The Parasite Life Cycle
An Quantitative Overview
The life cycle of malaria parasites is a good entry point for understanding malaria. Starting with the zygote stage in the mosquito, we describe parasite development in the mosquito through a bite that transmits parasites in saliva and infects a human. Next, we trace parasite development in the human until parasites are taken up in a blood meal and infect a mosquito. The life-cycle of the parasite is the scaffolding for the study of malaria.
Plasmodium falciparum and other malaria parasites have a complex life cycle (Figure 1): each stage has a different form, expresses different genes, and occupies different habitats in two different hosts.
P. falciparum is a eukaryotic organism, but it is only diploid for a short time as a zygote in the mosquito midgut; the moquito is thus called the definitive host. From the lumen (interior space) of the mosquito midgut, the parasite encysts in the mosquito midgut, ruptures into the hemocoel (open body cavity), and migrates to the salivary glands. P. falciparum sporozoites move from a mosquito into a human in mosquito saliva when it bites.
In the human, the mosquito moves from the dermis into the blood stream and then the liver, where it infects a hepatocye (a liver cell). After approximately six days in the liver, the parasites emerge into the blood stream again as merozoites that infect red blood cells. Inside the red blood cell, the parasites replicate, making more merozoites. Some of these merozoites make a developmental switch, so that in the next red blood cell they infect, they become either macrogametocytes (female) or microgametocytes (male). The gametocytes sequester in deep tissues, and then emerge into the bloodstream where they are taken up by a mosquito in a blood meal. Inside the mosquito, a macrogametocyte fuses with a microgametocyte to form a zygote.
The life cycle is merely a starting point for understanding malaria in humans. If we take a quantitative approach to the life cycle, we can ask how many times the parasite replicates in each stage and how long it takes. A study of the parasite life cycle can only take us so far.
If we want to understand malaria in humans, we must begin to develop a quantitative understanding of parasite population biology. This points us to a different set of questions: How long does a human infection last? What are lags for latency and incubation in humans and mosquitoe? How does the parasite manage to evade the immune system? What limits parasite densities in human blood? What is the relationship between infection and human disease? At what points in the life cycle can we intervene?
To understand malaria in humans, we must also study mosquitoes and the parasite in the mosquito. Like parasites, mosquitoes have a complex life cycle. Adult female mosquitoes feed on blood; the protein in blood is used by the mosquito to make mosquito eggs. The eggs are laid in aquatic habitats, where they hatch into a larval form. Mosquitoes are homometabolous insects; like butterflies, the larvae molt into four distinct larval instars befor pupating.
Some basic questions about the parasite life cycle that can not be answered by merely studying the parasite. Some details about parasites in the mosquito and human also matter. The life cycle require that a parasite get transmitted twice: gametocytes are taken up by a mosquito in a blood meal, infecting a mosquito; and sporozoites are passed from the mosquito in a bite, infecting a human. In biological terms, this is a generation. How long does it take from blood meal to bite? How long from bite to blood meal? If we follow the parasite through one full generation, how many offspring would there be? The measure of reproductive success for P. falciparum is how many zygotes per zygote: if we started counting from one infected mosquito, how many infected mosquitoes would there be after one parasite generation? How far do parasites move in infected mosquitoes from blood meal to bite? How far to parasites move in infected humans from bite to blood meal? The answer to these questions vary by location and time of year, and the underlying causes are related to mosquito ecology, human behaviors, and other factors.
Many of these questions will be in explored in other vignettes. Here, we walk through the life cycle stage by stage, drawing attention to some details and identifying some terms.
In the Mosquito
The zygote forms in a mosquito, so the mosquito is called the definitive host for Plasmodium falciparum. The following describes four stages of parasite development in the mosquito from the blood meal to the bite.
The zygote marks the beginning of the parasite’s life cycle, but to tell the story, we must go back just a bit to the end. A zygote forms when at least one macrogametocyte (female) and one microgametocyte (male) are present in a blood meal. While enzymes are digesting the blood, the zygote forms in the lumen (the interior space) of the mosquito mid gut. (We will come back to formation of gametocytes in humans at the end.)
The gametocytes are initially enveloped in the membrane of the red blood cell they infected in the human host. The microgametocyte exflagellates, the macrogametocyte sheds its protein coat, and the gametocytes become gametes. The microgamete finds a macrogamete, and they fuse to form a zygote.
- How does a microgamete find a macrogamete? [1]
The Zygote
The zygote stage is short; the whole process takes less than 24 hours, and there is only one round of replication: two cells (a microgametocyte and a macrogametocyte) fuse, and create a single ookinete with four distinct haploid gemomes. The ookinete invades the cells of the mid gut.
The zygoes stage is critical, however, for parasite genetics. It is important to understand that parasites can recombine sexually, and that each zygote can produce four distinct haploid genomes. The zygote is the only parasite life stage that is diploid.
This process of sexual recombination in parasites doesn’t work exactly the same way a it does in mammals, or other organisms that are [2]. In other organisms, the point of meiosis is to produce haploid gametes from a diploid cell. In Plasmodium, meiosis occurs directly after after fertilization in the developing zygote. To put it in other terms, humans spend decades as diploid organisms. The human germ line – sperm and eggs – are both diploid cells that are carried around inside us, separate from the somatic cells. At fertilization, two diploid cells fuse.
The process is different in parasites, because the parasite spends almost all of its time haploid. After fertilization, the parasite becomes diploid and remains diploid for only a few hours. The zygote DNA (2N) is duplicated (i.e., pre-meiotic replication) to form a tetraploid cell (4N), followed by two rounds of chromosome segregation to form four discrete haploid genomes, contained within a single nucleus in the fully mature ookinete. The process takes less than 24 hours.
For parasite genetics, the relationship between the microgametocyte and macrogametocyte matter. If the gametes are clones, then the four haploid cells can have different combinations of the somatic mutations that accumulated from mutations acquired at some point in development since the last zygote.
While the mature ookinete thus contains four distinct genomes, later events in the oocyst might change the balance.
The Ookinete
A motile, banana-shaped form that develops in the mosquito midgut lumen as the final stage of meiosis. The ookinete invades the midgut epithelium and becomes an oocyst.
The ookinete invades the mosquito gut wall and develops into an oocyst where endomitosis (sporogony) results in the production of hundreds of haploid sporozoites that will migrate to the mosquito’s salivary glands to infect the vertebrate host.
The Oocyst
A thick-walled parasite life-stage embedded in the midgut epithelium.
The time elapsed from the blood meal to the formation of an oocyst is typically 18-24 hours.
Inside the oocyst, hundreds of parasites form. The process is called sporogony.
- What is the distribution of the number of oocysts per mosquito? [4]
Sporozoites
Sporozoites migrate through the mosquito homocoel into the mosquito salivary glands. Once the sporozoites are found in the mosquito salivary glands, the mosquito is presumed to be infectious.