Parasites of humans, pets and livestock

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Introduction

The impact of eukaryotic protists on human health is not just about drug production. Indeed, they are the cause of many diseases. These infectious diseases can be classified into two groups according to the causative agents. Parasitic protozoa generally have the ability to attack healthy humans and have developed sophisticated strategies to invade their host and spread to new hosts. On the contrary, most fungi are opportunistic pathogens which will take advantage of the weakness of their host to colonize it; in general these parasites cannot persist if the immune system is effective.

Impact of human parasites

There are 70 species of protozoa and more than 300 species of parasitic worms. The latter are either nematodes such as roundworm or filaria, or flatworms such as taenia or fluke. Although widespread and having a strong impact on the health of populations, these animals are outside the scope of this book. Especially since protozoa have the greatest impact on health because they are responsible for nearly 99% of deaths. Table 15 gives the figures of a study carried out in 2013. This year, parasitic protozoa are believed to be responsible for the death of more than one million people compared to 13,000 for “worms”. They develop more particularly in poorly developed countries. As many such these countries are located in the hot regions of the world, where the vectors of these parasites live, they get the chance to proliferate. Even more so as health systems are often faulty and prophylaxis difficult to implement. Likewise, epidemiological data are often incomplete and figures varying from one to ten in prevalence are common. For example, in its 2015 annual report, the World Health Organization (WHO for World Health Organization) cites diarrhea as the seventh leading cause of death, second only to the AIDS virus as the cause of death from infectious disease. Each year, there are approximately 1.7 billion cases and 1.5 million deaths. This diarrhea is particularly deadly in children suffering from malnutrition, causing 760,000 deaths per year in those under the age of five. Their etiology is often not known. The bacteria Escherichia coli and rotaviruses seem to be the main causes. However, part of the cases are caused by protozoa like Entamoeba histolytica, Giardia intestinalis or Blastocystis hominis. Entamoeba histolytica is responsible for more than 10,000 deaths according to a 2013 study (Table 15), but between 50,000 and 100,000 deaths per year according to figures found more classically in the literature on amoebiasis.

However, all studies agree that the parasite which is by far responsible for the greatest number of deaths is Plasmodium falciparum (Box 22). The 2013 study estimated the death toll from malaria at 584,000 (Table 15). WHO data for 2015 is over 1.24 million deaths, again mostly children in poor countries. Then follow the Leishmania (Table 11), the Cryptosporidium (Figure 316 and Table 13), Entamoeba histolytica and the American and African trypanosomes (Table 11). Apart from Cryptosporidium and Entamoeba histolytica, all of these parasites are transmitted by insect vectors. Note that these statistics do not include parasites which are not fatal such as Trichomonas vaginalis (Figure 202), Giardia intestinalis (Figure 200), Toxoplasma, Babesia and other Apicomplexa (Figures 319 and 320), nor of course those which cause few cases such as Blastocystis hominis (Figure 262), Balantidium coli (Figure 296) or Naegleria fowleri…


Combating parasites

The strategies for combating parasites are divided into four main areas: control of the vector, prophylaxis to prevent infections, vaccines and drug treatment. Much of the vector control has consisted of the application of insecticides, as most parasitic diseases are transmitted by mosquitoes or flies. However, resistance appears quickly and the application of insecticides is not good for the environment. Note that a simple way to reduce mosquito populations is to eliminate their breeding grounds, which are often small receptacles containing stale water such as old tires, broken pots, poorly maintained gutters… Elimination of these centers of reproduction, often close to living quarters, greatly reduces the rate of infection! The use of traps is also very effective. The main obstacles to these methods are often the education of populations, especially in politically unstable countries or areas. Other more novel methods for large-scale vector control are being explored. A first method would consist in using bacteria of the genus Wolbachia, which are natural symbionts of insects. These bacteria are passed from insect mother to mother. This mode of transmission allows the invasion into insect populations. Often Wolbachia are asymptomatic, however, one strain decreases the life expectancy of the Aedes egyptii mosquito, which transmits dengue fever. It also limits the level of the virus in the mosquito. Transfer of this Wolbachia strain to Anopheles could lead to a drastic decrease in malaria transmission, if its effect on Anopheles and Plasmodium is identical. Especially since the maturation of the malaria parasite in the mosquito lasts at least ten days, i.e. a good part of the lifespan of an adult female, which is a fortnight in the wild. A small reduction in longevity could therefore severely limit the number of female flies carrying mature parasites. Another avenue is the use of entomopathogenic fungi, mainly Ascomycota of the genera Beauveria and Metarhizium. These fungi do not have the ability to suppress insect “blooms”, but their continued presence in biotopes may help reduce populations. A final method is the use of sterile males obtained after irradiation with ultraviolet rays. They will copulate with females. As with many insects, females copulate only once, the result being that these matings will have no offspring. This strategy is, for example, used to combat the tsetse fly which transmits African trypanosomes (Figure 211).

For parasites transmitted by contaminated food, the most effective prophylaxis is the construction of toilets to prevent the dispersion of infectious particles. For example, in India in 2015, a country that knows a lot of contaminations by amoebae, the toilet system is still not finished installing! For parasites transmitted by insects, prophylaxis involves avoiding bites. This can be achieved by the use of mosquito nets, appropriate clothing, spraying with repellents and taking preventive drugs. While no drugs are available for trypanosomes, several exist for plasmodia. The best known are quinine and especially chloroquine (Figure 373). However, resistance has developed with the intensive use of this drug and it is therefore not effective in all areas where malaria is present. The recommendation is to stop using it if locally more than 25% of the parasites are resistant. Vector control and prophylaxis can have very important positive effects. For example, sleeping sickness has declined sharply in Africa following campaigns to eradicate the tsetse fly and educate people to avoid bites, as there is no preventive drug treatment. Currently, it only causes a few thousand deaths per year. In the past three epidemics around the 1900s, 1920s and 1970s, the infection killed several hundred thousand people, probably over a million for the one that lasted from 1896 to 1906. The last epidemic is due to the relaxation of surveillance of the disease because in the 1960s, only 5,000 cases per year were reported. The epidemic began in 1970 and in 1998 40,000 cases were notified to WHO and at least 300,000 others were suspected. Efforts aim to control the fly and its bites, but also to diagnose patients early on and treating them with drugs to contain the spread of the infection. In 2009, less than 10,000 cases were reported and only 6,314 cases in 2012, nevertheless with an estimated total of 20,000 actual cases. WHO predicts that by 2020, sleeping sickness will no longer be a public health problem. [Translators note: Well, is it?] However, the fight against the tsetse fly and the trypanosome must not be relaxed!

As of 2015, there is still no effective vaccine against the parasites because most have escape mechanisms from the immune system (Box 33). This strategy is part of their adaptation to parasitic life and therefore prevents the definition of stable antigens that could be used. Likewise, these proteins are generally very polymorphic in populations, likely to allow multiple re-infections. The case of plasmodia is even more complex because the parasite undergoes many differentiations and has extracellular and other intracellular phases. In addition, five different species can cause the disease. It is therefore likely that an effective vaccine will have to act against proteins present on the surface of different parasites at different stages of the cycle. One of these potential targets is the Pf protein of “circumsporozoites” or CSPs. This 412 amino acid protein is involved in the invasion of liver cells and therefore has a high potential for early blockade of the invasion. A vaccine called “RTS,S”, using the conserved part of this protein (Figure 374), has recently started to be used in sub-Saharan Africa. Although having a low efficacy, this is the world’s first vaccine licensed against a human parasitic disease. Several other vaccines against malaria and other diseases caused by protozoa are under development.

The last strategy for controlling parasitic protozoa is chemotherapy. Because of the great resemblance of the biology of the parasites to that of our own cells - we are all eukaryotes! - the available treatments were for a long time ineffective and often dangerous. In addition, resistance appears quickly, making it difficult to use drugs on a large scale. Better knowledge of the biology of parasitic protozoa now allows molecules to be better targeted towards inhibiting specific parasite processes. The example of antimalarial drugs is once again enlightening. The first of these, quinine (Figure 373), is a secondary metabolite found in the bark of shrubs of the genus Cinchona that live in the Peruvian Andes. The effects of this plant were already known to the Quechua Indians. It was then brought back to Europe and was used as early as the 1630s to treat malaria in Italy. Its effect would be mainly at the level of the metabolism of heme (precursor to hemoglobin), for which it would inhibit the crystallization of toxic products of degradation in the vacuole of the parasite. High ingestion doses are however not without side effects. It was therefore replaced by chloroquine (Figure 373) in the 1940s. This drug was discovered by the pharmaceutical industry after testing several molecules for their antimalarial effects. Chloroquine is said to have the same type of effect on parasites as quinine. More effective and with fewer side effects than quinine, it has been widely used, and since the 1950s resistant strains of plasmodium have appeared. Another drug discovered in the 1950s is pyrimethamine (Figure 373). It is used in combination with sulfonamides and folinic acid. Very toxic, it cannot be used as a preventive treatment. In addition, resistance is now present in the parasite populations. Several other molecules resulting from the systematic screenings undertaken in the years 1930 to 1960 are available: atovaquone, primaquine, doxycycline… The most recent effective drugs are now based on artemisinin (Figure 373). This molecule comes from a small flowering plant, Artemisia annua, a mugwort, whose effects have been suggested for nearly 2,000 years by traditional Chinese medicine. Artemisinin was isolated in the 1970s and has been in use since the 1990s. It was declared in 2001 as “the greatest hope in the fight against malaria” by the WHO. Its action would be at the level of the production of toxic free radicals for Plasmodium. To prevent the development of resistance, it is only used in combination with other antimalarials, especially since it does not always kill parasites. However, in 2009, partially resistant strains were discovered in Cambodia! Currently, several avenues are being followed to find new molecules. For example, the presence of an apicoplast makes it possible to imagine that molecules directed against this organelle, and therefore herbicides, could be effective. However, systematic drug screening continues to yield new drugs. In 2015, the drug DDD107498 was discovered. It has little toxicity to humans and kills parasites. A single dose might be sufficient to cure the sick. Its action is at the translation elongation factor eEF2, very conserved protein, of the parasite. The drug blocks the translocation of the ribosome along the mRNA, thus inhibiting protein synthesis.


Opportunistic fungal pathogens

Opportunistic pathogens are mainly Eumycota, but various other organisms, such as Microsporidia (Table 8) or the Chlorophyta alga Prototheca wickerhamii, can cause various infections ranging from allergies and benign superficial diseases to fatal systemic invasions. Superficial yeast infections affect the skin or hair, and are caused by fungi called “dermatophytes”. These are the most common yeast infections with an estimated 20% of the world population being affected and around 200,000,000 new cases per year (Table 16). Among the most famous is the “athlete’s foot” disease. Subcutaneous yeast infections are often caused by the same fungi but have managed to penetrate deeper, usually through an injury. The eyes are also a prime target, especially in people wearing contact lenses. The more serious yeast infections are systemic yeast infections where a large part of the body is colonized by the fungus. They often prove to be fatal. The WHO estimated in 2014 that fungi collectively killed more people than malaria! The cost of treating these systemic mycoses is also prohibitive. In 2014, it was €100,000 on average per patient. The main reason is that the treatment is very long, several months, with injections of large quantities of expensive antifungals. Systemic mycoses are therefore now a real public health problem in Western societies and their impact on the general human health is substantial (Table 16). These diseases have increased in recent years because of the increase in AIDS, medical operations requiring immunosuppressive treatments such as transplants or cancer treatment. Patients in intensive care are also a population at risk. The other factors influencing the appearance of systemic or more superficial mycoses are the presence of other diseases, in particular those affecting the respiratory system, malnutrition, diabetes, alcoholism, leukemia, or the consequences of antibiotic treatment as it modifies the microflora. However, some serious disease causing species also successfully attack seemingly healthy people.

The same species of yeast can cause different types of infections. Consequently, an infection from one fungus can cause different symptoms ranging from no effect to death through a temporary fever. Conversely, different fungi can cause the same symptoms. These two characteristics make it difficult to obtain epidemiological data. Table 16 gives the figures for 2014, estimated by the LIFE site (Leading International Fungal Education). Currently, yeast infection is caused mainly by Candida (Table 16) and especially Candida albicans (Box 16), a human commensal Saccharomycotina that is normally found in the intestine, respiratory system, mouth and vagina. In general, its growth is contained by other present microorganisms. Under conditions of disturbance, it multiplies rapidly and causes candidiasis. This condition can have very different symptoms depending on the organ affected: mouth, skin, reproductive system, eyes, etc. In some hospitals, it can account for up to 10% of nosocomial (originating in the hospital) illnesses. As this organism can be present in healthy individuals, diagnosis is difficult. The other important human pathogenic fungi are acquired from the environment and are not passed from person to person either. In the West, Aspergillus fumigatus, an Eurotiomycetes species, is responsible for fatal aspergillosis (Table 9 and Table 16). This fungus mainly affects the respiratory system and then spreads throughout the body (Table 16). It is also often responsible for the development of respiratory allergies such as asthma. The spores of species of the Alternaria genus, of the class Dothideomycetes in Ascomycota, are also often implicated as allergens. Blastomyces dermatitis, Histoplasma capsulatus and Coccidioides immitis, three Eurotiomycetes species, cause often fatal systemic infections which are accompanied by filament/yeast phase transitions (Table 9). Cutaneous mycoses are mainly caused by a variety of “dermatophyte” fungi belonging to the class of Eurotiomycetes, such as Trichophyton or Microsporum (Table 9). Cryptococcus neoformans is a Basidiomycota which after penetration via the lungs will reach the brain where it causes meningitis and encephalitis. Pneumocystis carinii, an obligate parasite of mammalian lungs, belonging to Taphrinomycotina, is responsible for fatal pneumonia. Although rarer with around one case per million inhabitants, zygomycosis caused by Mucoromycotina of various genera is however very serious; amputation of colonized parts is often the only effective treatment. Systemic zygomycosis is fatal in 90% of cases!

Despite this impressive catalog, among the hundreds of thousands of species of Eumycota, only a hundred species are capable of causing disease in humans. Indeed, the optimum growth temperature of the majority of fungi is between 20 and 30°C; 37°C is often a lethal temperature. Their maintenance in a warm-blooded organism is therefore problematic (for them!). Nevertheless, healthy humans harbor numerous fungal commensals, most of which are unimportant from a disease perspective. For example, examination of commensal fungi in the mouth reveals that the majority of humans carry fifteen different genera of fungus, some even carrying up to forty different genera, mostly Ascomycota. In most people, the presence of these fungi is asymptomatic or without serious health consequences. Mention may for example be made of Malassezia globosa and Malassezia restricta which are Basidiomycota yeasts inhabiting the surface of rather oily skin. They feed on sebaceous secretions where they break down lipids into free fatty acids and only consume saturated fatty acids. They therefore leave unsaturated fatty acids as waste, which can cause inflammation of the skin and in the hair: dandruff. Dandruff fungi secrete antifungals such as zinc pyrithione… However, under certain conditions, commensal fungi, mainly Candida, can proliferate and cause mycosis. Other yeast infections are caused by fungi in the environment that have adaptations that allow them to enter the body and survive the conditions found in the human body (Box 34). The dermatophytes responsible for skin infections are keratinophilic fungi which in nature have specialized in the degradation of substances rich in proteins such as skin, hair, horns or bones. Aspergillus fumigatus is a soil fungus that produces small sized spores capable of penetrating to the lung in which it is able to persist. The same goes for Cryptococcus which often live in bird droppings. This species makes its sexual reproduction on eucalyptus, a very different biotope from the human body! In fact, from an evolutionary point of view, it seems that these fungi have put in place mechanisms to persist in amoebae, which are their main predators. The same mechanisms also allow them to subsist in more complex hosts, such as animals. This has been clearly shown in the case of Cryptococcus neoformans.


Treatment of fungal infections

From a treatment perspective, the problems encountered with yeast infections are similar to those encountered with parasitic protozoa. Eumycota are evolutionarily very close to animals, so their functions at the molecular level are almost identical. There are therefore problems in finding effective antifungals that are not toxic to humans. In addition, like most microbes, resistance to these antifungals builds quickly. Current treatments are mainly based on the use of amphotericin B (Figure 375) and triazoles such as itracinazole or fluconazole. These agents act either directly on ergosterol or on its synthesis. Ergosterol is a specific Eumycota membrane sterol that is not found in humans. Its role is not very well understood but seems multiple in ensuring the fluidity and integrity of the membrane. It seems necessary for the function of certain membrane enzymes. The developing resistances result from various modifications, such as the decrease in the quantity of membrane ergosterol, the elimination of the active products, the increase in the number of targets, that is to say of the enzymes of biosynthesis, decrease of the affinity of these targets or alteration of the synthesis of ergosterol. Lately, to find new molecules, particular attention is paid to proteins which ensure the step of elongation of translation because, in certain fungi, there is a third soluble factor, eEF3, to carry out an elongation cycle. The activity of this factor would be ensured by ribosomes in other organisms. It could therefore be the target of specific antifungals. Many other avenues are being explored, such as molecules that would inhibit the synthesis of the fungal cell wall. Finally, surgical removal is often necessary to prevent rapid spread of the fungus.


Protist pathogens in other animals

Our pets are also prone to attacks from eukaryotic protists. For example in dogs, among the ten most common diseases two are caused by parasitic protozoa: piroplasmosis caused by Apicomplexa of the genus Babesia and leishmaniasis caused by Kinetoplastida of the genus Leshmania. The cat is also susceptible to piroplasmosis but also to toxoplasmosis caused by the Apicomplexan Toxoplasma gondii (Figure 319). The dermatophyte fungi that cause ringworms also often infect cat breeding centers. Cattle are attacked by Apicomplexa of the genera Babesia and Theileria, especially in Africa where epidemics have a significant impact on herds. Birds are not spared. Coccidiosis caused by various coccidia is a very common disease of hens. It is characterized by anemia associated with a drop in egg laying.

While mammals and birds are rather sensitive to parasitic protozoa because they are warm-blooded, cold-blooded animals such as fish or insects will also be sensitive to fungi. For example, fish in aquaria or fish farms are parasitized by Ciliophora of the genera Ichthyophthirius, Cryptocaryon or Chilodonella, Kinetoplastida of the genus Bodo, Myxozoa of the genus Myxobolus (animals; Figure 99), various Microsporidia (Figure 107), Dinoflagellata of the genera Amyloodinium or Oodinium… but also Oomycota of the genera Saprolegnia or Branchiomyces. Bees will be sensitive to Microsporidia, particularly Nosema apis responsible for nosemosis and to various Eurotiomycetes including Ascosphaera apis, Aspergillus fumigatus, Aspergillus flavus or Aspergillus niger which will cause larval mummifications, a disease known as chalkbrood.


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