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This week begins a 4 part series on one of the most significant public health burdens in modern times, as well as throughout the vast collective experience of human history: malaria. The name comes from old Italian, meaning "bad air", as the disease was very prevalent in that part of the world even going back as far as the Roman empire. The disease name is derived from words meaning "bad air" because it was believed that the illness was associated with sickening "miasmas" that carried illness and death in the air. Still, the disease is documented far earlier in human history throughout South America and Asia. In fact, there are records of malaria going back as far as 2700 BCE in China. So we are talking about a disease that has afflicted human beings for a very long time. In fact, we are talking about a critter that we have probably lived with for most of our hominid existence: the Plasmodium parasite.
Malaria is a very complex disease that encompasses four important domains, which I will discuss during the course of this series. The first is the infectious agent itself, which is a parasite, and involves very complex life cycles for each of the species that infect humans. The second domain is that of the vector, which is again a mosquito, albeit of a different genus, and also involves complex ecologies depending on the particular species of Anopheles. The third is that of the disease itself and how it clinically manifests, which can vary by the species of Plasmodium parasite and by other specific epidemiologic indicators. The fourth domain, is that of geography, i.e. the physical landscape, which exerts tremendous influence on each of the first three domains particularly with respect to the ecology and epidemiology involved.
So, on to part 1 of the series and its focus: the Plasmodium parasite. Here are a couple of images of one particular species, Plasmodium falciparum:
This week begins a 4 part series on one of the most significant public health burdens in modern times, as well as throughout the vast collective experience of human history: malaria. The name comes from old Italian, meaning "bad air", as the disease was very prevalent in that part of the world even going back as far as the Roman empire. The disease name is derived from words meaning "bad air" because it was believed that the illness was associated with sickening "miasmas" that carried illness and death in the air. Still, the disease is documented far earlier in human history throughout South America and Asia. In fact, there are records of malaria going back as far as 2700 BCE in China. So we are talking about a disease that has afflicted human beings for a very long time. In fact, we are talking about a critter that we have probably lived with for most of our hominid existence: the Plasmodium parasite.
Malaria is a very complex disease that encompasses four important domains, which I will discuss during the course of this series. The first is the infectious agent itself, which is a parasite, and involves very complex life cycles for each of the species that infect humans. The second domain is that of the vector, which is again a mosquito, albeit of a different genus, and also involves complex ecologies depending on the particular species of Anopheles. The third is that of the disease itself and how it clinically manifests, which can vary by the species of Plasmodium parasite and by other specific epidemiologic indicators. The fourth domain, is that of geography, i.e. the physical landscape, which exerts tremendous influence on each of the first three domains particularly with respect to the ecology and epidemiology involved.
So, on to part 1 of the series and its focus: the Plasmodium parasite. Here are a couple of images of one particular species, Plasmodium falciparum:
Plasmodium falciparum
Plasmodium falciparum in red blood cells
Malaria is caused by a protozoa, which means that the organism is single-celled and eukaryotic, unlike viruses and bacteria (and also unlike helminths, which are indeed both parasites and eukaryotes, but worms are multicellular and protozoa are unicellular). The malaria parasite is of the genus, Plasmodium, which is comprised of many species. There are four species that are most relevant for human infection and these are Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum is associated with the greatest morbidity and mortality, and is mostly responsible for the large number of deaths in young children in countries in sub-Saharan Africa. We will see how and why this is the case when we talk about how malaria manifests as a disease. P. vivax is the most globally widespread species of malaria parasite, and therefore accounts for the greatest distribution of malaria in the world. The other two species are of intermediate status, though they can also cause severe disease and death. The species of parasite share important similarities in their life-cycles, but there are also important differences among them, which affects their virulence and other clinical aspects of disease such as drug resistance.
The life cycle of this parasite is extraordinarily complex and involves multiple stages within each of its definitive (i.e. mosquitoes) and intermediate (i.e. humans) hosts. Let's stop for a second here. What do I mean by intermediate and definitive hosts? In parasitology, there are many parasites that have evolved complex life cycles that require more than one host animal species for completion. When this is the case, the definitive host refers to that animal host in which the sexual reproductive stage of the parasite occurs. Any other animal host corresponding to other intermediate non-sexual stages of the parasite is known as an intermediate host. In the life cycle of Plasmodium, mosquitoes are the definitive hosts and humans (among other vertebrate animals) are the intermediate hosts.
So let's examine this life cycle in some detail. Here is a nice depiction of the complete life cycle published by the Centers for Disease Control and Prevention (CDC):
When the mosquito takes a blood meal, she injects her saliva, which is a cocktail of chemicals to aid in her collection of blood. As she does this, if she is infected with the malaria parasite, she will also inject a particular stage of Plasmodium that collects in her salivary glands: the sporozoites. The sporozoites are the form of the parasite that cause the initial infection in humans (or any other intermediate host). The first picture in this posting was a close-up of a sporozoite. Here it is again:
Here is another nice picture depicting the sporozoite next to two other stages of the parasite that we'll be discussing shortly:
The sporozoites are completely motile, slender protozoan cells that, when introduced into the subcutaneous tissues and capillary beds of the host, make their way to the liver by way of the venous circulation. They can make their way from the point of inoculation by the mosquito to target cells in the liver in minutes if they are successful in evading the immune system. There will be many sporozoites introduced into the host with a single mosquito bite, and each seeks out a hepatic cell (liver cell) in the host where it will begin the next stage of its development. Once inside a hepatic cell, the sporozoite will begin to replicate itself thousands of times over the next 5 to 15 days. As it does so, it forms a hepatic schizont in the hepatic cell, which is essentially a small parasite factory. When the schizont ultimately ruptures, it releases tens of thousands of the new stage of the Plasmodium parasites: the merozoites. This legion of merozoites will emerge from each hepatic cell that was infected with a sporozoite (except in the case of those Plasmodium species that harbor an additional stage, called the hypnozoite, which we'll discuss shortly). So, between roughly one to two weeks after the initial mosquito bite, the host is under attack by a tremendous army of parasites.
And, yet, up to and including this point in the infection, we feel nothing....
No signs. No symptoms.
OK. The merozoites are released into the circulating blood from the hepatic schizonts, and they are in search of something: red blood cells. The merozoites seek out these red blood cells, or erythrocytes as they are also known, and attach and enter the cells by way of specific receptors on the eryrthrocyte surface.Once it gains entry, this stage of the parasite begins to change again, differentiating into a trophozoite, which is the feeding stage of the parasite. At this point the trophozoite is feeding on the hemoglobin of the erythrocyte that it has hijacked. It will then begin replication creating new intraerythrocytic merozoites, enlarging the cell and forming another schizont.
Still we feel nothing from the infection...
When the schizont ruptures it will release approximately 20 merozoites back into the extracellular fluid. Here is an excellent photo of infected and rupturing erythrocytes, releasing the newly formed merozoites:
Now we begin to feel something....
As the new batch of merozoites are released from the burst erythrocytes, other pyrogenic (fever inducing) toxins are also released from the ruptured cell, which elicits an immune response. Indeed, on a population level, the malaria parasite is probably the most powerful stimulator of the human immune system known. The release of these merozoites and toxins from the lysed red blood cells correspond to the characteristic paroxysms of fever and chills. But we are saving a detailed discussion of the actual malarial disease for a later post, so let's return to the life cycle.
This second stage of asexual reproduction (the first being the in the hepatic schizont), which leads to the rupturing of the erythrocytic schizont and the release of about 20 merozoites takes about 48 hours for P. falciparum, P. vivax, and P. ovale, and about 72 hours for P. malariae. Once the newly formed merozoites are released from the ruptured erythrocytes, each then seeks out a new host erythrocyte and the process repeats again and again. The fecundity of this parasite is incredible. A single P. falciparum merozoite, for example, can potentially lead to 10 billion new parasites through these recurrent cycles!
After a number of the replicative cycles of the merozoites across multiple erythrocyte infection episodes, some gametocytes will begin to form along with the merozoites. The gametocytes will perform no further function in the intermediate human host. These gametocytes are, in fact, the sexual stage of the parasite and must be transfered to the mosquito since this is the definite host. And you will remember that the definitive host is where sexual reproduction takes place. The gametocytes can be taken up by any subsequent mosquito seeking a blood meal. Here's a picture of this stage:
Once the gametocytes are inside the mosquito gut, the next stage of development can begin, which is known as the sporogonic cycle. As the erythrocytes are ingested by the mosquito, the gametocytes are released into the gut and they begin sexual reproduction. Any merozoites that are also ingested are simply digested with all the other material and play no further role in the parasite's life cycle. But the macrogametocytes (female) and microgametocytes (male) survive and fuse in the mosquito gut, thus forming the zygote. This zygote will change form over the next 12-14 hours by elongating and developing into an ookinete, which then actively seeks out the wall of the mosquito gut, penetrates it, and finally develops into an oocyst. Over the next several days, the oocyst swells as it forms upwards of around 10,000 sporozoites within. When the oocyst ruptures it releases the sporozoites, which then migrate to the salivary glands of the mosquito where they are ready to be introduced into a new human host with the mosquito's next blood meal.
This completes this the general Plasmodium life cycle. And you thought your life was complicated! Please. Here is the CDC chart one more time to bring it all together:
The whole of the sporogonic life cycle in the mosquito takes approximately 7 to 12 days. But the time required can vary markedly, which depends on several things. First, it depends on the species of Plasmodium that is involved. Second, it depends on temperature, with higher temperatures corresponding to shorter duration needed for development. Third, it depends on humidity, with increased humidity also corresponding to less time to complete this phase of the parasite's life cycle. As an example, an outside temperature of 20 degrees C will extend the sporogonic cycle of P. falciparum to 23 days, which is longer than the average lifespan of many anopheline mosquitoes. As we will see later in this series, geography is a major influence on these three important determinants of the Plasmodium life cycle in the mosquito.
Below I am posting a very nice short video that displays the whole life cycle in an animation. It provides a good summary to everything discussed up to this point:
Now let's examine some important biologic differences between the Plasmodium species. P. vivax and P. ovale are unique in that not all sporozoites entering the hepatocytes proceed immediately to forming a schizont for the development of merozoites. A few will, instead, lie dormant in their host hepatocytes forming what are known as hypnozoites, i.e. a "sleeping" stage. The parasite can lie dormant in this stage for months to years. Later the hypnozoites will differentiate and form schizonts, which will give rise to a new wave of merozoites. This variant in P. vivax and P. ovale is the cause of relapse malaria. It also requires a specific treatment regimen that targets the hypnozoites so that relapses will not occur. While P. falciparum does not have a hypnozoite stage, and thus does not relapse, it is important to keep in mind that ineffective treatment or holoendemic geography (both of which will be discussed later in the series) can lead to low persistent parasitemia, which can cause recrudescent clinical infection. So it is important to distinguishing between recrudescent and relapse malaria by distinguishing between Plasmodium species.
Gametocyte production is an important biologic variant across Plasmodium species. Following infection with P. falciparum, gametocytes don't begin to appear until after several rounds of intraeryrthrocytic cycles of the merozoite form of the parasite (typically not less than 10 days). In P. vivax, however, gametocytes begin to appear in peripheral blood almost as soon as the intraerythrocytic merozoites begin their cycling. As a result gametocytes can be present and available for transmission to new mosquitoes before symptoms occur and treatment is sought. This means that the gametocytes that are transferred prior to treatment are not subject to selective pressures that would select for drug-resistant mutants. Therefore, drug-sensitive parasites are not at a selective disadvantage compared to dug-resistant parasites. On the other hand, P. falciparum transmission from humans to mosquitoes can be blocked since early treatment with an effective drug can stop erythrocytic schizont production before gametocytes are formed. However, inevitably treatment will not be effective enough to prevent all gametocytes from developing in all cases. So those that do develop will be derived from parasites that survived treatment and, thus, may be drug resistant. This staggering of gametocyte production assists the selection of drug resistant parasites, and indeed we do see much greater drug resistance in P. falciparum than in P. vivax.
Another important distinction between the Plasmodium species is their affinities for different erythrocyte types. This distinction also contributes to differences in their virulence. P. vivax and P. ovale only invade the young reticulocytes, which means that peripheral parasite density is typically low in these infections because the reticulocytes only comprise about 1% of the total erythrocytes in humans. P. malariae prefers older erythrocytes and so typically results in infections that are also limited. Only P. falciparum infects all types of erythrocytes. Thus, P. falciparum is able to produce high density parasitemias that result in high morbidity and mortality relative to the other three species.
This will conclude Part 1 of the series and our discussion of the parasite that causes malaria. There is much yet to cover. More nuance of the parasite will become apparent as we discuss the other facets of the disease. Next time I'll describe the malaria vector: anopheline mosquitoes.
The life cycle of this parasite is extraordinarily complex and involves multiple stages within each of its definitive (i.e. mosquitoes) and intermediate (i.e. humans) hosts. Let's stop for a second here. What do I mean by intermediate and definitive hosts? In parasitology, there are many parasites that have evolved complex life cycles that require more than one host animal species for completion. When this is the case, the definitive host refers to that animal host in which the sexual reproductive stage of the parasite occurs. Any other animal host corresponding to other intermediate non-sexual stages of the parasite is known as an intermediate host. In the life cycle of Plasmodium, mosquitoes are the definitive hosts and humans (among other vertebrate animals) are the intermediate hosts.
So let's examine this life cycle in some detail. Here is a nice depiction of the complete life cycle published by the Centers for Disease Control and Prevention (CDC):
When the mosquito takes a blood meal, she injects her saliva, which is a cocktail of chemicals to aid in her collection of blood. As she does this, if she is infected with the malaria parasite, she will also inject a particular stage of Plasmodium that collects in her salivary glands: the sporozoites. The sporozoites are the form of the parasite that cause the initial infection in humans (or any other intermediate host). The first picture in this posting was a close-up of a sporozoite. Here it is again:
Here is another nice picture depicting the sporozoite next to two other stages of the parasite that we'll be discussing shortly:
The sporozoites are completely motile, slender protozoan cells that, when introduced into the subcutaneous tissues and capillary beds of the host, make their way to the liver by way of the venous circulation. They can make their way from the point of inoculation by the mosquito to target cells in the liver in minutes if they are successful in evading the immune system. There will be many sporozoites introduced into the host with a single mosquito bite, and each seeks out a hepatic cell (liver cell) in the host where it will begin the next stage of its development. Once inside a hepatic cell, the sporozoite will begin to replicate itself thousands of times over the next 5 to 15 days. As it does so, it forms a hepatic schizont in the hepatic cell, which is essentially a small parasite factory. When the schizont ultimately ruptures, it releases tens of thousands of the new stage of the Plasmodium parasites: the merozoites. This legion of merozoites will emerge from each hepatic cell that was infected with a sporozoite (except in the case of those Plasmodium species that harbor an additional stage, called the hypnozoite, which we'll discuss shortly). So, between roughly one to two weeks after the initial mosquito bite, the host is under attack by a tremendous army of parasites.
And, yet, up to and including this point in the infection, we feel nothing....
No signs. No symptoms.
OK. The merozoites are released into the circulating blood from the hepatic schizonts, and they are in search of something: red blood cells. The merozoites seek out these red blood cells, or erythrocytes as they are also known, and attach and enter the cells by way of specific receptors on the eryrthrocyte surface.Once it gains entry, this stage of the parasite begins to change again, differentiating into a trophozoite, which is the feeding stage of the parasite. At this point the trophozoite is feeding on the hemoglobin of the erythrocyte that it has hijacked. It will then begin replication creating new intraerythrocytic merozoites, enlarging the cell and forming another schizont.
Still we feel nothing from the infection...
When the schizont ruptures it will release approximately 20 merozoites back into the extracellular fluid. Here is an excellent photo of infected and rupturing erythrocytes, releasing the newly formed merozoites:
Now we begin to feel something....
As the new batch of merozoites are released from the burst erythrocytes, other pyrogenic (fever inducing) toxins are also released from the ruptured cell, which elicits an immune response. Indeed, on a population level, the malaria parasite is probably the most powerful stimulator of the human immune system known. The release of these merozoites and toxins from the lysed red blood cells correspond to the characteristic paroxysms of fever and chills. But we are saving a detailed discussion of the actual malarial disease for a later post, so let's return to the life cycle.
This second stage of asexual reproduction (the first being the in the hepatic schizont), which leads to the rupturing of the erythrocytic schizont and the release of about 20 merozoites takes about 48 hours for P. falciparum, P. vivax, and P. ovale, and about 72 hours for P. malariae. Once the newly formed merozoites are released from the ruptured erythrocytes, each then seeks out a new host erythrocyte and the process repeats again and again. The fecundity of this parasite is incredible. A single P. falciparum merozoite, for example, can potentially lead to 10 billion new parasites through these recurrent cycles!
After a number of the replicative cycles of the merozoites across multiple erythrocyte infection episodes, some gametocytes will begin to form along with the merozoites. The gametocytes will perform no further function in the intermediate human host. These gametocytes are, in fact, the sexual stage of the parasite and must be transfered to the mosquito since this is the definite host. And you will remember that the definitive host is where sexual reproduction takes place. The gametocytes can be taken up by any subsequent mosquito seeking a blood meal. Here's a picture of this stage:
Once the gametocytes are inside the mosquito gut, the next stage of development can begin, which is known as the sporogonic cycle. As the erythrocytes are ingested by the mosquito, the gametocytes are released into the gut and they begin sexual reproduction. Any merozoites that are also ingested are simply digested with all the other material and play no further role in the parasite's life cycle. But the macrogametocytes (female) and microgametocytes (male) survive and fuse in the mosquito gut, thus forming the zygote. This zygote will change form over the next 12-14 hours by elongating and developing into an ookinete, which then actively seeks out the wall of the mosquito gut, penetrates it, and finally develops into an oocyst. Over the next several days, the oocyst swells as it forms upwards of around 10,000 sporozoites within. When the oocyst ruptures it releases the sporozoites, which then migrate to the salivary glands of the mosquito where they are ready to be introduced into a new human host with the mosquito's next blood meal.
This completes this the general Plasmodium life cycle. And you thought your life was complicated! Please. Here is the CDC chart one more time to bring it all together:
The whole of the sporogonic life cycle in the mosquito takes approximately 7 to 12 days. But the time required can vary markedly, which depends on several things. First, it depends on the species of Plasmodium that is involved. Second, it depends on temperature, with higher temperatures corresponding to shorter duration needed for development. Third, it depends on humidity, with increased humidity also corresponding to less time to complete this phase of the parasite's life cycle. As an example, an outside temperature of 20 degrees C will extend the sporogonic cycle of P. falciparum to 23 days, which is longer than the average lifespan of many anopheline mosquitoes. As we will see later in this series, geography is a major influence on these three important determinants of the Plasmodium life cycle in the mosquito.
Below I am posting a very nice short video that displays the whole life cycle in an animation. It provides a good summary to everything discussed up to this point:
Now let's examine some important biologic differences between the Plasmodium species. P. vivax and P. ovale are unique in that not all sporozoites entering the hepatocytes proceed immediately to forming a schizont for the development of merozoites. A few will, instead, lie dormant in their host hepatocytes forming what are known as hypnozoites, i.e. a "sleeping" stage. The parasite can lie dormant in this stage for months to years. Later the hypnozoites will differentiate and form schizonts, which will give rise to a new wave of merozoites. This variant in P. vivax and P. ovale is the cause of relapse malaria. It also requires a specific treatment regimen that targets the hypnozoites so that relapses will not occur. While P. falciparum does not have a hypnozoite stage, and thus does not relapse, it is important to keep in mind that ineffective treatment or holoendemic geography (both of which will be discussed later in the series) can lead to low persistent parasitemia, which can cause recrudescent clinical infection. So it is important to distinguishing between recrudescent and relapse malaria by distinguishing between Plasmodium species.
Gametocyte production is an important biologic variant across Plasmodium species. Following infection with P. falciparum, gametocytes don't begin to appear until after several rounds of intraeryrthrocytic cycles of the merozoite form of the parasite (typically not less than 10 days). In P. vivax, however, gametocytes begin to appear in peripheral blood almost as soon as the intraerythrocytic merozoites begin their cycling. As a result gametocytes can be present and available for transmission to new mosquitoes before symptoms occur and treatment is sought. This means that the gametocytes that are transferred prior to treatment are not subject to selective pressures that would select for drug-resistant mutants. Therefore, drug-sensitive parasites are not at a selective disadvantage compared to dug-resistant parasites. On the other hand, P. falciparum transmission from humans to mosquitoes can be blocked since early treatment with an effective drug can stop erythrocytic schizont production before gametocytes are formed. However, inevitably treatment will not be effective enough to prevent all gametocytes from developing in all cases. So those that do develop will be derived from parasites that survived treatment and, thus, may be drug resistant. This staggering of gametocyte production assists the selection of drug resistant parasites, and indeed we do see much greater drug resistance in P. falciparum than in P. vivax.
Another important distinction between the Plasmodium species is their affinities for different erythrocyte types. This distinction also contributes to differences in their virulence. P. vivax and P. ovale only invade the young reticulocytes, which means that peripheral parasite density is typically low in these infections because the reticulocytes only comprise about 1% of the total erythrocytes in humans. P. malariae prefers older erythrocytes and so typically results in infections that are also limited. Only P. falciparum infects all types of erythrocytes. Thus, P. falciparum is able to produce high density parasitemias that result in high morbidity and mortality relative to the other three species.
This will conclude Part 1 of the series and our discussion of the parasite that causes malaria. There is much yet to cover. More nuance of the parasite will become apparent as we discuss the other facets of the disease. Next time I'll describe the malaria vector: anopheline mosquitoes.