Brooke Rough Draft

Immunology of Parasites

Parasites’ survival depends on their ability to invade and establish themselves in a suitable host. Without the environment of a host, parasites are unable to grow, multiply, and live. This battle for survival by parasites is no easy fight. They are constantly faced with brutal host immune systems consisting of both innate and adaptive immune responses. Parasites’ flexibility and co-evolution with host immune systems has largely contributed to their continued existence. Over the years parasites have become equipped with a variety of mechanisms they are able to employ towards evading host immune
responses. This paper highlights a few of these invasion and evasion mechanisms, discusses the host-pathogen evolutionary battle, and illustrates the clinical importance of the issues.

Parasitism Defined

Parasitism is defined by as a type of symbiotic relationship between organisms of different species in which one, the parasite, benefits from a prolonged, close association with the other, the host, which is harmed (1). Parasites can be described according to their lifestyles. Those that live inside their hosts are termed endoparasites, such as the hookworm, which lives in the intestines of its mammalian hosts. Those that live on their host’s outer surface are termed ectoparasites, such as the tick. Obligatory parasites are unable to survive without a host, while facultative parasites can exist independently of their hosts. No matter the type, parasites have a remarkable ability to adapt to the environment found inside a host whose immune system aims to kill them (1).

Life cycles and Initial Invasion

The first step of the parasite’s battle for host resources is to enter a suitable host. However, most parasites are restricted in their ability to choose their battles, that is, to choose the host they will invade. Instead, host selection is usually by chance as most parasites have limited mobility and dependent lifestyles. Though they are unable to choose their battles, parasites’ characteristic life cycles and modes of transmission have enabled them to survive among a variety of host species they encounter.

Modes of transmission are related to parasites’ life cycles, and there are a variety of life cycles. If the parasite’s life cycle requires only one host species then it is considered a direct cycle. A parasite that requires multiple hosts to complete its life cycle is considered to have a complex life cycle (1). The hookworm Necator americanus is an example of a parasite with a direct life cycle. The adult hookworm lives in the intestine and lays eggs. The eggs are passed in the stool, where they can re-infect the same host or hosts of the same species that come into contact with them. In this way, the hookworm can progress from immature, to its mature and reproductive form all using only one host. The heartworm, Dirofilaria immitis, in contrast has a complex life cycle. The adult form thrives in dogs or cats. It lays its larvae that are taken up by the mosquito. The mosquito serves as an intermediate host for the immature heartworm to develop into a mature adult, and acts as a vector, transporting it to other cats and dogs. In this way the hookworm relies on multiple hosts to complete its life cycle. Polyhostal parasites and parasites with more complex life styles increase their chance for survival by having more genetic variability than monohostal parasites and parasites with direct life cycles (2,3).

Stages of form change throughout the parasite’s life cycle promote the parasite’s survival through different protective mechanisms. One class, the amoebae exist in two stages throughout their life cycle. Acanthamoeba polyphaga, is one such amoeba. It is commonly found in soil, and can enter the central nervous system through skin tears in humans to cause encephalitis (26, 27). The trophozoite stage is one in which the parasite moves, obtains food, and multiplies in the intestine of its host. When conditions in the host become unacceptable, the trophozoite goes through a process of encystation. In the cyst stage, the amoeba has a protective cell wall that allows them to withstand previously intolerable conditions. They can leave the intestine through feces and survive for months outside the host. Upon reentry through ingestion, the cyst’s cell wall protects them from the harsh gastric secretions of the stomach. Once in the more tolerable environment of the intestines, they reenter their multiplying trophozoite stage (1).

The helminthes are another class of parasites with a different kind of life cycle. Nematodes, cestodes, and tremetodes are types of helminthes and they can exist in three forms: eggs, larva, and adult worms. Like the cysts of amoebae, the eggs of helminthes can survive for multiple weeks in the environment until contact with a host (1).

Hemoflagellates are a class of parasites with a four stage life cycle and dependence on an arthropod vector. The four forms are amastigote, promastigote, epimastigote, and trypomastigote. Transformation throughout the four stages is necessary for the parasites’ survival, as each stage allows variable expression of different genes necessary for establishment in the host. For example, Leishmania species are hemoflagellates able to survive and multiply within macrophages (4). As users of an arthropod vector, their transmission depends not only on their ability to avoid the immune response of the vertebrate hosts they infect, but also the responses of their vector.

Transformation throughout their four stages facilitates this survival in both the vector and vertebrate host. While in the sandlfy vector, Leishmania parasites transform from amastigotes into procyclic promastigotes. This transformation allows them to express lipophosphoglycan (LPG)—which helps them attach to the gut epithelium, and metallopreatease gp63—which is thought to serve protection them from destructive gut enzymes (4).

Following attachment, the procyclic promastigotes can further transform into infective non-dividing metacyclic promastigotes. The metacyclics complete a process of LPG elongation that results in a thickened glycocalyx and allows them to avoid destruction by host complement systems and the membrane attack complex (5,6).

As the metacyclic transformation takes place, gp63 surface expression is increased. This ultimately encourages opsonisation of the blood parasites by macrophage receptors CR1 and CR3, enabling the parasite to enter the host macrophage through phagocytosis. Once in the macrophage, they will rely on other mechanisms to prevent killing by the host immune system. Though this is the main route Leishmania species use to infect host macrophages, they have been found to use a variety of other macrophage receptors as well. These receptors include the mannose-fucose receptor, CR4, the fibronectin receptor, the receptor for advance glycosylation end-products, the Fc receptor, and the C-reactive protein receptor. Using multiple receptor systems gives the parasite easier access into macrophages (4).

Similarily to Leishmania, other parasites have found the use of multiple invasion routes to be beneficial to establishment in the host. Plasmodium falciparum, which causes malaria, uses multiple pathways to gain entry into erythrocytes. The two pathways used are sialic acid-dependent (SA-dependent) or sialic acid-independent (SA-independent), and the different pathways evolved as a way to help the P. faciparum evade human antibodies (7).
During invasion, the creation of a parasitophorous vacuole is popular among many intracellular parasites. The parasitophorous vacuole is formed by layers of endoplasmic reticulum, that may serve to isolate the parasite from cell lysozymes and avoid lysing the cell during invasion (21, 22). After invasion, the parasitophorous vacuole membrane (PVM) functions as an organelle to allow the exchange of molecules between the parasitophorous vacuolar space and the host cell cytoplasm (23, 24, 25).

Host conditions can negatively or positively affect parasite invasion abilities. A malnourished host can be predisposed to parasitic infections because malnutrition may cause decreased IL-4 expression and increased IFN-gamma expression. This contributes to reduced IgE, MMC, and gut eosinophils, prolonging parasite survival in the host (8).

Further Evasion of Host Defenses

Once parasites have entered a host they must confront brutal innate, adaptive, or both types of immune responses waiting for them. They have developed multiple weapons for this. Their most commonly used and successful means of survival is through evasion, or “hiding” from the host’s immune system.

One successful way to do this is by releasing immunomodulatory molecules to counteract the host immune response, such as enzymes. Onchocerca vovulus, the world’s second leading cause of blindness, clones a gene for an extracellular superoxide dismutase (SOD). SODs are enzymes that protect cells from superoxide radicals. The cloning of this SOD enzyme allows the parasite to avoid reactive oxygen species and reactive nitrogen species method of killing by macrophages (14). In several studies, helminthes have been found to have excretory-secretory (ES) products that inhibit host macrophages proinflammatory cytokines. Specifically, the hookworm Necator americanus secretes an enzyme, a metalloprotease, that degrades eotaxin, a chemoattractant that recruits eosinophils to sites of infection (9). Eosinophils are white blood cells that combat parasitic infection by releasing granules with antimicrobial chemicals into their environment (28). By degrading the eotaxin, N. Americanus is able to “hide” from eosinophils (9). Other proteases found in the excretory-secretory products of helminthes include serine, cysteine, aspartic, and Ca+ dependent metallo-proteases (8, 10). Similarly, Acanthocheilonema viteae’s release of ES-62 inhibits macrophage production of IL-12, IL-6 and TNF-alpha, which in turn helps the parasite avoid the host immune methods of killing, such as the recruitment of natural killer cells, induction of fever, formation of the Membrane Attack Complex, and increase in vascular permeability (11). ES-62 has also been shown to reduce lymphocyte responsiveness in vitro by interfering with proinflammatory cascades (12,13).

The phosphorylation cascade, is a target for disruption by other parasites as well. The parasitophorous vacuole membrane of Toxoplasma Gondii is able to independently phosphorylate I kappa B-alpha, which is the inhibitor of NF kappa-B. NF kappa-B’s migration to the nucleus activates the transcription of inflammatory cytokines. By phosphorylating the inhibitor of NF kappa-B, the parasite manipulates the inflammatory response in its host (19, 20).

Other parasites have specific structures designed to inhibit immune cytokines. Trypanosoma cruzi, which causes Chagas’ disease in humans, displays several surface molecules on their cell surface that are important to their survival (15). Glycoinositolphospholipids (GIPLs) are one of these most abundantly expressed molecules. In several studies of macrophages and dendritic cells stimulated with GIPL and inflammatory agents, GIPLs significantly decreased TNF-alpha, IL-10, and IL-12 secretion by the antigen presenting cells. For this reason, people with Chagas’ disease may be asymptomatic for years or decades while the parasite damages their nervous system, digestive system, and heart (16).
While parasites like the ones previously mentioned avoid host immune attacks by inhibiting proinflammatory cytokines, others like Leishmania chagasi, evade recognition by activiating regulatory cytokines present in the host. In studies done in vivo, L. chagasi activated TGF-beta in its environment, downgrading the immune response. In the same study, more TGF-beta was found in bone marrow of humans acutely infected with the parasite, than in noninfected controls (17).

Coevolutionary Arms Race

These are a few of the examples of mechanisms parasites employ to survive in hosts equipped to destroy them. Like immune systems of any species, these mechanisms have not always been present, but evolved over time. As hosts acquired immune system develops defenses to kill parasites, the parasites “battle back” by evolving ways to avoid these specific defenses, and vice versa (8, 11, 17, 18). This evolutionary battle is known as the coevolutionary arms race, and it results in evolutionary change in all species involved.

Ongoing discovery of new immune cytokines provides evidence of this evolution. The ability of N. Americanus to produce a protease that degrades eotaxin was discussed earlier. Researchers also tested this protease’s ability to degrade other cytokines. Results showed that the protease was specific for eotaxin, because it was unable to degrade LTB4, IL-5, IL-8 or eotaxin-2. This specificity for eotaxin represents an example of the host-parasite battle. As the parasite was constantly faced with eotaxin and subsequent eosinophil attraction, the parasite evolved to be able to secrete the protease able to destroy eotaxin. However, the host immune systems refused to surrender. Eotaxin-2 is a chemokine that the N. Americanus’s protease is unable to destroy, indicating that eotaxin-2 was likely developed by the host as a counter method of the parasites immunosuppressive attack. Notably, while eotaxin-2 is considerably different in its amino acid sequence than eotaxin, it acts through the same signal receptor as eotaxin, therefore doing the essential same task of recruiting eosinophils to infection sites. This receptor, CCR3, happens to be used by a variety of other chemokines as well. Researchers point out that, although the reasons for this are unclear, it may be a result of evolutionary pressure put on the signal receptor by continued parasite evasion strategies (8).

Clinical Importance

Understanding the techniques used by parasites in their evolutionary battle for survival is of invaluable importance. The evasion techniques used by parasites are potential targets for drug therapy and immunizations against disease. Additionally, many parasites serve as hosts for bacteria and other microorganisms, so controlling parasitic infections would help to control other pathogenic bacterial infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is one such bacterium that is able to infect and replicate in the previously discussed amoeba parasite Acanthamoeba polyphaga. Recently, MRSA has become an increasing concern in the health-care setting due to its resistance to many antibiotics. Normally, A. polyphagia eats and digests bacteria. However, after ingesting MRSA, the MRSA is not killed, but rather it is able to survive and replicate in the amoeba. Since A. polyphagia is wide-spread in the environment and able to form cysts, cysts infected with MRSA can be transmitted through both airborne and direct contact routes, and they are able to live on surfaces for longer periods of time. The pathogenic bacteria Legionella has longer been known to invade, infect, and use amoeba in their transmission. By doing so, they have become more resistant to biocides and antimicrobials and more invasive than the same bacteria that did not first incubate itself in an amoeba. Replication within amoeba may have the same effect on MRSA, making and already highly resistant bacteria even more uncontrollable (29, 30).


The survival of parasites is enhanced through various evasions strategies including properties of life cycles, and various methods of immunosuppression. However these mechanisms do more than to simply ensure the continued existence of parasitic organisms. Through an ongoing process of co-evolution, they continue to be important clinically, as they reform our present immune system and affect the immunity of other microorganisms also. For this reason the immunology of parasites will continue to be a topic researched by those interested in the survival of any population. 

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