Relapse and Drug resistance in plasmodium infection: The hypnozoites implicated

It always starts with moderate to severe chills at any time of the day or at night, one starts to feel intense headache and a high fever; the chills subsides a bit with profuse sweating, malaria continues to be a very important vector-borne disease with annual death rate of over three million.

^{Image credit Pxhere.com. CC0 creative commons license.}

Medical advancements in the facilities and procedures of malaria treatment have however reduced this tally over the past couple of years but the infection continues to persist and remains the most popular infection, at least in the tropics as some parts of the world such as the United States have completely curbed the main cause of this infection and some countries such as Iceland are naturally safe from malaria as (the insect vector of the malaria parasite) mosquitoes are not found in this region.

Mosquitoes? Kill them all!

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Mosquitoes (pictured above) are slender body flies with a prominent forward projecting proboscis with non-pendulous Palps which are held rigid and straight. Taxonomically, mosquitoes belong to the subfamily Culcinae which is classified into three, the Megarhins, Anophelini, and Culcini. The Megarhins mosquitoes are not currently known to cause any infection, but of medical importance are the class Anophelini and Culcini whose genera are vectors of some disease causing parasites. Of importance here is the class Anophelini which consists of three genera out of which only the genus Anophelene is known to be an important vector.

Anopheles mosquitoes are true flies with a characteristic wing venation and a pair of vestigial wings known as halters with enables them to maintain balance during flight, they posses proboscis equipped with the ability to cut through the human skin and plant flowers. Male Anopheles mosquitoes feeds mainly on plant juices and hence do not transmit any disease with their sole purpose being fertilization of the female counterparts after which they die off.

Female Anopheles mosquitoes are tasked with the production of offspring; however, to complete this task, there is a compulsory need for a blood meal for the maturation of their ovaries. Hence the female mosquitoes are equipped with a stronger proboscis which can cut through the skin of mammals and a sucking apparatus which enables them to obtain blood. Mosquitoes' ovaries matures days after a good blood meal and the mosquitoes produce eggs which matures into an adult mosquito within a couple of weeks or a month depending on the environmental conditions.

The environmental conditions has a major influence on the life span of mosquitoes, but not exactly as you would think, in a favorable environment, female mosquitoes obtain enough blood and hence complete their task of reproduction very early and die off a while after this; hence mosquitoes tend to have a shorter life span under favourable environmental conditions.

The vector story

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The female Anopheles mosquitoes would have been mere ‘blood feeders’ had they not been the major route of the extremely virulent protozoan parasite–plasmodium, though they have been associated with some other infections.

But unfortunately, mosquitoes are the definitive host of Plasmodium which is the cause of malaria infections.
The Plasmodium are unicellular microorganisms belonging to the phylum Apicomplexa, class Hematozoea and order Haemosporida.

Charles Laveran in 1880 first described this parasite and in 1920, Ronald Ross was awarded a Nobel Prize for demonstrating female Anopheles mosquitoes as the vectors of this parasite. Since these incidents, over a hundred species of the plasmodium parasites have been identified with only four species of plasmodium known to infect humans; Plasmodium falciparum, plasmodium vivax, plasmodium malariae and Plasmodium ovale have been described to cause different forms of malaria in Man with P. Falciparum and P.Vivax accounting for most of the infections with most cases reported in Africa, India and other tropical countries. Plasmodium falciparum is distinguished as specie of the plasmodium parasite that causes cerebral malaria, cerebral malaria is a severe complication of plasmodium falciparum infection which frequently leads to death even when appropriate therapy has been given. This infection is characterized by paralysis, hyperpyrexia and coma as the capillaries of the brain are plugged with pressurized red blood cells each containing the malaria pigment. This infection occurs most in toddlers and children between the age of 3-4.

Life style and cycle of the plasmodium parasite

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Apicomplexa of the order Haemosporida completes the life cycle in two hosts, a vetebrate host which is the intermediate host and an invertebrate definitive host of the plasmodium parasite where they multiply sexually, producing sporozoites which are the infective form Of the parasites, the body temperature of the mosquitoes are favourable for the development and maturation of the parasites.

The immune system of mosquitoes are strong enough to subside the pathogenicity of these parasite and hence these parasites do not bind attack the mosquitoes hence they live and multiply sexually. The sporozoites inhabits the salivary glands of the female Anopheles mosquitoes equipped with all features which it needs to survive in its next host when the female mosquitoes feeds on them for her blood meal.

^{Plasmodium parasite life cycle. Image credit Wikimedia. A creative commons license}

During the feeding process, the female Anopheles mosquitoes pierce the skin of its host and while sucking blood from the pierced skin, saliva from the salivary glands of the female mosquito is injected into the blood stream of its host, the saliva contains the infective form of the parasites and hence marks the continuation of the life cycle of the plasmodium, in a different host.

Summarily, the life cycle of the plasmodium parasite in the vetebrate host is characterized by the proliferation of the parasites asexually, this alternation of generation marks the complexity of the life cycle of the plasmodium. The sporozoites from the mosquitoes enters the blood stream and are cleared within a short period of time as the blood circulates; these sporozoites are transported to the liver where they inhabit the hepatocytes and develops into schizonts the schizonts contains thousands of merozoites and develops within an interval of 6-16 days depending on the specie of the parasite, p. Falciparum completes this stage earlier than other species (6days) while p. Malariae schizonts develops with 13-16 days. After maturation, the hepatocytes ruptures, releasing thousands of merozoites which re-enters the blood stream and Invade the red blood cells and multiply, feeding on haemoglobin.

The effect of malaria infection felt by the patient is associated with this stage the merozoites matures into trophozoites, feeds on the haemoglobin, destroying the red blood cells leading to the jaundice and blood stools which are symptoms of malaria infection, excess destruction of the red blood cells leads to anaemia. These symptoms subsides after the commencement of drug therapy as the drugs usually containing quinine and the immune system works in synergy to clear the parasite. The patient feels completely healed a short period after this treatment is commenced but unfortunately, it is not over yet!

Relapse in malaria infection — the unsettled scores

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Malaria parasites are very viable and extremely stubborn microbes, hence malaria is a very tricky infection. The emergence of drug therapy for these parasites eventually hastened the healing of the patient, but the parasites have evolved more stages in their life cycle which ensures the continuity of their life even after severe attack by these chemicals, hence, a normal person may be carrier of the parasite.

When the merozoites accumulates in the red blood cells, their maturity continues and some merozoites develops into gametocytes. Male and female gametocytes are produced in response to treatment with anti-malaria drugs such as chloroquinone and quinine related drugs and also to hostile conditions and remain dormant in the blood where they are taken up by the mosquitoes during their blood meal, hence continuing the cycle again.

However, for a mosquito to be infected with the plasmodium parasite from its vetebrate host, the blood of the human carrier must contain at least twelve gametocytes per micro liter of blood (12gametocytes/um) and the number of female gametocytes must exceed that of male gametocytes, the mosquitoes ingests both the gametocytes and the asexual forms of the plasmodium parasite from its host, but only the gametocytes —the sexual forms develops new plasmodium parasites. Hence the gametocytes presents a comfortable means of plasmodium parasite ‘recycling ’.

In the stomach of the mosquitoes, the male gametocytes (microgametocytes) fertilizes the female gamete to produce a ‘zygote’ which matures into an ookinete ,the ookinete matures into an Ocyte which develops into sporozoites and the cycle continues again. On the other hand, some sporozoites from the mosquitoes may remain dormant causing no febrile condition in the human host and not reproducing during this time, during this stage, the sporozoites transforms into a uninucleate parasite of 4-6Um in diameter size known as a Hypnozoite or sleeping forms.

These hypnozoites are reactivated when the conditions are favourable and transforms into secondary exo-erythrocytic schizonts and release merozoites which infects the red blood cells leading to a relapse of malaria infection, the activation of the hypnozoites may not occur till after 2 years of previous infection, hence the individual falls sick again with malaria even though he/she was not bitten by an infected mosquito.

Relapse in malaria infection is associated with vector transmitted malaria infection, trophozoite-induced malaria, that is malaria contracted through blood transfusion, use of contaminated syringes or other sharp objects(mainline malaria) and from mother to child in cases of a defective placenta (congenital malaria) are not associated with any case of malaria infection relapse/reoccurrence. Fortunately, relapse of malarial infection does not occur in the most pathogenic specie of malaria, plasmodium falciparum, this is because unlike other species, it doesn’t produce hypnozoites, hence hypnozoites are the main reason for relapse of malarial infections.

Drug resistance in malaria infection

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According to WHO, antibiotics resistance is the most pressing problem of the health sector today, microbes develops resistance to the chemicals which are meant to destroy them, hence these drugs becomes non-functional towards these strains of microbes which developed resistance. Unfortunately, through vertical and horizontal gene transfer, this trait is transferred to other microbes of the same specie, this renders drugs useless towards the microbes in question, WHO predicts a world where antibiotics becomes ineffective, which may usher in an apocalyptic scene.

Malaria parasites also develops resistance to the drugs which are meant to eradicate them, drug resistance creates a clinical situation in which the initial peak of the malarial infection is partially controlled and a recrudescence of the resistant parasites occurs shortly after, thus when malaria medications are not properly adhered to, the malaria infection subsides after a short period of time and reoccurs, this time more severe and resistant to drugs.

Non adherence to professional prescriptions for a given drugs have been implicated as the major cause of drug resistance, not only in malaria infection but in every case of antimicrobial resistance.

Patients tend to halt their medication once the sickness subsides and hence the merozoites develops into hypnozoites and is reactivated when treatment is discontinued, but during the hypnozoite stage, they develop features which helps them survive peculiar attacks, if medication is followed up satisfactorily, these hypnozoites are completely destroyed and the individual only falls sick again with malaria if bitten by another infected mosquito.

Resistance to drugs develops to a stage where the symptoms no longer subsides following treatment, hence the malaria symptoms continues amidst medication, which is fatal. Hence adherence to the right prescription of the right drugs by the right professional is the right practice if the malaria parasites must be defeated, the hypnozoites just as bacteria spores and virons makes the management of disease conditions a very tedious and tricky one.

REFERENCES

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1. Medical parasitology, 4th edition by D.R. Arora and B.B. Arora (pgs 73 - 87)
2. How mosquitoes fight malaria -sciencemag
3. Malaria -healthline -Wikipedia

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