Taxoplasmosis
Taxoplasmosis
Taxoplasmosis
Lloyd H Kasper, Dartmouth College, Hanover, New Hampshire, USA Article Contents
. Overview and Background
Toxoplasmosis is the disease caused by infection with the obligate intracellular parasite, . Epidemiology
Toxoplasma gondii. Both acute and chronic toxoplasmosis are conditions in which the . Life Cycle and Morphology
parasite is responsible for the development of clinically evident disease. . Modes of Transmission
. Host–Parasite Interrelationships and Laboratory
Culture
Overview and Background . Molecular Approaches
. Pathogenesis and Phases of Disease Development
Toxoplasma gondii is an intracellular coccidian that infects
. Host Immune Response
a wide range of mammals and birds. It was first described in
. Clinical and Laboratory Diagnosis
1908 by Nicolle who, along with his colleague Manson,
. Treatment and Prevention
identified the parasite in the African rodent, Ctenodactylus
gondi, from which it derives its species name. T. gondii has
been assigned to the phylum Apicomplexa and class
Sporozoa. The genus name refers to the bow-shaped
(toxon) morphology of the organism. In humans, acute Life Cycle and Morphology
toxoplasmosis caused by infection with this parasite is of
limited duration. Toxoplasmic encephalitis, due to recru- There are two distinct aspects of the life cycle of T. gondii: a
descent infection, occurs in the setting of a compromised nonfeline and a feline cycle. The nonfeline, asexual
immune system such as those with acquired immune tachyzoite form of this parasite occurs within intermediate
deficiency disease (AIDS). Congenital toxoplasmosis is an hosts, such as humans, mice, sheep and swine. T. gondii
infection of newborns resulting from the transplacental grows in all mammalian cells except red blood cells, which
passage of parasites from an infected mother to the fetus. they enter but do not divide in. During acute infection,
Toxoplasma infection in domestic animals, in particular parasites can be found in many organs of the body.
ruminants, is a frequent cause of abortion and is of Tachyzoites grow readily in culture. They are crescent-
considerable veterinary concern. shaped eukaryotic cells approximately 7 mm in length and
2 mm wide (Figure 1). The tachyzoites contain many
cytological features of eukaryotic cells, including a
nucleus, Golgi apparatus and endoplasmic reticulum
Epidemiology (ER). Recently, the tachyzoites have been shown to
contain an apicoplast which is a deoxyribonucleic acid
T. gondii can infect virtually any nucleated host cell, which (DNA)-containing organelle unique to many of the
may account for its broad distribution. Human infection apicomplexans.
with this parasite is prevalent throughout the world, The tachyzoite contains well over 1000 proteins, a
making it one of the most common parasitic infections of number of which have been catalogued to parasite-specific
humans. Generally, hot, arid climatic conditions are organelles. Among the predominant proteins are the
associated with low prevalence of infection. In the United surface antigens (SAGs), as well as proteins derived from
States and most European countries, the incidence of the characteristic apicomplexan organelles, including the
becoming seropositive increases with age and exposure. micronemes, rhoptries and dense granules. Some of the
For example, in the USA, 5–30% of individuals aged 10– parasite proteins, in particular the SAG proteins, are
19 years and 10–67% of those over the age of 50 years parasite life-cycle stage specific, for example bradyzoite
demonstrate serological evidence of previous exposure. surface antigens (Kasper and Ware, 1989).
The increase in the proportion of the population becoming Tachyzoites have a three-layer membrane: a pellicle and
seropositive is approximately 1% per year. In Central a posterior and anterior polar ring. The subpellicular
America, France, Turkey and Brazil, the incidence of cytoskeleton is composed of microtubules that stretch
seropositivity is much higher and may approach 90% of from anterior to posterior aspects of the tachyzoite. The
adults by the time they reach 40 years of age. The high conoid, a hollow truncated cone of fibres, is located at the
prevalence rate is probably due to the ubiquity of the anterior pole. At least two unconventional myosins have
parasite in the environment and exposure via the ingestion been identified from the parasite (Heintzelman and
of undercooked meat or contaminated soil. Schwartzman, 1997). Toxoplasma invasion of mammalian
cells is powered by the actin cytoskeleton of the parasite
(Dobrowolski and Sibley, 1996). Two intracellular
ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net 1
Toxoplasmosis
Figure 1 Structure of a tachyzoite of Toxoplasma gondii (a) Freeze–fracture electron micrograph of a tachyzoite. (b) Diagram of organelles that are not
demonstrated in (a). The surface antigens are involved in attachment and are the primary antigens identified by the infected host. Microneme proteins
are released at the onset of the invasion process. The contents of the rhoptries are secreted during the process of invasion. Dense granule proteins are
secreted from the parasite after invasion, during replication, and before egress from the infected host cell.
organelles, the rhoptries and micronemes, end within the culture), the cell ruptures, releasing tachyzoites that infect
conoid and are involved in host cell invasion. The rhoptries adjoining cells. In this manner, an infected organ soon
are club shaped and have characteristics associated with shows evidence of a cytopathic process. Most of the
secretory glandular cells. Micronemes contain N-terminal tachyzoites are eliminated by the host humoral and cell-
signal sequences that may serve to target proteins to the mediated immune response. Some 7–10 days after the
ER, as well as hydrophobic stretches which may be systemic tachyzoite infection, tissue cysts that contain
involved in transmembrane domains. The dense granules many bradyzoites develop. The mechanism responsible for
are secretory organelles which are located throughout the stage conversion from tachyzoite to bradyzoite is not well
parasite and contain N-terminal signal sequence proteins. understood. Although a role for nitric oxide has been
These organelles are similar in appearance to the dense suggested, recent observations in inducible nitric oxide
matrix granules found in mammalian exocrine or neu- synthase-deficient mice indicate that other host factors are
roendocrine cells. A unique organelle found within the involved in this transformation. The slow-growing brady-
stacked Golgi apparatus and common to a variety of zoites contained within a tissue cyst are found primarily in
Apicomplexa including Plasmodia is the apicoplast (Koh- the central nervous system or muscle of the host. These
ler et al., 1997). This 35-kilobase circular extrachromoso- cysts contain a variable number of bradyzoites depending
mal DNA organelle is surrounded by four membranes. on the age of the cyst.
Phylogenetic analysis of the tufA gene encoded by the Morphologically, the bradyzoites are similar to tachy-
apicoplast grouped this organellar genome with cyano- zoites with only nominal differences noted in the structure
bacteria and plastids, showing consistent clustering with of their rhoptries. When cysts are ingested (i.e. humans eat
green algal plastids. This would suggest that the Apicom- undercooked meat products), the cyst membrane under-
plexa acquired a plastid by secondary endosymbiosis, goes rapid digestion in the presence of the acidic pH of
probably from a green alga, or that they evolved from the gastric secretions. In nonfeline hosts, the ingested brady-
same common ancestor as dinoflagellates? zoites enter the small intestinal epithelium and transform
Once the tachyzoite enters the host cell it begins to into rapidly dividing tachyzoites. Spontaneous release of
replicate by endodyogeny, a process similar to binary encysted parasites which undergo rapid transformation
fission. Division time is usually 6–8 h for the more virulent into tachyzoites within the central nervous system is the
strains. When the number of parasites within the infected hallmark of active infection.
cell approaches a critical mass (usually 64–128 in tissue
2
Toxoplasmosis
The sexual life cycle of the parasite occurs within the Transplacental transmission
intestine of the cat. The enteroepithelial cycle begins in the
intestine of the cat with the ingestion of the bradyzoite About one-third of all women infected during pregnancy
tissue cysts, and culminates after several intermediate will transmit the parasite to the fetus. Gestational age at the
stages in the production of microgametes and macro- time of infection is the most critical factor to determine the
gametes. Gamete fusion produces a zygote that is excreted outcome for the fetus. There are few data to support
in the faeces as an unsporulated oocyst. Unsporulated recrudescent maternal infection as the source of congenital
oocysts are spherical and approximately 12 mm in dia- disease. Maternal infection early in pregnancy has the
meter. Once outside the cat, sporulation (the process of lowest transmission rate, but is of greatest severity to the
becoming a sporozoite) occurs in 2–5 days. Each oocyst fetus. In the third trimester, the incidence of infection is
contains two sporocysts, within which four sporozoites can greatest (65%), but the disease is usually asymptomatic at
be identified. At the ultrastructural level, the sporozoite birth. Few women (less than 20%) infected with T. gondii
appears similar to the tachyzoite, with some differences show clinical signs of infection.
observed in the number of suborganelles. The sporulated
oocyst may be ingested by an intermediate host such as a
pregnant woman emptying a litter box, a pig in the barn
yard, or perhaps a mouse. Once freed from the oocyst by
Host–Parasite Interrelationships and
digestion, the released sporozoites infect the intestinal Laboratory Culture
epithelium of the nonfeline host. Upon infection of the host
cell, the sporozoite produces a unique vacuolar space Unlike many other microbial organisms that utilize
before transformation into the rapidly dividing asexual phagocytosis as a mode of entry into the host cell, the
tachyzoite. Apicomplexa penetrate by a complex process that requires
the various specialized organelles discussed above. The
first step in the invasion process is attachment of the
parasite to the host cell (Figure 2). Recent evidence suggests
Modes of Transmission that this attachment process may be mediated in part by
3
Toxoplasmosis
SAG-1, the major surface antigen of the parasite (Grim- Molecular Approaches
wood et al., 1996). Following attachment, transmembrane
proteins are secreted from the micronemes and assist the In-depth genetic analysis of the parasite has been achieved
entry process, perhaps by anchoring the parasite to the because the natural biology of the system allows for genetic
membrane of the host (Carruthers and Sibley, 1997). mapping of the F1 progeny from a cross. Both the asexual
Within seconds, proteins are secreted from the rhoptries tachyzoite and bradyzoite stage of the parasite are haploid.
that enhance entry of the parasite into the host. Some of the The parasite genome is estimated at 8 107 base pairs. By
rhoptry proteins may be inserted into the membrane of the pulse field analysis there are 11 genetic linkage groups that
parasitophorous vacuole (PVM) (Beckers et al., 1994). correspond to 10 bands, ranging from 2 to 4 8 megabase
Once invasion is complete (the entire process occurs in pairs. The parasite also contains two extrachromosomal
seconds), the parasite resides, develops, and replicates organellar genomes, a mitochondrion and the recently
within the PVM. The fate of the vacuole and PVM differs described plastid-like 35 kb circle.
from that of the phagolysosome. The PVM, formed during Restriction fragment length polymorphism analysis has
the process of invasion, prevents acidification and protects demonstrated that the recombination frequency is low (1%
the parasites from digestion by the host cell (Joiner et al., recombination). Markers at the ends of any one chromo-
1990). Lipids that comprise the PVM appear to be derived some show linkage except for the very largest chromosome.
from the host cell membrane and are not secreted by the Using this linkage characteristic it has been possible to
parasite (Suss-Toby et al., 1996). Host cell proteins are accomplish rapid mapping of any number of natural
completely excluded from the PVM. The host cell ER can polymorphisms. As an alternative to the complete sequen-
be identified in close proximity to the PVM during parasite cing of the parasite genome, construction of an expressed
replication, implicating a role in nutrition. Secretory sequence tag (EST) database has been accomplished. This
vesicles have been identifed near the ER and the Golgi library, obtained from the sequencing of random clones,
apparatus. The transport of plasma membrane proteins is can allow for the expression of stage-specific, or perhaps
similar to that observed for other eukaryotic cells. tissue-specific, genes. Amongst other efforts, this EST
Following invasion, tubovesicular network proteins accu- library has recently been used to obtain evidence for a
mulate within the vacuolar space. The PVM fails to fuse family of structurally related surface antigens of the
with any host cell organelles, suggesting that the protein parasite. A summary of the Toxoplasma sequences with
signals required for docking are absent. The PVM contains known homologues in GenBank can be found at the
pores that allow the passive bidirectional transfer of Toxoplasma Genome website (http://www.ebi.ac.uk/
molecules, such as amino acids, of molecular weight less parasites/toxo/toxpage.html).
than 2000 Da. Thus, nutrition to the parasite may be
provided through these presumptive nutritional pores.
Tachyzoite parasites are readily grown in tissue culture,
most frequently using human fibroblasts. Alternatively,
Pathogenesis and Phases of Disease
tachyzoites can be isolated from the peritoneal fluid of Development
infected mice. Regular passage and culture in either the
cultured cells or the peritoneal fluid of mice maintains the Upon host ingestion, parasites invade via the gastrointest-
parasites. Tachyzoites can be stored frozen in liquid inal tract from which they are disseminated to a variety of
nitrogen and thawed when necessary, with very high organs, in particular lymphatic tissue, skeletal muscle,
success. The most commonly used parasite lines include myocardium, retina, placenta and central nervous system.
RH and Me49 (or its clonally derived P strain). Three The mode of parasite dissemination is not understood
strains (types I, II, III) have been identified based on although it has been suggested that monocytes are
several features including pathogenicity in humans and responsible for this transport (Fadul et al., 1995). Within
mice (Howe and Sibley, 1995). Representative parasite the host organs, the parasite undergoes asexual replication
lines from these three types are available and can be (endodyogeny) and after 64–128 divisions leaves via a
cultured in the laboratory. Bradyzoites can be obtained Ca2 1 -dependent mechanism. In this fashion, cell death,
from tissue, in particular the brains of infected mice. focal necrosis and inflammation become the hallmark of
Alternatively, they can be grown in culture from tachy- the infection.
zoites when the tissue culture is stressed by alteration in In the nonimmunocompromised host, tachyzoites are
physiological conditions. sequestered by a variety of immune mechanisms. Once the
tachyzoites have been cleared from the acutely infected
host, tissue cysts containing bradyzoites appear primarily
within the central nervous system and retina. A number of
immune factors, including raised antibody levels, inter-
feron (IFN)g, CD4 1 and CD8 1 T cells, have been
implicated in the clearance of parasites during acute and
4
Toxoplasmosis
chronic infection. In the immunocompromised or fetal importance of T cells in host resistance to this parasite is
host, these immune factors, which control the spread of unequivocal. Adoptive transfer of primed T cells, in
tachyzoite infection and tissue destruction, are lacking. particular CD8 1 , are protective against lethal parasite
Persistence of infection in the nonimmunocompromised challenge (Khan et al., 1994). Immunogenetic studies
host by cysts containing bradyzoites is common. During indicate that major histocompatibility complex (MHC)
this subclinical period, bradyzoites are in a slow metabolic class I and II protein are involved in susceptibility and
phase, although episodic cyst degeneration and rupture resistance in mice. Regardless of the MHC class, all mouse
does occur within the central nervous system. This strains develop a strong T helper cell type 1 response to
degenerative process with development of new cysts infection. This is characterized principally by an increase in
containing bradyzoites is the most likely source of the production of IFNg and tumour necrosis factor a,
persistent antibody titres in the normal host. Degeneration cytokines that are essential for host protection during the
of these cysts is the most probable source of recrudescent acute and chronic stages of infection.
infection in individuals who are immunocompromised. Acute infection in the naive host results in a strong
Lymph nodes will demonstrate follicular hyperplasia innate immune response characterized by natural killer cell
and irregular clusters of tissue macrophages with eosino- and macrophages. Macrophage activation can lead to
philic cytoplasm during the early stage of infection. parasite death by either an oxygen-dependent or indepen-
Granulomas are rarely seen in these specimens. In the dent process. Early activation of the immune system limits
eye, infiltrates of monocytes, lymphocytes and plasma cells proliferation of the tachyzoites and directs the develop-
are present. Granulomatous lesions and retinochoroiditis ment of an antigen-specific T-cell response. Interleukin
can be observed in the posterior chamber. Other ocular (IL)-12-producing dendritic cells are an important com-
complications of infection include iridocyclitis, cataracts ponent of early activation of the T-cell response (Sousa
and glaucoma. Within the central nervous system both et al., 1997). Following infection, both gd (Kasper et al.,
focal and diffuse meningoencephalitis appear with necrosis 1996) and ab (Gazzinelli et al., 1994) T cells are elicited in
and microglial nodules. In the AIDS population, poly- response to membrane-associated or cytoplasmic parasite
morphonuclear leucocytes may be present in addition to antigens. The specific role for CD4 1 T cells remains
the monocytes, lymphocytes and plasma cells observed in uncertain, although they are probably important in the
individuals without AIDS. Interstitial pneumonitis with early production of IL-12. CD4 1 as well as CD8 1 T cells
thickened and oedematous alveolar septa can occur in the have been shown to undergo activated induced cell death
neonate and immunocompromised patient. Cysts and following primary infection (Denkers et al., 1996; Khan
aggregates of parasites in cardiac muscle tissue can be et al., 1996). Induction of CD8 1 T cells is essential for host
observed in patients with AIDS who die from toxoplas- immunity to the parasite. These activated T cells produce a
mosis. Focal necrosis surrounded by inflammatory cells is wide range of cytokines and are protective when adoptively
associated with hyaline necrosis and disrupted myocardial transferred into the naive host. In addition, CD8 1
cells. intraepithelial T cells isolated from the intestine after oral
infection can protect against lethal parasite challenge
(Buzoni-Gatel et al., 1997). In the absence of CD8 1 T
cells, mice are highly susceptible to infection. The essential
Host Immune Response character of this cell type has been demonstrated repeat-
edly using mice that have either been depleted of CD8 1 T
Acute Toxoplasma infection evokes a cascade of immuno- cells or have a genetic deletion of the CD8 1 phenotype.
logical events in the normal host including the production CD8 1 T cells are also important in the establishment of
of antibody and a strong cell-mediated immune response long-term immunity to the parasite.
(Figure 3). Immunoglobulin (Ig)M, IgA and IgG antibodies
can be detected in serum following parasite exposure. An
early rise in the level of both IgA and IgM occurs following
primary infection of the naive host. The polyclonal IgG Clinical and Laboratory Diagnosis
antibodies evoked by infection are parasiticidal in the
presence of serum complement and are the basis for the Acute and chronic infection with T. gondii in the
Sabin–Feldmann dye test. Serum IgA antibody directed at immunocompetent individual is almost always asympto-
SAG-1 (p30) is a useful indicator of infection in congenital matic except for lymphadenopathy. It is estimated that
and acute toxoplasmosis. Antibody titration is the basis for 35% of all cases of chorioretinitis in the USA and Europe
most clinical diagnostic tests in women of childbearing age are due to congenital infection. Toxoplasmosis is the major
and in infants in whom a diagnosis of toxoplasmosis is opportunistic infection of the central nervous system in
suspected. patients with AIDS. Ocular infection is being observed
The most prominent immunological feature of the host with increasing frequency as a complication of AIDS.
to this parasite is the robust cell-mediated response. The Most cases of toxoplasmic encephalitis are believed to be
5
Toxoplasmosis
Toxoplasma
Oral ingestion
Gut epithelial cells
Peyer
patch
CD4+
lamina
propria CD8+
intraepithelial
lymphocyte
Systemic
response Cytotoxic
lymphocytes
CD8+
TH1 hyperinflammation
T cells
(IFNγ, TNFα, NO)
CD4+
TH2 downregulation
of hyperinflammatory
response (IL-10, TGFβ)
Figure 3 Host immune response to Toxoplasma gondii. Interaction of the parasite with the host elicits a complex series of immunological events. The
parasite is acquired by oral ingestion and following release from the tissue cyst comes into contact with the gut mucosa. The parasite infects enterocytes and
stimulates the production of proinflammatory cytokines, in particular interleukin (IL)-12, by various cells within the Peyer patch. This innate immune
response mediates antigen-specific CD8 1 T-cell immunity at both the mucosal and systemic level. The responding T cells exhibit cytolytic activity against
parasite-infected targets and release interferon (IFN)g, which is microbicidal to the replicating parasite via the induction of nitric oxide (NO). The activated T
cells also downregulate the proinflammatory response by the production of both IL-10 and transforming growth factor (TGF) b. This counterinflammatory
response allows for homeostasis and prevents tissue damage due to hyperinflammation secondary to the production of IFNg and TNFa.
due to recrudescent infection. Individuals with AIDS and protein concentration and an increase in the level of IgG.
positive serology for T. gondii are at very high risk for These changes in the CSF are consistent with toxoplasmic
developing encephalitis. A presumptive clinical diagnosis encephalitis, but are not diagnostic. The eye examination
of toxoplasmic encephalitis in patients with AIDS is based will reveal lesions of yellow-white, cotton-like patches with
on clinical presentation, positive serology and radiological indistinct margins. Well-circumscribed white plaques
evaluation. The altered neurological state is due not only to characterize older retinal lesions.
the necrotizing encephalitis caused by direct invasion of the Serological diagnosis is the best method for diagnosis of
parasite, but secondary effects as well, including vasculitis, previous exposure to the parasite. More than 97% of
oedema and haemorrhage. Examination of the cerebrosp- patients with AIDS and toxoplasmosis are seropositive for
inal fluid (CSF) may show an increase in the number of IgG antibody to the parasite in their serum or CSF. A wide
mononuclear cells (10–50 cells per ml), a slight increase in range of serological tests can be used to measure antibody
6
Toxoplasmosis
to T. gondii. Infection can be established by determining protein synthesis, such as clindamycin, chlortetracycline
the simultaneous presence of IgA, IgM and IgG anti- and azithromycin, which have been shown to reduce
Toxoplasma antibody. An initial rise in IgA followed by parasite growth. It has been suggested that the target for
IgM is consistent with the diagnosis of acute parasite clindamycin efficacy is the apicoplast. Hydroxynaphtho-
infection. The Sabin–Feldmann dye test, the indirect quinone blocks pyrimidine salvage and has demonstrated
fluorescent antibody test and enzyme-linked immunosor- toxoplasmacidal activity. Recent observations have iden-
bent assay are all satisfactory to measure the presence of tified two novel targets; the apicoplast and the shikimate
circulating IgG anti-Toxoplasma antibody. Positive IgG plant-like metabolic pathway (Roberts et al., 1998) of the
titres ( 4 1 : 10) can be detected as early as 2–3 weeks post parasite.
infection. A raised IgG titre without an increase in either Primary infection with Toxoplasma can be reduced by
IgA or IgM concentration suggests previous exposure to not eating undercooked meat and avoiding oocyst-
the parasite. In the neonate, a persistent IgG or a positive contaminated material (e.g. a cat litter box). Meat should
IgM titre (after the first week to exclude the possibility of be frozen or heated to 60<C to kill cysts. Care should be
placental leak) suggests infection. An increased IgM titre given to washing hands thoroughly after working in the
beyond the first week is indicative of acute infection. garden, and all fruits and vegetables should be washed.
Patients with toxoplasmic encephalitis will have focal or Blood intended for seronegative immunocompromised
multifocal abnormalities demonstrable on computed individuals should be screened for antibody to T. gondii.
tomography (CT) or magnetic resonance imaging (MRI) Although it is not routinely performed, seronegative
that must be distinguished from other conditions such as women should be screened for serological evidence of
central nervous system lymphoma. A single lesion on MRI infection several times during pregnancy if they are
increases the suspicion of primary lymphoma. Improved exposed to environmental conditions that would put them
clinical and MRI status in response to a therapeutic trial of at risk of becoming infected with T. gondii.
anti-Toxoplasma medications is frequently used to estab-
lish retrospective diagnosis. Recent studies have shown
that treatment of presumptive toxoplasmic encephalitis
with pyrimethamine–clindamycin results in greater than
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