16 Parasite survival strategies and persistent infections
So far, we have concentrated on the battery of mechanisms available to the host, both natural and adaptive, to keep out and destroy the parasite. Powerful as these are, they are obviously not 100% effective; otherwise healthy people would never have infections. In fact, most of the common infectious organisms described in this book have developed ‘answers’ to host defences because their ability to survive as human parasites has depended upon this. They successfully infect humans and are of concern to the physician precisely because they have developed strategies for evading or actively interfering with host defences.
• Killing or avoiding being killed by phagocytes. Successful parasites have evolved numerous ingenious antiphagocytic devices. Antiphagocytic devices (Fig. 16.1) range from killing or inhibiting the phagocyte itself, via more subtle ways of eluding contact, to protection against intracellular death allowing the microorganism to survive within the phagocyte – a very serious challenge to the host.
• Interfering with the activation of complement. Microorganisms can acquire or mimic complement regulators, actively inhibit complement components, or enzymatically destroy complement components. A variety of microbes can bind complement regulators, including E. coli, streptococci and Candida albicans. The smallpox and vaccinia viruses produce proteins that mimic host complement regulators. Staph. aureus, streptococci, herpes simplex virus, Schistosoma and Trypanosoma express complement inhibitors. Proteases that destroy complement components are produced by Pseudomonas, Serratia marcescans and Schistosoma mansoni. Other strategies are to physically block complement lysis – the insertion of the C567 complex is prevented by the long side chains of the cell wall polysaccharides of smooth strains of Salmonellae and by the capsules of staphylococci, which do not activate complement, and the cell wall of Gram-positive bacteria prevents lysis by the complement membrane attack complex (Fig. 16.2). However, some pathogens take the opposite approach, choosing to enter host cells by exploiting opsonization with complement components – HIV-1 and Mycobacterium tuberculosis exploit the CR3 receptor in this way.
• Producing iron-binding molecules. Nearly all bacteria need iron, but the host’s iron-binding proteins such as transferrin limit the availability of this element. Accordingly, certain bacteria (e.g. Neisseria) produce their own powerful iron-binding proteins to circumvent the shortage
• Blocking interferons. Host cells respond to double-stranded DNA (dsRNA) from infecting microbes (including all viruses), by forming interferons alpha and beta. These are produced rapidly, within 24–h, after infection and are part of the non-adaptive response. Certain viruses are either poor inducers of interferons (hepatitis B) or produce molecules that block the action of interferons in cells (hepatitis B, HIV, adenoviruses, Epstein–Barr virus, vaccinia virus). Interferon gamma (IFNγ), an essential part of the adaptive response, is also affected.
Figure 16.2 Bacteria avoid complement-mediated damage by a variety of strategies. (1) An outer capsule or coat prevents complement activation. (2) An outer surface can be configured so that complement receptors on phagocytes cannot obtain access to fixed C3b. (3) Surface structures can be expressed that divert attachment of the lytic complex (MAC) from the cell membrane. (4) Membrane-bound enzyme can degrade fixed complement or cause it to be shed. (5) Complement inhibitors can be captured onto the surface. (6) Direct inhibition of the C3 and C5 convertases blocks complement activation.
(Panels 1–4 reproduced from: Male, D., Brostoff, J., Roth, D.B., Roitt, I. (2006) Immunology. Mosby Elsevier, with permission.)
The success of microbes in evading or interfering with adaptive (immune) defences is discussed in this chapter. The strategies involved are more sophisticated than those for evading innate defences, because lymphocytes are programmed so that their cell receptors can recognize virtually any shape (B cells) or amino acid sequence (T cells), provided it is not identical to self. For example:
• The polysaccharide capsules of bacteria prevent non-immune contact between phagocytes and the bacterial cell wall, but are quickly recognized as foreign by B-cell surface receptors (immunoglobulin), leading to the formation of antibody with consequent opsonization and phagocytosis of the bacteria
• Many microorganisms such as bacteria and fungi can resist intracellular destruction by macrophages, but their peptides are presented in association with major histocompatibility complex (MHC) molecules on the macrophage surface, and their presence is detected by T cells. A new set of cytotoxic and other immune mechanisms is then brought into action.
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.
• 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.
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:
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
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).
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:
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).
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.
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.
(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.
|Microbe’s strategy||Parasite||Corresponding host antigen|
|Mimicry||Epstein–Barr virus||Human fetal thymusa|
|Streptococci||Cardiac muscle (meromyosin)|
|Mycobacterium tuberculosis||65 kDa heat shock protein|
|Neisseria meningitidis||Embryonic brain, vitronectin|
|Trypanosoma cruzi||Heart myosin, nerve|
|Antigen uptake||Neisseria meningitides||Vitronectin|
|Schistosoma||Glycolipids, HLA I, HLA II|
|Ascaris||Blood group antigens|
d The homologous malaria protein thrombospondin-related anonymous protein (TRAP) shares sequence with the circumsporozoite protein that mediates binding to hepatocytes. HLA, human leukocyte antigen; Ig, immunoglobulin.
Figure 16.6 Molecular mimicry by the microbe can induce host cell damage, for example rheumatic heart disease following streptococcal infection is caused by antibodies reacting with meromyosin, the cross-reacting determinant.