2 Attachment to and Entry of Microorganisms into the Body 43 Urinogenital Tract Urine is normally sterile, and since the urinary tract is flushed with urine every hour or two, invading microorganisms have problems in gaining access and becoming established. The urethra in the male is sterile, except for the terminal third of its length, and microorganisms that progress above this point must first and foremost avoid being washed out during urination. That highly successful urethral parasite, the gonococcus, owes much of its success to its special ability to attach very firmly to the surface of urethral epithelial cells, partly by means of fine hairs (pili) projecting from its surface (Fig. 2.11).* Similarly, uropathogenic E. coli (UPEC) adhere to uroepithelial cells by means of a well-characterised pilus. The bladder is not easily infected in the male; the urethra is 20 cm long, and generally bacteria need to be intro- duced via an instrument such as a catheter to reach the bladder. The female urethra is much shorter, only about 5 cm long, and more readily traversed by microorganisms; it also suffers from a dangerous prox- imity to the anus, the source of intestinal bacteria. Urinary infections are about 14 times as common in women, and most women have urinary tract infections at some time. Bacteruria,t however, often occurs without frequency, dysuria, or other symptoms. Even the urethral deformations taking place during sexual intercourse may introduce infection into the female bladder.$ Spread of infection to the kidney is promoted by the refluxing of urine from bladder to ureter that occurs in some young females. Urine, as long as it is not too acid, provides a fine growth medium for many bacteria and the entire urinary tract is more prone to infec- tions when there is interference with the free flow and flushing action of urine, or when a 'sump' of urine remains in the bladder after urina- tion. Urinary infections are thus associated with structural abnormal- ities of the bladder, ureter, etc., with stones, or with an enlarged prostate that prevents complete emptying of the bladder. Incomplete emptying also leads to urinary infection in pregnant women, and this * The gonococcus is soon killed in urines that are acid (<pH 5.5), and this helps explain why the bladder and kidneys are not invaded. The prostate is at times affected and the gonococcus accordingly grows in the presence of spermine and zinc, materials that are present in prostatic secretions and that would inhibit many other bacteria. t By the time it has been voided and tested in the laboratory, urine always contains bacteria. For routine purposes it is not regarded as significant unless there are more than 105 bacteria (ml urine) -1. But many women have frequency and dysuria with smaller numbers of bacteria in urine and in some cases, perhaps, the infection has spread no further than the urethra. $ The importance of sexual activity is often assessed by comparing nuns or prostitutes with 'ordinary' women. Bacteruria is 14 times commoner in ordinary women than in nuns, and in one study, sexual intercourse was the commonest precipitating factor for dysuria and frequency in young women. On the other hand, an innocent bubble bath may facilitate spread of faecal organisms into the urethra. 44 Mires' Pathogenesis of Infectious Disease Fig. 2.11 Electron micrograph showing gonococci closely attached to the surface of a human urethral epithelial cell: 40-50 pili (P) project from the gono- coccal surface. Adherence of Neisseria gonorrhoeae to urethral mucosal cells: an electron microscope study of human gonorrhoea. (Reproduced from Ward, M. E. and Watt, P. J. (1972). J. Infect. Dis. 126, 601-604.) is partly due to the sluggish action of muscles in the bladder wall. But the bladder is more than an inert receptacle for infected urine, and responds with inflammation and secretory antibody production. The normal bladder wall, moreover, appears to have some intrinsic but poorly understood antibacterial activity. Uropathogenic strains of E. coli bind to epithelial cells lining the bladder, which respond by exfoli- ating. As a host defence this is not enough because the bacteria then invade deeper tissues. The vagina has no particular cleansing mechanism and would appear to present an ideal site for colonisation by commensal microor- ganisms. During reproductive life, however, from puberty until the menopause, the vaginal epithelium contains glycogen because of the action of circulating oestrogens. Doderlein's bacillus (a lactobacillus) colonises the vagina, metabolising the glycogen to produce lactic acid. The lactic acid gives a vaginal pH of about 5.0, and together with other 2 Attachment to and Entry of Microorganisms into the Body 45 products of metabolism inhibits colonisation by all except Doderlein's bacillus and a select number of bacteria, including various nonpyo- genic streptococci and diphtheroids. Normal vaginal secretions contain up to 10 8 bacteria m1-1. Other microorganisms are unable to establish infections, except the specialised ones that are therefore responsible for venereal diseases. Oestrogens thus generate an antimicrobial defence mechanism just at the period of life when contaminated objects are being introduced into the vagina. Before puberty and after the menopause, the vaginal epithelium lacks glycogen, the secretion is alkaline, and bacteria from the vulva, including staphylococci and streptococci, can become established. The ascent of microorganisms from vagina to uterus is blocked at the cervix because of the downward flow of mucus and the action of cilia, together with local production of lysozyme. Once the cervical barrier has been interfered with, after abortion, miscarriage, childbirth or the presence of an intrauterine contraceptive device, invasion of the uterus, fallopian tubes, etc., becomes easier. Gram-negative intestinal bacteria, group B streptococci or anaerobes are likely culprits. The cervix is less of a barrier to those expert invaders N. gonorrhoeae and C. trachomatis. Conjunctiva The conjunctiva is kept moist and healthy by the continuous flow of secretions from lachrymal and other glands. Every few seconds the lids pass over the conjunctival surface with a gentle but firm windscreen wiper action. Although the secretions (tears) contain lysozyme (see Glossary) and other antimicrobial substances such as defensins (see Glossary), their principal protective action is the mechanical washing away of foreign particles. Microorganisms alighting on the conjunctiva are treated like inanimate particles of dirt or dust and swept away via the tear ducts into the nasal cavity. Clearly there is little or no oppor- tunity for initiation of infection in the normal conjunctiva unless microorganisms have some special ability to attach to the conjunctival surface. The conjunctiva, however, suffers minor injuries whenever we get 'something in the eye', and these give opportunities for infection, as would defects in the cleansing mechanisms due to lachrymal gland or lid disease. The Chlamydia responsible for inclusion conjunctivitis and for that greatest eye infection in history, trachoma,* are masters in the art of conjunctival infection. They attach to heparan sulphate-type receptors on cell surfaces, doubtless also taking advantage of breaches in the defence mechanisms. The conjunctiva is also infected from the * World-wide 500 million people are infected, and 5 million blinded by it. 46 Mims' Pathogenesis of Infectious Disease 'inside' during the course of measles, when the virus spreads via the circulation and is somehow seeded out to conjunctival blood vessels (see p. 141). The conjunctiva is infected by mechanically deposited rather than by airborne microorganisms. Flies, fingers and towels play an impor- tant role in diseases such as trachoma, and it is significant that the types of Chlamydia trachomatis that cause urethritis (see p. 61) also often infect the eye, presumably being borne from one to the other by contaminated fingers. Certain enteroviruses (enterovirus 70, coxsackie virus A24) cause conjunctivitis, and conjunctivitis due to adenovirus 8 is one of the many diseases that can be caused by the physician (iatro- genic diseases). It is transmitted from one patient to the next by the instruments used in extracting foreign bodies from the eye. Micro- organisms present in swimming baths have a good opportunity to infect the conjunctiva, water flowing over the conjunctiva depositing microorganisms and at the same time causing slight mechanical and chemical damage. Both the Chlamydia and adenovirus 8 have been transmitted in this way. During the birth of an infant, gonococci or Chlamydia from an infected cervix can be deposited in the eye to cause severe neonatal conjunctivitis. Certain free-living protozoa (Acanthamoeba) present in soil and sometimes in water supplies, can infect the cornea to cause keratitis. This occurs in India, perhaps because of foreign bodies or other infections in the eye, and also in those wearing contact lenses. In the two preceding sections, several references have been made to Chlamydia as an important agent of occulogenital disease. Chlamydia are obligate intracellular parasites, sometimes referred to as 'energy parasites'. Not much is known about the details of the infection process in vivo but a great deal has been learnt about the biology of infection using cultured epithelial cells in vitro as model systems. Both of the two major species (Chlamydia trachomatis and C. psittaci) attach to host cells, enter by endocytosis, avoid lysosomes, and initiate their complex replication cycle, leading to development of characteristic inclusion bodies within infected cells. While there are intrinsic strain differences in ability to infect cells productively, it has now been beau- tifully demonstrated that the route of entry into cells has a profound effect on the ability of organisms to replicate. The elegant work of Pearce and colleagues in Birmingham has shown that there are two routes of entry into cells - microfilament-dependent (phagocytic) and pinocytic - for this pathogen involving, one must assume, two different receptor systems. The important point is that while the pinocytic route is a more efficient means of entry, the phagocytic route results in a ten- fold greater level of productive infection. Elementary bodies (EBs) enter and differentiate into reticulate bodies (RBs), the replicative form of the organism, which then differentiate into more infectious EBs. The replication of RBs is controlled in a highly complex manner by the availability of nutrients - energy components (ATP) and in 2 Attachment to and Entry of Microorganisms into the Body 47 particular amino acids, a point to which we shall return in Ch. 10. Owing to the lack of a genetic transfer system for Chlamydia, the rate of progress in identifying the molecular components which mediate and regulate these complex processes has been vastly slower compared to the study of other bacterial systems. However, a protein has now been identified which, in a manner yet to be fully understood, plays an important role in the early stages of infection. It is a lipoprotein which has sufficient partial sequence homology and several important prop- erties in common with the macrophage infectivity potentiator (Mip) protein of Legionella pneumophila (a peptidyl-prolyl cis/trans isomerase, described in Ch. 4) to warrant its designation, chlamydial- like Mip. The Normal Microbial Flora The commensal microorganisms that live in association with the body surfaces of man have repeatedly been referred to in this chapter. It has been calculated that the normal individual houses about 1012 bacteria on the skin, 101~ in the mouth and nearly 1014 in the alimentary canal. For comparison there are about 1013 cells in the body. Most of these are highly specialised bacteria,* utilising available foods, often with mech- anisms for attachment to body surfaces, and looking very much as if they have an evolutionary adaptation to a specific host. Is the normal microbial flora of any value? There is no doubt that intestinal microorganisms play a vital role in the nutrition of many herbivorous animals. The caecum of the rabbit and the rumen of the cow were referred to on p. 30. The most important beneficial effect in man is probably the tendency of the normal micro- bial flora to exclude other microorganisms. Intestinal bacteria such as E. coli, for instance, fail to establish themselves in the normal mouth and throat, and disturbances in the normal flora induced by long * The specialised secretion of the genital mucosa of both sexes (smegma), has its own resident bacterium, Mycobacterium smegma, which often contaminates urine. Skin resi- dents include certain yeasts, Pityrosporum ovale and Pityrosporum orbiculare. Pityrosporon ovale appears to be responsible for that widespread but humble human condition, dandruff. It is a good parasite, present on most male scalps, feeding on dead skin scales with minimal inconvenience to the host. Fascinating mites (Demodex follicu- lorum and brevis) reside unobtrusively in hair follicles or sebaceous glands, feeding on epithelial cells and on sebum. These mites are present in all human beings, and their spectacular success as parasites is reflected by a healthy person's astonishment when shown an adult mite attached to the base of his plucked eyelash. Other mites of the same genus parasitise horses, cattle, dogs, squirrels, etc. 48 Mims" Pathogenesis of Infectious Disease courses of broad-spectrum antibiotics may permit the overgrowth of Candida albicans in the mouth or staphylococci in the intestine. In one unusual experiment none of 14 volunteers given 1000 Salmonella typhi by mouth developed disease (see also p. 25), but one of four did so when the antibiotic streptomycin was given at the same time. Streptomycin probably promoted infection by its bacteriostatic action on commensal intestinal microorganisms. It is known that other Salmonella infections of the intestine persist for longer when antibi- otics are given. The composition of the intestinal flora in man is complex, with several hundred different species recovered from the colon, but there are only a small number of predominant types of bacteria and these are mostly anaerobic. The picture is greatly influenced by diet; for instance, Sarcina ventriculi, an intestinal bacterium, is virtually confined to vegetarians, in whom it is present in large numbers. Because of their numbers, the intestinal bacteria have considerable metabolic potential (said to be equal to that of the liver) and products of metabolism can be absorbed. For instance, intestinal bacteria are important in the degradation of bile acids, and glycosides such as cascara or senna taken orally are converted by bacteria into active forms (aglycones) with pharmacological activity. Metabolic products occasionally cause trouble. Substances like ammonia are normally absorbed into the portal circulation and dealt with by the liver, but when this organ is badly damaged (severe hepatitis) they are able to enter the general circulation and contribute to hepatic coma. Adult Bantus, Australian aborigines, Chinese, etc. differ from Anglo-Saxons in that the small intestinal mucosa fails to produce the enzyme lactase. This is presumably related to the fact that these people do not normally drink milk as adults. If lactose is ingested, it is metabolised by the bacteria of the caecum and colon, with the production of fatty acids, carbon dioxide, hydrogen, etc., giving rise to flatulence and diar- rhoea. The resident bacteria are highly adapted to the commensal life, and under normal circumstances cause minimal damage. They are present throughout life, and avoid inducing the inflammatory or immune responses that might expel them. In the normal individual, the only other microorganisms that can establish themselves are by definition 'infectious'. These sometimes cause disease and are eventually elimi- nated. In other words, if it is inevitable that the body surfaces are colonised by microorganisms, it can be regarded as an advantage that colonisation should be by specialised nonpathogenic commensals. Human infants like other infants are born germ-free, and the microbial colonisation of skin, throat, intestine, etc. during and after birth forms a fascinating story. The traditional way to obtain evidence about the function of some- thing is to see what happens when it is removed. There have been many studies on germ-free animals, including mice, rats, cats, dogs 2 Attachment to and Entry of Microorganisms into the Body 49 and monkeys. The mother is anaesthetised shortly before delivery, and infants are delivered by caesarean section into a germ-free envi- ronment or 'isolator' and supplied with sterile air, food and water. Germ-free individuals, not unexpectedly, have a less well-developed immune system, because of the absence of microorganisms. Antigens are present in food, but the intestinal wall is thinner, and immunoglobulin synthesis occurs at about 1/50th of the rate seen in ordinary individuals. Germ-free animals that are coprophagous (rabbits, mice) also show a great enlargement of the caecum, which may constitute a quarter of the total body weight. It can cause death when it undergoes torsion. The caecum rapidly diminishes to normal size when bacteria are fed to the germ-free individual. Otherwise, the germ-free individual seems better off and generally has a longer life span. Even caries is not seen, because this requires bacteria (see pp. 39-42). At one time it was a fashionable belief that the normal intestinal microorganisms produced 'toxins' that were harmful, and large segments of colon were removed from patients with diseases attributed to the action of these toxins. Toxins, especially endotoxin, are indeed absorbed from the intestine, but under normal circumstances this is not now thought to have harmful effects. On the other hand, there have been suggestions that carcinogenic substances, formed from the cholic acid in bile by intestinal bacteria, are important in cancer of the intes- tine, especially when the bowel contents move slowly (e.g. on low-fibre diets) and carcinogens have longer encounters with epithelial cells. Also, bacterial overgrowth in the stomach results in increased produc- tion of nitrites which can combine with amines to form carcinogenic nitrosamines. It must be remembered that pathogenic as well as commensal microorganisms are absent from the germ-free animal, and in experi- mental animals it is possible to eliminate only the specific microbial pathogens, leaving the normal flora intact. This can be done by obtaining animals (mice, pigs, etc.) by caesarean section and rearing them without contact with others of the same species, but not in a germ-free environment. Alternatively germ-free animals can be selec- tively contaminated with commensal microorganisms. These specific pathogen-free (SPF) animals have increased body weight, longer life span and more successful reproductive performance, with more litters, larger litters and reduced infant mortality. Furthermore, it has long been known that chickens, pigs, etc. grow larger when they receive broad-spectrum antibiotics in their food, presumably because certain unidentified microorganisms are eliminated. But even if we were to conclude that the normal microbial flora, as opposed to the pathogens, on the whole does more harm than good, this conclusion, although of great interest, would have little practical significance. Colonisation by commensal microorganisms is the unavoidable fate of all normal indi- viduals, and the germ-free life will remain an impossibly artificial 50 Mires' Pathogenesis of Infectious Disease condition; expensive, technically demanding and psychologically crip- pling for an intelligent animal.* The elimination of specific pathogenic microorganisms, however, is a less theoretical matter. Specific pathogen-free mice are routinely main- tained in laboratories and are much superior to non-SPF animals, as mentioned above. The population of the developed countries of the world (USA, Canada, northern Europe) can be likened to SPF mice, most of the serious microbial pathogens having been eliminated by vaccines, quarantine and other public health measures, or kept in check by good medical care and antibiotics. The peoples of the devel- oping countries of the world, on the other hand, are comparable to the conventionally reared, non-SPF mice, who are exposed to all the usual murine pathogens. The comparison is complicated by the often inade- quate diet of those in the developing world. A World Health Organisation (WHO) survey of 23 countries showed that in developing countries the common pathogenic infections such as diphtheria, whooping cough, measles and typhoid have respectively 100, 300, 55 and 160 times the case mortality seen in developed countries. Compared with those in the developed countries those in the devel- oping countries often tend to be smaller, with a shorter life span, and poorer reproductive performance (abortions, neonatal and infantile mortality). They are the non-SPF people. Opportunistic infection There is one important consequence of the existence of the normal microbial flora. These microorganisms are present as harmless commensals, and are normally well behaved. If, in a given individual, this balance is upset by a decrease in the normal level of resistance, then the commensal bacteria are generally the first to take advantage of it. Thus damage to the respiratory tract upsets the balance and enables normally harmless resident bacteria to grow and cause sinusitis or pneumonia. Minor wounds in the skin enable skin staphy- lococci to establish small septic foci, and skin sepsis is particularly common in poorly controlled diabetes. This is probably due to defective chemotaxis and phagocytosis in polymorphs, which show impaired energy metabolism. High concentrations of blood sugar and the pres- ence of ketone bodies may play a part, but a more direct effect of diabetes is suggested by the observation that adding insulin to diabetic * A boy who developed aplastic anaemia when 9 years old was maintained in a 2.5 m x 2.7 m germ-free type isolator, shielded from contact with the microbial hazards of the outside world. Life was not easy, although he felt less abnormal when he was able to wear his protective astronaut-type suit at a science fiction convention. He was spared from infection and died at the age of 17 years, from complications of repeated blood transfusions. 2 Attachment to and Entry of Microorganisms into the Body 51 polymorphs in vitro rapidly restores their bactericidal properties. Commensal faecal bacteria infect the urinary tract when introduced by catheters, and commensal streptococci entering the blood from the mouth can cause endocarditis if there are abnormalities in the heart valves or endocardium. The tendency of commensal bacteria to take opportunities when they arise and invade the host is universal. These infections are therefore called opportunistic infections. Opportunistic infections are common nowadays. This is partly because many specific microbial pathogens have been eliminated, leaving the opportunistic infections relatively more numerous than they were. Also, modern medical care keeps alive many people who have impaired resistance to microbial infections. This includes those with congenital immunological or other deficiencies, those with lymphoreticular neoplasms, and a great many patients in intensive care units or in the terminal stages of various illnesses. Modern medical treatment also often requires that host immune defences are suppressed, as after organ transplants or in the treatment of neoplastic and other conditions with immunosuppressive drugs. Mso, certain virus infections (e.g. cat leukaemia, MDS in man) can cause a catastrophic depression of immune responses (see Ch. 7). In each case opportunistic microorganisms tend to give trouble. There are other opportunistic pathogens in addition to the regular commensal bacteria. Candida albicans, a common commensal, readily causes troublesome oropharyngeal or genital ulceration. Pseudomonas aeruginosa is essentially a free-living species of bacteria, sometimes present in the intestinal tract. In hospitals it is now a major source of opportunistic infection. This is because it is resistant to many of the standard antibiotics and disinfectants, because its growth require- ments are very simple, and because it is so widely present in the hospital environment. It multiplies in eyedrops, weak disinfectants, corks, in the small reservoirs of water round taps and sinks, and even in vases of flowers. Pseudomonas aeruginosa causes infection espe- cially of burns, wounds, ulcers, and the urinary tract after instrumen- tation.* It is a common cause of respiratory illness in patients with cystic fibrosis.t When resistance is very low, it can spread systemati- cally through the body, and nowadays this is a frequent harbinger of * Pseudomonas demonstrated its versatility by causing a profuse rash in users of a hotel jacuzzi (whirlpool). The bacteria multiplied in the hot, recirculated, inadequately treated water, and probably entered the skin via the orifices of dilated hair follicles. t Cystic fibrosis, the most common fatal hereditary disease in Caucasians (about I in 20 carry the gene), involves defects in mucus-producing cells. The lung with its viscid mucus becomes infected with Staphylococcus aureus and Haemophilus influenzae, but the presence of Pseudomonas aeruginosa is especially ominous. Pseudomonas strains from cystic fibrosis patients often produce a jelly-like alginate rather than the regular 'slimy' type of polysaccharide (see Table 4.1), and this may physically interfere with the action of phagocytes. Lung damage is largely due to the action of bacterial and phago- cytic proteases. 52 Mims' Pathogenesis of Infectious Disease immunological collapse. Viruses also act as opportunistic pathogens. Most people are persistently infected with cytomegalovirus, herpes simplex virus, varicella zoster virus, etc. (see Ch. 10), and these commonly cause disease in immunologically depressed individuals. Cytomegalovirus, for instance, is activated within the first 6 months after most renal transplant operations, as detected by a rise in anti- body titre, and may cause hepatitis and pneumonia. The fungal para- site Pneumocystis carinii is an extremely common human resident, normally of almost zero pathogenicity, but can contribute to pneu- monia in immunosuppressed individuals. Clostridium difficile is another example of an opportunistic pathogen which causes a spec- trum of disease (ranging from antibiotic-associated diarrhoea to fatal pseudomembranous colitis) sometimes after a course of antibiotics. Resident spores do not normally germinate in the presence of a normal microflora; antibiotic-induced imbalance in the latter creates the conditions for rapid vegetative growth of C. difficile and release of toxins (see Ch. 8). Exit of Microorganisms from the Body After an account of the entry of microorganisms into the body, it seems appropriate to mention their exit. General principles were discussed in the first chapter. Nearly all microorganisms are shed from the body surfaces (Fig. 2.1). The transmissibility of a microorganism from one host to another depends to some extent on the degree of shedding, on its stability, and also on its infectiousness, or the dose required to initiate infection (see Table 11.1). For instance, when ten bacteria are enough to cause oral infection (Shigella dysenteriae), the disease will tend to spread from person to person more readily than when 10 6 bacteria are required (salmonellosis). The properties that give increased transmissibility are not the same as those causing patho- genicity. There are strains of influenza virus that are virulent for mice, but which are transmitted rather ineffectively to other mice, transmis- sibility behaving as a separate genetic attribute of the virus. For other microorganisms also, such as staphylococci and streptococci, transmis- sibility may vary independently of pathogenicity. Types of transmis- sion are illustrated in Fig. 2.12. Respiratory tract In infections transmitted by the respiratory route, shedding depends on the production of airborne particles (aerosols) containing microor- ganisms. These are produced to some extent in the larynx, mouth and [...]... 48, 81 1-8 18 Mackowiak, P A (19 82) The normal microbial flora N Engl J Med 307, 83 Mims, C.A (1981) Vertical transmission of viruses Microbiol Rev 45, 26 7 -2 86 Mims, C A (1995) The transmission of infection Rev Med Microbiol 6, 22 1 7 -2 22 7 Nataro, J P and Kaper, J B (1998) Diarrheagenic Escherichia coli Clin Microbiol Rev 11,14 2- 2 01 Newhouse, M et al (1976) Lung defense mechanisms N Engl J Med 29 5, 990,... 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J R (1999) Cell adhesion molecules in the pathogenesis of and host defence against microbial infection J Clin Pathol Mol Pathol 52, 22 0 -2 3O Ketley, J M (1997) Pathogenesis of enteric infection by Campylobacter Microbiology 143, 5 -2 1 Lentz, T L (1990) The recognition event between virus and host cell receptor: a target for antiviral agents J Gen Virol 71,75 1-7 66 Lodge, J M., Bolton, A J., Martin, G... tests of the syringe and plunger type Chlamydia 2 61 Attachment to and Entry of Microorganisms into the Body T a b l e 2. 3 Principal sexually transmitted diseases in man Microorganism Viruses Disease Herpes simplex Genital herpes type 2 Human Genital warts papillomavirus HIV- lb Hepatitis B Chlamydia MDS Hepatitis C trachomatis (types D-K) a Comments Very c o m m o n - reactivates Very c o m m o n - involvement... enzymes of humans 57 58 Mims' Pathogenesis of Infectious Disease faecal contamination of the e n v i r o n m e n t and spread to other individuals In animal communities and in primitive h u m a n communities, there is a large-scale recycling of faecal m a t e r i a l back into the mouth C o n t a m i n a t i o n of food, w a t e r and living areas ensure t h a t this is so, and the efficiency of this... cows and sheep, leading to gangrenous mastitis (black udder) 77 Mires' Pathogenesis of Infectious Disease 78 (see pp 7 7-7 8) and serum amyloid protein, which undergo 1000-fold increases in concentration, as well as mannose-binding protein, haptoglobulins (a2-glycoproteins), protease-inhibitors, and fibrinogen The exact function of these acute phase proteins is not clear, but they are protective; they... terminal ileum in vitro J Med Microbiol 48, 80 0-8 10 Bolton, A J., Osborne, M P and Stephen, J (20 00) Comparative study of invasiveness of Salmonella serotypes Typhimurium, Choleraesuis and Dublin for Caco -2 cells, HEp -2 cells and rabbit ileal epithelia J Med Microbiol 49, 50 3-5 11 Bolton, A J., Osborne, M P., Wallis, T S and Stephen, J (1999) Interaction of Salmonella choleraesuis, Salmonella dublin... Microbiology 145, 24 3 1 -2 441 Buckley, R M et al (1978) Urine bacterial counts after sexual intercourse N Engl J Med 29 8, 32 1-3 23 Curtiss, R III, MacLeod, D L., Lockman, H A., Galan, J E., Kelly S M and Mahairas, G G (1993) Colonization and invasion of the intestinal tract by Salmonella In 'The Biology of Salmonella' (F C Cabello, C E Hormaeche, P Mastroeni and L Bonina, eds), pp 19 1-1 98 Plenum Press, . the base of his plucked eyelash. Other mites of the same genus parasitise horses, cattle, dogs, squirrels, etc. 48 Mims& quot; Pathogenesis of Infectious Disease courses of broad-spectrum. interfere with the action of phagocytes. Lung damage is largely due to the action of bacterial and phago- cytic proteases. 52 Mims& apos; Pathogenesis of Infectious Disease immunological collapse CH4. This is particularly prominent after inges- tion of beans, which have a polysaccharide not handled by digestive enzymes of humans. 58 Mims& apos; Pathogenesis of Infectious Disease faecal