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Description of the Pathogen
Giardia was probably described in the late 1600s, when van Leeuwenhoek likely discovered it in his own stool. It was in the early 1900s that the parasite received the genus name Giardia. The designated species name for the human parasite has been lamblia ; intestinalis and duodenalis are also used. The genus Giardia is in the category of intestinal flagellates in the division Protozoa. The life cycle of G. lamblia has two stages: the motile dividing trophozoite present in the intestine of the host, and the environmentally resistant infectious cyst excreted in the feces. The trophozoite is 9 to 21 µm long and 5 to 15 µm wide ( Fig. 279.1A ). It has a convex dorsal surface and a flat ventral surface containing a disk with contractile proteins used for attachment (sucking or adhesive disk). There are four pairs of posteriorly directed flagella that are involved in locomotion and perhaps attachment. The protozoan has two anteriorly placed diploid nuclei, each with a prominent central karyosome and a complete copy of the genome. In stained preparations, the nuclei create the characteristic facelike image. Each of the two Giardia nuclei maintains a high degree of homozygosity, most likely through fusion and exchange of DNA during encystation. Median bodies—tight collections of microtubules—are visualized transversely in a clawlike manner in G. lamblia and have been used to identify morphologically distinct types of Giardia. Of the Giardia spp., only G. lamblia has been successfully cultured in vitro. Growth is enhanced by the presence of biliary lipids and a high concentration of cysteine, consistent with the predilection of Giardia for colonizing the upper small bowel. The trophozoite divides by longitudinal binary fission and has a doubling time in culture of 6 to 12 hours. It is an aerotolerant anaerobe that scavenges oxygen to enhance survival. Giardia uses glucose as the major source of carbohydrate energy, metabolizing it to the end products of acetate, ethanol, alanine, and carbon dioxide; adenosine triphosphate (ATP) is generated during this process. Metabolism of arginine via the arginine dihydrolase pathway is another mechanism for ATP generation.
The differentiation of Giardia into species traditionally depended on morphology and the host of origin, with a number of species described: G. lamblia in humans, Giardia muris in mice, Giardia agilis in amphibians, Giardia psittaci in parakeets, and Giardia microti in voles and muskrats ( Table 279.1 ) However, molecular studies later revealed morphologically identical Giardia that were found in both humans and animals. The earliest molecular typing of these Giardia isolates divided them into at least three groups, which were subsequently renamed and expanded into eight genotypes or referred to as assemblages A to H based on sequence differences in housekeeping genes (see Table 279.1 ). Assemblages A (often subtype AII) and B are associated with most but not all human infections and a number of nonhuman mammalian hosts. Their biology, biochemistry, and molecular mechanisms differ and fit criteria to be separate species. Occasional infections with non-A, non-B assemblages, including assemblage E, have been reported in humans. Improved sequencing methods using a broader sampling of isolates will better define genetic diversity and range of Giardia genotypes.
TABLE 279.1
Typing of Giardia Species
Modified from Feng Y, Xiao L. Zoonotic potential and molecular epidemiology of Giardia species and giardiasis. Clin Microbiol Rev . 2011;24:110–140.
| NAME | GENOTYPE | HOST RANGE |
|---|---|---|
| Giardia agilis | Amphibians | |
| Giardia ardeae | Birds | |
| Giardia microti | Muskrats and voles | |
| Giardia muris | Rodents | |
| Giardia psittaci | Birds | |
| Giardia lamblia | Assemblage A | Humans, primates, dogs, cats, cattle, sheep, deer, rodents |
| Assemblage B | Humans, primates, dogs, cattle, horses, beaver | |
| Assemblage C | Dogs | |
| Assemblage D | Dogs | |
| Assemblage E | Cattle, goats, sheep, pig | |
| Assemblage F | Cats | |
| Assemblage G Assemblage H |
Rodents Marine vertebrates |
Different G. lamblia genotypes have unique capacities to establish infection and to cause disease in animal models and experimental human infections, but whether specific genotypes differ in virulence in human natural infections is unclear.
Some Unique Biologic Aspects
The genome of the prototypic assemblage A isolate, WB ( http://giardiadb.org ), is approximately 11.7 Mb, distributed over five chromosomes. Analysis of its small subunit ribosomal RNA sequence and genes of certain pathways indicate that it is one of the earliest-branching eukaryotes. The genome is compact and simplified, including DNA synthesis, transcription, RNA processing, and cell-cycle machinery. The parasite contains only a few introns, extremely short promoters, sometimes 60 bp or less, overlapping transcriptional controlling elements, and mitosomes, remnants of earlier mitochondria. Pathways to synthesize phospholipids, fatty acids, cholesterol, and purine and pyrimidine nucleosides are reduced or lacking, so these essential metabolic building blocks are largely scavenged from the small intestine milieu. There are only enzymes sufficient for remodeling but not synthesis of lipid membrane components. Except for alanine, amino acids are taken up from the environment.
Because Giardia is an early-branching, highly adapted organism and an important disease-causing parasite, many aspects of its unique biology have been extensively studied and reviewed elsewhere. However, a few important examples of its particularities include surface antigenic variation, a unique vesicular transport system devoid of a Golgi apparatus, and the processes of encystation and excystation.
Giardia is the only known intestinal dwelling organism to undergo frequent surface antigenic variation. A single variant-specific surface protein (VSP) is expressed on the surface of Giardia and, after several generations, is replaced by another VSP. VSPs are a family of about 250 cysteine-rich proteins with similar motifs and general structure and a conserved transmembrane carboxyl-terminal sequence. Although all VSPs are transcribed, only one is expressed. The others VSPs are possibly eliminated by interference RNA mechanisms. Antigenic variation occurs during infection of humans and animals, in vitro in culture, and during encystation. Although it is important in evading the host immune response, certain VSPs are favored or disallowed even in the absence of an adaptive immune response. Specific VSPs seem to have unique physical-chemical characteristics that allow them to be biologically selected and expressed or disfavored and not expressed, depending on the intestinal environment and host.
G. lamblia trophozoites encyst to form fibrillary, oval, thin-walled cysts 8 to 12 µm long and 7 to 10 µm wide (see Fig. 279.1B ). Giardia encystation is a model system for vesicular transport and developmental biology because Giardia lacks a typical Golgi apparatus that is an essential component of vesicular transport in most higher organisms. Encystation induced in vitro is a complex process involving many of Giardia's basic processes The early phase is characterized by the formation of highly characteristic encystment vesicles (ESVs), in which cyst wall proteins (CWPs) 1 through 3 and other molecules are processed. The late phase of encystation consists of transport of the CWPs to the cell surface, their assembly with N -acetylgalactosamine (GalNAc) into the cyst wall, and then nuclear division and DNA replication without cell division so that cysts are generated with a ploidy of 16N. At ultrastructural analysis, the cyst wall contains CWPs and GalNAc polymer in insoluble fibrils.
Excystation is a highly coordinated process that is initiated when cysts are exposed to environmental stimuli, such as gastric acid and pancreatic enzymes. The process is complex and well described morphologically but not well understood on a molecular level. An excyzoite containing four nuclei (4N each) is released; this divides twice without further DNA replication, resulting in four daughter trophozoites.
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