Parasite survival strategies can take as many forms as there are parasites, but they can be usefully classified according to the immune component that is evaded and the means selected to do this (see Ch. 12). As a result, the microbe is able to undergo what are often quite lengthy periods of growth and spread during the incubation period before being shed and transmitted to the next host, as occurs in hepatitis B and tuberculosis. Shedding of the microbe for just a few extra days after clinical recovery gives more extensive transmission in the community, and this is a worthwhile result for the microbe.

Viruses are particularly good at thwarting immune defences

Viruses are able to thwart immune defences for a number of reasons:

• Their invasion of tissues and cells is often ‘silent’. Unlike most bacteria, they do not form toxins, and as long as they do not cause extensive cell destruction there is no sign of illness until the onset of immune and inflammatory responses, sometimes several weeks after infection, as occurs in hepatitis B virus and EBV infections.

• Viruses such as rubella virus, wart viruses, hepatitis B virus and EBV can infect cells for long periods without adverse effects on cell viability.

Some microbes are able to persist in the host

Certain microbes are able to remain (persist) in the host for many years, often for life. From the microbe’s point of view, persistence is worthwhile only if shedding occurs during the persistence. Persistent microbes fall into two categories:

• those that are shed more or less continuously, such as the Epstein–Barr virus (EBV) into saliva, hepatitis B virus into blood, and eggs into faeces in various helminth infections

• those that are shed intermittently, such as herpes simplex virus (HSV), polyomaviruses, typhoid bacilli, tubercle bacilli and malaria parasites.

Virus latency is a type of persistence and is based on an intimate molecular relationship with the infected cell. The viral genome continues to be present in the host without producing antigens or infectious material, and only does so very occasionally, when the virus reactivates (becomes patent) (Box 16.1).

Box 16.1 Lessons in Microbiology

Trail of illness from a slippery cook

In 1901, Mary Mallon, from Long Island, New York, took a job as cook with a family in New York City. Soon afterwards, the family washerwoman and a visitor to the house became ill with enteric fever (typhoid). Mary moved to another job and a few weeks later all seven family members plus two of the servants went down with enteric fever. Similar infections followed her movements as a cook and in 1906 the authorities tried to dissuade her from such work. She was indignant at the suggestion that she was carrying a dangerous germ, knowing that she was healthy, and failed to keep promises to have regular checks and give up work. She was suspicious of officials and aggressive, on one occasion advancing towards the questioner brandishing a carving knife. She was later arrested and put in an isolation hospital. After appealing to the US Supreme Court, she was released in 1910 with promises not to work as a cook. Then in 1914 typhoid epidemics broke out in a hospital and in a sanatorium where she had worked as a cook. She was traced, living under a false name, and in the interests of public safety, she was detained permanently on North Brother Island, where she died in 1938. In her cooking career she had been responsible for about 200 cases of typhoid in eight different families and had started seven epidemics of the disease. Her favourite recipe, an iced peaches dessert, may have been a good source of infection.

Mary had recovered fully from an attack of typhoid earlier in life, but she had gallstones and this enabled the bacteria to persist in her gallbladder for many years, appearing intermittently in the faeces. About 5% of cases become carriers, either in gallbladder or urinary bladder, and they play a central role as foci of infection. Nowadays, Mary would have to have acquired her original infection in a region such as the Indian subcontinent where typhoid is endemic. Each year, there are up to 22 million typhoid cases worldwide, 300 of which are in the USA, most being travellers to the Indian subcontinent (see also Ch. 22).

Strategies for evading host defences cause a rapid ‘hit-and-run’ infection

One evasion strategy for microorganisms is to cause a rapid ‘hit-and-run’ infection. The microbe invades, multiplies and is shed within a few days, before adaptive immune defences have had time to come into action. Infections of the body surfaces (rhinoviruses, rotaviruses) come into this category. Otherwise, the principal strategies employed by parasites to elude the lymphocyte (as discussed in the following pages) are:

• concealment of antigens

• antigenic variation

• immunosuppression.

Concealment of antigens

A spy in a foreign country can conceal his presence from the police by hiding, by never venturing out of doors, or by adopting the disguise of a native. Parasites have the same choices. Places to hide include the interior of host cells (though the MHC molecules act as ‘informers’ for this compartment, picking up and transporting microbial peptides to the cell surface where they will be recognized) and particular sites in the body where lymphocytes do not normally circulate (‘privileged sites’, the equivalent of ‘no-go’ areas).

Remaining inside cells without their antigens being displayed on the surface prevents recognition

If a microbe can remain inside cells without allowing its antigens to be displayed on the cell surface, it will remain unrecognized (‘incognito’) as far as immune defences are concerned. Even if specific antibody and T-cell responses have been induced, the microbe inside such a cell is unaffected. Persistent latent viruses such as HSV in sensory neurones behave in this way. During reactivation, of course, re-exposure and boosting of immune defences is inevitable.

Other strategies are possible. Several viruses (HIV in macrophages, coronaviruses) display their proteins ‘secretly’ on the walls of intracellular vacuoles instead of at the cell surface, and bud into these vacuoles. Adenoviruses have taken more active steps to avoid antigen display. One of the adenoviral proteins (E19) combines with class I MHC molecules and prevents their passage to the cell surface so that infected cells are not recognized by cytotoxic T cells.

Colonizing privileged sites keeps the microbe out of reach of circulating lymphocytes

The vast numbers of microbes that colonize the skin and the intestinal lumen, together with those that are shed directly into external secretions, are effectively out of reach of circulating lymphocytes. They are exposed to secretory antibodies, which although able to bind to the microbe (e.g. influenza virus) and render it less infectious, are generally unable to kill the microbe or control its replication in or on the epithelial surface (Figs 16.3, 16.4). A local inflammatory response, however, can enhance host defences.

Figure 16.3 Viral infection of cell surfaces facing the external world. Infection of the surface epithelium of, for instance, a secretory or excretory gland allows direct shedding of the virus to the exterior, as well as avoidance of host immune defences.

Figure 16.4 Wart virus replication in epidermis – a privileged site? Cell differentiation such as keratinization controls virus replication, and as a result virus matures when it is physically removed from immune defences.

Within the body, it is more difficult to avoid lymphocytes and antibodies, but certain sites are safer than others. These include the central nervous system, joints, testes and placenta. Here, lymphocyte circulation is less intense, and access of antibodies and complement is more restricted. However, as soon as inflammatory responses are induced, then lymphocytes, monocytes and antibodies are rapidly delivered and the site loses its privilege.

Additional privileged sites can be created by the infectious organism itself. A good example is the hydatid cyst that develops in liver, lung or brain around growing colonies of the tapeworm Echinococcus granulosus (Fig. 16.5), inside which the worms can survive even though the blood of the host contains protective levels of antibody.

Figure 16.5 Hydatid cysts. Multiple, thin-walled, fluid-filled cysts in a surgical specimen. The lung is a common site. Growing within a cyst is a survival strategy for Echinococcus granulosus.

(Courtesy of J.A. Innes.)

Perhaps the most highly privileged site of all is host DNA, and this is occupied by the retroviruses. Retroviral RNA is transcribed by the reverse transcriptase into DNA as a necessary part of the replicative cycle, and this then becomes integrated into the DNA of the host cell (see Ch. 21). Once integrated, and as long as there is no cell damage and viral products are not expressed on the cell surface where they can be recognized by immune defences, the virus enjoys total anonymity. This is what makes complete cure and complete removal of virus from a patient infected with HIV such a daunting task. The intragenomic site becomes even more privileged if the egg or sperm is infected. The viral genome will then be present in all embryonic cells and transferred from one generation to another as if it were the host’s own DNA. Luckily, this does not happen with HIV or with human T-cell lymphotropic virus (HTLV) 1 and 2. However, the ‘endogenous’ retroviruses of humans present in profusion as DNA sequences in our genome, but not expressed as antigens, come into this category. They are part of our inheritance. This surely represents the ultimate, the final logical step in parasitism, at the borderline between infection and heredity.

Mimicry sounds like a useful strategy, but does not prevent the host from making an antimicrobial response

If the microbe can in some way avoid inducing an immune response, this can be regarded as a ‘concealment’ of its antigens. One method is by mimicking host antigens, as such self antigens are not recognized as foreign. Numerous examples are known of parasite-derived molecules that resemble those of the host (Table 16.1). In the case of viral proteins, mimicry based on amino acid sequence homology (sharing of 8–10 consecutive amino acids) is seen to be common when computer comparisons are made between viral and host proteins. Perhaps the most celebrated example, however, is the cross-reaction between group A beta-haemolytic streptococci and human myocardium. This cross-reaction underlies the development of rheumatic heart disease, following repeated streptococcal infection because of antibody made against the cross-reacting determinant meromyosin (Fig. 16.6). The fact that the host makes such autoantibodies shows that in this case mimicry does not protect the bacteria. The conclusion is that, although mimicry sounds like a useful strategy for microbes and occurs quite frequently, it is probably an accident rather than a sinister microbial strategy. It does not prevent the host from making an antimicrobial and autoimmune response.

Table 16.1 Some examples of mimicry or uptake of host antigens by parasites

Microbe’s strategy	Parasite	Corresponding host antigen
Mimicry	Epstein–Barr virus	Human fetal thymus^a
	Streptococci	Cardiac muscle (meromyosin)
	Mycobacterium tuberculosis	65 kDa heat shock protein
	Neisseria meningitidis	Embryonic brain, vitronectin
	Treponema	Cardiolipin^b
	Mycoplasma pneumoniae	Erythrocytes^c
	Plasmodium falciparum	Spondin^d
	Trypanosoma cruzi	Heart myosin, nerve
	Schistosoma	Glutathione transferase
Antigen uptake	Neisseria meningitides	Vitronectin
	Haemophilus influenzae	Vitronectin
	Cytomegalovirus	β₂-microglobulin
	Schistosoma	Glycolipids, HLA I, HLA II
	Filarial nematodes	Albumin
	Ascaris	Blood group antigens