims' Pathogenesis of Infectious Disease interruption to their blood supply. Bacterial multiplication is actually inhibited in the presence of oxygen, and patients with gas gangrene are treated by exposure to oxygen in a pressure chamber. Clostridium tetani also requires local anoxic conditions in tissues, whether pro- duced by severe wounds or by trivial injuries due to splinters, thorns or rusty nails. It may be noted that some of the most successful invaders of the respiratory tract show optimal growth in the presence of up to 5-10% CO2 (e.g. tubercle bacilli,* pneumococci). The gases bathing the lower respiratory tract normally contain about 5% CO2. Foreign bodies in tissues often act as determinants of local microbial virulence. The term foreign bodies includes foreign particles that are too large to be phagocytosed. Foreign bodies presumably act by inter- fering with the blood supply and also by serving as a continuous source of multiplying microorganisms, giving them physical protection in nooks and crannies from phagocytes and other antimicrobial forces. Foreign bodies potentiate various clostridial infections (see above) and particularly staphylococci infections. Necrotic bone fragments in chronic osteomyelitis act as foreign bodies, hindering treatment and giving a source of bacteria for flare-up of infection many years later. The ability of staphylococci to cause a local lesion after introduction into the skin is increased about 10000-fold if the bacteria are implanted on a silk thread. Skin is generally more susceptible to infec- tion when wet, as well as following injury. Wet pastures and minor foot injuries predispose to various types of'footrot' in cattle, sheep and pigs, due to infection with Fusiformis spp. or other bacteria. Patients with plastic devices inserted at the body surface or in deeper tissues show increased susceptibility to commensals such as S. epidemidis. The devices act by interrupting the integrity of host defences or by forming a surface for bacteria to grow on, and include catheters in veins, cere- brospinal fluid shunts, prosthetic hips and knees, cardiac pacemakers, etc. Certain drugs influence resistance to infectious disease and, of the self-administered drugs, alcohol is the commonest. In various studies, intoxicated animals have been found to have impaired ciliary activity, impaired removal of inhaled bacteria, defects in phagocytosis or poor closure of the glottis. Most of these phenomena have not been satisfac- torily demonstrated in man, and polymorph function, for instance, appears normal, although there is impaired migration of polymorphs from blood vessels. The position is clearer for chronic alcoholics, many of whom have alcoholic liver disease. These individuals have reduced polymorph counts in the blood and are more likely to develop bacterial (especially pneumococcal) pneumonia. Alcoholics also show increased * Tubercle bacilli commonly cause lesions in the apical regions of the lung, perhaps because oxygen and CO2 tensions in these regions favour bacterial growth or depress host defences. [...]... 56 4-5 68 Jindal, S and Malkovsky, M ( 199 4) Stress response to viral infection Trends Microbiol 2, 89 Joklik, W K ( 198 5) Recent progress in reovirus research Annu Rev Genet 19, 53 7-5 75 Kan, Y W and Dozy, A M ( 198 0) Evolution of the haemoglobin S and C genes in world populations Science 2 09, 388 Luzatto, L ( 197 9) Genetics of red cells and susceptibility to malaria Blood 54, 96 1 -9 76 MacKenzie, J S ( 198 2)... Immun 51 ,90 1 Peterson, P K., Chao, C C et al ( 199 1) Stress and the pathogenesis of infectious disease Rev Infect Dis 13, 71 0-7 12 Pincus, S H., Rosa, P A., Spangrude, G J and Heinemann, J A ( 199 2) The interplay of microbes and their hosts Immunol Today 13, 47 1-4 73 11 Host and Microbial Factors Influencing Susceptibility Report of Study Group ( 197 9) Acne J Invest Dermatol 73, 43 4-4 42 Weinberg, E D ( 197 8)... immunity via the cruel lottery of the disease process' (Sir Gustav Nossal, Kyoto, November 199 3) References Ada, G L ( 199 3) Towards phase III trials for candidate vaccines Nature (Lond.) 364, 48 9- 4 90 ASM News ( 199 3) Vaccine linked to rare adverse health effects ASM News 59, 54 7-5 48 Berzofsky, J A., Ahkers, J D., Derby, M A., Pendleton, C D., Arichi, T and Belyakov, I M ( 199 9) Approaches to improve engineered... R ( 199 7) Adjuvants - a classification and review of their modes of action Vaccine 15, 24 8-2 56 Crowle, A J ( 198 8) Immunization against tuberculosis; what kind of vaccine? Infect Immun 56, 276 9- 2 773 Donnelly, J J., Ulmer, J B., Shiver, J W and Liu, M A ( 199 7) DNA vaccines.Ann Rev Immunol 15, 61 7-6 48 Fenner, F ( 198 2) A successful eradication campaign Global eradication of smallpox Rev Infect Dis 4, 91 6... effect of sulfur dioxide and suspended sulfates on acute respiratory disease Arch Environ Health 27, 12 9- 1 33 Gardner, I D ( 198 0) The effect of ageing on susceptibility to infection Rev Infect Dis 2, 80 1-8 10 Godlee, F ( 199 1) Air pollution - road traffic and modern industry Brit Med J 303, 153 9- 1 543 Gracey, M S ( 198 1) Nutrition, bacteria and the gut Brit Med Bull 37, 7 1-7 5 Huxley, E J et al ( 197 8) Pharyngeal... determining the duration of resistance Clearly the longer protection lasts the better; no vaccine would prove popular if an injection were required every 6 m o n t h s t h r o u g h o u t life The duration of resistance to disease depends to some extent on the 399 400 Mims' Pathogenesis of Infectious Disease type of infection In the case of systemic infections with an incubation period of a week or two, a... 504 Cann, A J ( 199 7) 'Principles of Molecular Virology', 2nd edn, Academic Press, London Chandra, R K ( 198 3) Nutrition, immunity and infection: present knowledge and future directions Lancet i, 688 Cohen, S and Williamson, G M ( 199 1) Stress and infectious disease Psychol Bull 1 09, 5-2 4 Coutsoudis, A et al ( 199 2) Vitamin A supplementation enhances * During sleep, normal individuals often aspirate material... water-extractable antigens, and from E coli 1100 prc,teins have been resolved by two-dimensional gel electrophoresis 395 396 Mims" Pathogenesis of Infectious Disease Table 12.1 Microorganism Sizes of genome of microorganisms No of genes a Viruses Polyomavirus 6 Poliovirus 5 Influenza virus 10 Adenovirus 30 Herpes virus 160 Poxvirus (vaccinia) 300 Chlamydias Trachoma 800 Mycoplasmas Mycoplasma spp 90 0... Pathogenesis of Infectious Disease specific IgG antibody levels and total lymphocytic numbers while improving morbidity in measles Pediatr Infect Dis 11,203 Dorman, C J ( 199 4) 'Genetics of Bacterial Virulence' Blackwell Scientific Publications, Oxford Fields, B N and Byers, K ( 198 3) The genetic basis of viral virulence Phil Trans R Soc Lond B 303, 2 09 (survey of reovirus studies) French, J G et al ( 197 3) The... This is so for polio, measles, yellow fever or tuberculosis Sometimes a given disease is caused by a number of microorganisms which differ antigenically, and resistance to only one 401 Mims' Pathogenesis of Infectious Disease 402 of them will not provide resistance to the disease There are dozens of antigenically distinct types of streptococci, for instance, and resistance to streptococcal infection is . water-extractable antigens, and from E. coli 1100 prc, teins have been resolved by two-dimensional gel electrophoresis. 396 Mims& quot; Pathogenesis of Infectious Disease Table 12.1. Sizes of. Pathol. 121,531. Blalock, J. E. ( 199 4). The syntax of immune neuroendocrine communi- cation. Immunol. Today 15, 504. Cann, A. J. ( 199 7). 'Principles of Molecular Virology', 2nd edn,. ( 198 0). The effect of ageing on susceptibility to infection. Rev. Infect. Dis. 2, 80 1-8 10. Godlee, F. ( 199 1) Air pollution - road traffic and modern industry. Brit. Med. J. 303, 153 9- 1 543.