Cell Biology of the Apicomplexa: Part 1 Lecture Notes

Key Words

Protozoa, eukaryotic evolution, subcellular organelles, parasite life cycles, Apicomplexa, Plasmodium, Toxoplasma, apical complex, rhoptry, microneme, plastid, inner membrane complex, parasitophorous vacuole, conoid, cytokinesis, schizogony, endodyogeny

Lecture Notes

Introduction
While animals and plants are more visible to the naked eye, protozoa (unicellular organisms) constitute the majority of Eukaryotic life.  Studying the biology of a model parasitic protozoan can therefore provide insight into the basic biology of eukaryotes (whose cells contain a nucleus, as distinct from bacteria and archaebacteria).  Of course, studying these organisms also provides insight into host-parasite interactions and mechanisms of pathogenesis.

The Phylum Apicomplexa encompasses over 5,000 species of unicellular parasitic protozoa, many of which cause serious disease in humans.  For example, Plasmodium parasites are transmitted by mosquitoes, infect red blood cells and cause malaria, a disease with devastating impact on children in sub-Saharan Africa, Southeast Asia and South America.  Other Apicomplexan parasites of medical importance include Cryptosporidium and Toxoplasma, which infect a large percentage of the population worldwide, and can cause debilitating and potentially fatal illness in immunocompromised individuals.  Toxoplasma is a leading cause of congenital neurological birth defects, transmitted by consumption of undercooked meat or ingestion of material contaminated with cat feces (this is why pregnant women are advised not to empty the kitty litter box!)

Using Toxoplasma as a model to understand what is shared with other eukaryotes, and what is unique
Although they cause very different diseases, all apicomplexan parasites originated from a common ancestor and consequently share many characteristics: 

• All are obligate intracellular parasites ... they must invade and replicate within host cells in order to survive.
• They traverse a complex life cycle, differentiating (developing) through various forms, often in different host species/tissues in the course infection.  In particular, sexual and asexual reproduction often occur in different species (such as mosquitoes and humans for Plasmodium).
• From a cell biological perspective, apicomplexan parasites contain all of the organelles one might expect in a eukaryote, including the nucleus, endoplasmic reticulum, Golgi apparatus, and mitochondrion.

Apicomplexan parasites also possess distinctive subcellular organelles, including:

• Specialized secretory organelles, termed rhoptries and micronemes, that deploy their cargo in a coordinated fashion during parasite attachment to the host cell, invasion, establishment of the intracellular "parasitophorous vacuole" within which they reside and replicate, and modulation of the host cell.
• A plastid organelle, known as the "apicoplast" (apicomplexan plastid), acquired through "secondary endosymbiosis", in which an ancestral parasite ate a eukaryotic alga, and retained the algal plastid (see lecture 2).

Despite the medical importance, and inherent biological interest, of these parasites, the feasibility of laboratory investigation depends on accessibility to experimental manipulation.  Several key features make Toxoplasma experimentally tractable as a model organism:

• Easily cultivated in the laboratory.
• Mouse infection and disease provides a good model for human toxoplasmosis.
• Genetic crosses can be carried out in cats (without harming the cat).
• Amenable to modern molecular techniques (parasite genes can be removed, replaced, or foreign genes can be inserted).
• Complete genome sequence is available, along with various tools and reagents for functional genomics (e.g. microarrays) and bioinformatic analysis (see lecture 3)
• Outstanding ultrastructural resolution for cell biological studies.

How Toxoplama (and other apicomplexan parasites) replicate.
Once the parasite has invaded a host cell, its survival is critically linked to replication. The replicative process occurs entirely within a specialized intracellular vacuole termed the parasitophorous vacuole.  As the parasite divides, the host cell swells and eventually bursts (a lytic infection), causing disease through direct tissue damage.  Similarly, in malaria, Plasmodium parasites lyse infected red blood cells, causing anemia (other factors may also exascerbate anemia in severe disease).  Toxoplasma damages multiple organs systems, but is particularly noted for its ability to quickly destroy brain and fetal tissues.

Apicomplexan parasites replicate via an unusual process in which daughter parasites are assembled within a single mother cell.  In the asexual "tachyzoite" stages of Toxoplasma infection, two daughter cells emerge from each mother (endodyogeny).  In Plasmodium "merozoites", up to 16 or more daughters form within a single mother cell ("schizogony").  Assembly of daughter cells within the mother offers several advantages, such as the ability to eliminate indigestible waste products (such as the toxic heme left over after digestion of hemoglobin by Plasmodium) by simply leaving them behind.  These parasites don't need lysosomes!  Assembly of the cytoskeleton from the top (apical end) down, also ensures that polarity is preserved, as required for invasion of the host cell.  Replication by endodyogeny or schizogony also poses challenges: a complex process is required to ensure that each daughter inherits a complete set of organelles.   Note that unlike division in the typical 'textbook' eukaryotic cell, "M" phase (including organellar replication) is a lengthy process, completely encompassing the DNA replication hallmark of "S" phase.  This suggests that unique checkpoints are likely to operate in the apicomplexan cell cycle.

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