In a distant part of Venezuela a little kid starts to have second thoughts on whether continue eating his meal after he heard his parents talking about the relative who was hospitalized after eating “bad-pork”. At the same time, over in Michigan, Tim and Jane take their puppy to the veterinarian for its first shots and deworming. Crossing the Atlantic Ocean, in Kenya, a woman’s forearm starts to itch after washing the clothes near the river. Further North, in Germany, a physician who just returned from a trip to Turkey, notices that he has been having episodes of intermittent fever. Parasites have, still are, and will continue to co-exist with humans. Since the beginning of time, parasitic infections have affected humans. These diseases, while not a cause of high mortality, they all lead to disability, social burden, chronic disease, and may be associated with stigma. Sadly, most parasitic infections affect the world’s poorest people. Despite industrialization, modern medicine, and globalization, these infections are still a major cause of disease in developing countries. Two major causes by which parasitic diseases continue to cause such high burden in the world is related to their intrinsic ability to infect and evade the immune system. On the other side, these infections continue to afflict millions of people because the lack of their ability to debilitate the host and because they affect developing countries.
Parasite co-existence with humans and other hosts has been driven by mutation processes along with natural selection giving rise to new phenotypes. Parasites have evolved to develop ingenious ways to evade the immune response from the host. These mechanisms have allowed them to persist in harsh environments thus giving them the opportunity to continue with their life cycle and spread to a new host. Most parasitic infections can go unnoticed because the parasite does not elicit an immune reaction in the host. In order to survive, feed, and reproduce; parasites can evade, sabotage, or manipulate the immune system of the host. For example, parasites can invade an immune-privileged tissue such as the central nervous system or the eyes. Tachyzoites of Toxoplasma gondii are known to hide in neuroretinas causing ocular toxoplasmosis. By hiding in such tissue, the tachyzoites can evade the cells of the immune system [1]. Likewise, onchospheres from Taenia solium survive in protected places like the CNS. Most T. solium infections resolve without any obvious symptoms, but residual brains calcifications can be detected by brain CT [2]. Another way by which parasites can become “invisible” to the immune system is in the example we have learned from trypanosomes. While most protozoan microorganisms replicate inside a host’s cell, trypanosomes freely circulate in blood. Most trypanosomes die soon after they have entered blood circulation because of a strong IgM response from the host. Less than 1% of surviving trypanosomes survived because of their variable surface glycoprotein coat (VSG) which has a different epitope for the antibody already in circulation. The surviving parasites multiply and again induce a strong immune response, but then again a small number survives because of their different VSG. VSG switching leads to antigenic variation and fluctuations in parasitemia which causes cycles of intermittent fever [3]. Parasites can also actively modulate the host’s immune response. Serine proteases released from schistosoma cercariae can cleave IgE from the host and thus interfere with recognition and complement-mediated lysis [4]. Likely, trypanosomes can interfere with innate immunity. Trypanosome lytic factors (TLF) are secreted proteins found in serum which can kill trypanosomes by forming pores in the parasite’s endosomes leading to transmembrane flux of chloride ions and osmotic swelling. However, T. brucei spp. can neutralize the lytic portion of TLFs by neutralizing it with a serum resistance-associated protein or by stiffening the endosome’s lipid membrane thus making it more difficult for the TLF to insert into the membrane [5]. Another example on how parasites can modulate the immune system is in the intracellular protozoan parasite Leishmania spp. Leishmania can delay neutrophil apoptosis for up to 24 hours by inhibiting pro-caspase processing, thus the parasite will be protected from other immune system cells inside the neutrophil. Promastigote infected neutrophils will eventually die and secrete chemotactic factors, such as IL-10 and IL-12, for macrophages to engulf them. Cleverly, Leishmania promastigotes are also engulfed by the macrophages, which are their primary host cell in which they reproduce and mature into amastigotes. Ironically, the cells supposed to kill the parasite are the ones harboring it. This is possible because amastigotes can delay phagolysosome fusion and by diluting the hydrolytic enzymes below their effective level. Also, glycosylinositolphospholipd, which is a component of the amastigote’s glycocalyx can suppress the expression of nitric oxide synthase (NOS) of the macrophage, thus preventing death from reaction nitrogen species. Likely, trypanothione reductase can neutralize reactive oxygen species and NOS, thus rendering the parasite immune to killing by the macrophage [6]. Another example of immune evasion strategy is mediated by interacting with C-type lectins (CTLs). CTLs are a family of proteins that form cell surface receptors on macrophages and NK cells. These receptors mediate the first steps in adhesion of the leukocytes to the endothelium in order to permeate into the site of infection. Toxocara caniis larvae is known to secrete excretory-secreted antigens which contain a CTLs domain that is similar to the host’s CTLs. These CTLs analogs will thus bind to tissue endothelium preventing leukocyte infiltration to the site of infection [7]. Similarly, Schistosoma mansoni secretes lectins which bind to plasma components of Biomphalaria snail and act in a similar fashion as CTLs, but these bind to snail’s haemocyte surface lectins [8]. Following on Schistosoma spp. immune evasion strategies, adult worms are known to have an affinity for IgG and complement factor C3. Affinity to these molecules is mediated by the presence of IgG-Fc and C3 receptors on the surface of adult male worms. These receptor will thus render the effector molecules ineffective [9]. It is also hypothesized that these receptors may serve as a mechanism for molecular mimicry of host’s molecules. Alongside, S. mansoni schistosomula have been shown to express MHC class I molecules as well as ABO and Lewis blood antigens. Schistosomula-expressed MHC molecules are acquired from the host and not synthesized by the parasite; a possible mechanism by which this occurs is that the parasite’s cell membranes is able to fuse with the host’s cells thus antigens flow from one cell to other and are eventually expressed [10]. We have observed on different immune evasion mechanism by parasites.
Parasitic infections continue to afflict millions of people because the high social burden and morbidity caused by these diseases. Neglected tropical diseases (NTDs) have a high prevalence in developing countries, especially in rural areas. Currently, NTDs affect 1.4 billion people in 149 countries and the economic burden for these countries rises every year to billions of dollars. Surprisingly, NTDs have been around since ancient times in human history. Ancient writings have been found describing some NTDs, such as schistosomiasis, dracunculiasis, and hookworm infections. Devastatingly, these infections are known to lead to chronic conditions, disability, and even disfigurement. Chronic hookworm infection is one of the most prevalent human parasitic infections. Ancylostoma duodenale and Necator americanus are the two main species that cause hookworm disease in humans. The life cycle of both hookworms is almost identical and they are distinguished by their morphological features. Infections occurs when hookworm larvae in filariform in soil penetrate intact skin. Then, the parasite travels through the blood and lymphatic system, the heart, lungs, and it is eventually swallowed to the small intestines where it matures and starts hatching eggs that pass through feces. It is then in the intestines where adult hookworms cause the most damage to the host. By using their “teeth” they attach to mucosal surface and start feeding on blood. Infected patients then start to develop iron-deficiency anemia, abdominal pain, stunted growth, protein deficiency, and even death. Another hookworm infection caused by A. braziliense causes cutaneous larval migrans, for which like out from a sci-fi movie, larvae migrate within the skin causing an intense, itchy eruption. Linked to the symptomatology of hookworm infection, debilitating chronic infection eventually leads to socio-economic burden. It is known that hookworm infection (as well as the other of the soil-transmitted helminthes) affects cognitive and memory ability, thus infected children demonstrate reduced school performance and attendance. Also, chronically infected agricultural workers tend to have decreased productivity and thus may have difficulty keeping the family income. Current control strategies against hookworms are frequent periodic deworming with benzimidazole as well as improving sanitary disposal of human feces to break the parasite’s life cycle [11].
Parasitic infections can also lead to disability. Onchocerciasis, also known as river blindness, is caused by a filarial nematode Onchocerca volvulus. 20 to 30 million people are infected with onchocerciasis mostly in West and Central Africa. Transition and infection is caused by a blackfly which takes a blood meal in the human and injects the parasite into the skin. Microfilariae migrate in the skin of the host where they cause itching and even disfigurement. From the skin, some microfilariae may reach the eye, where they form opacities, inflammation of the sclera, cornea, iris, and retina. If untreated, these opacities become larger and eventually block light from entering the eye thus leading to impaired vision or total blindness. Also, accumulation of filariae in subcutaneous tissue leads to disfigurement. Chronic inflammation of the skin causes it to lose its elasticity thus making it look loose and aged. The socio-economic harms caused by chronic onchocerciasis are devastating. When, the head of the household becomes blind due to the infection it becomes a burden to the family income. They will not be able to work. In some villages of sub-Saharan Africa up to 10% of the population is blind from ochocerciasis thus debilitating the economy of the whole village [11]. Coupled with economic difficulties, depression in the patient and their families makes the situation more overwhelming. Resources are already lacking in such endemic areas, thus these situations make it more difficult for the population to improve their economy. An extreme case of physical disfigurement is the one caused by another filarial worm, Wucheria bancrofti, which causes lymphatic filariasis. Similarly to onchocerciasis, an insect vector is required to spread the disease, in the case of W. bancrofti a mosquito takes a blood meal and injects the larvae through the skin. Eventually, the larvae migrate and make their way through to reach the lymphatics, where they mature to adult worms that can live for up to 8 years. Now, this scenario brings us back to on the immune evasion strategies of parasites because these worms can reside on the “headquarters” of the immune system. Inside the lymphatic vessels, adult worms block the vessels (lymphangiectasia) which eventually leads to accumulation of connective tissue cells and fibers, thus enlargement of limbs. Along with continuous secretion of inflammatory cytokines and secondary bacterial infections, it leads to massive swelling and granulomatous response in the lymphatics, leading to a condition known as elephantiasis. As a result of this devastating disability and disfigurement; socioeconomic consequences arise. These infections mainly occur in young adults whom usually are agricultural workers. Forced by the diseases, these patients have to abandon their jobs. In fact, the annual loss in the country of India due to lymphatic filariasis pathology is of $842 million dollars [11]. Moreover, a deep stigma follows people with elephantiasis. Patients with these conditions are frequently perceived as lacking hygiene, being cursed, or dirty. Family fragmentation due to abandonment is also common. Inevitably, these series of events lead to depression for which in some cases patients do not seek medical treatment. Even the term elephantiasis may not be the best term to describe their condition since it falls into making a somewhat offensive analogy from their physical appearance. Altogether these conditions eventually lead to a cycle of poverty and disease. While tremendous effort has taken place in controlling these infections, they continue to spread to new geographic areas and are still a cause of high morbidity. More resources and attention must be given to parasitic diseases. It is thus important to continue funding, researching, and implementing alternatives in the treatment of these diseases. The fact that we may not be in close contact with these type of diseases should not be an excuse to forget that they exist.
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- Tarleton, R.L. and W.M. Kemp, Demonstration of IgG-Fc and C3 receptors on adult Schistosoma mansoni. J Immunol, 1981. 126(1): p. 379-84.
- Simpson, A.J., et al., Evidence that schistosome MHC antigens are not synthesized by the parasite but are acquired from the host as intact glycoproteins. J Immunol, 1983. 131(2): p. 962-5.
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Parasites and Us 