Emma Wilson
4.2 Life cycle and pathogenesis
4
GAMETOGENY GAMETOGENY
Invasion of extraintestinal tissues Ingestion of cyst
(A)
Cat sheds oocysts in faeces 1-2 weeks following infection- up to 10 million may be shed
SPOROGENY
(B)
ingestion of cyst excretion of oocysts
TISSUE
CYST OOCYST
BRADYZOITES Ingestion by SPOROZOITES mammals
TACHYZOITES Congenital
infection
Figure 4.1 Toxoplasma gondiilife cycle.Toxoplasmaexists in one of three states: 1) sexually as sporozoites within a dormant highly resistant oocyst; or asexually as 2) bradyzoites within a latent tissue cyst; or 3) as fast replicatingtachyzoites. A. Sexual reproduction can only occur in feline intestinal epithelial cells. B. Excretion of oocysts leads to their ingestion by mammalian intermediate hosts, asexual reproduction by tachyzoites and their dissemination throughout host tissues. Tachyzoites then convert to cysts, formingbradyzoites.
The definitive host is the feline, and thus sexual reproduction of sporozoites can only occur in gut epithelium of the cat. Although it is not unusual for a parasite to have such restrictions, the reasons for this specificity are unknown.
Following ingestion, parasites are released and invade the intestinal epithe- lium, where they undergo gametogony and oocyst formation. Oocysts are incredibly resilient structures known to resist desiccation and concentrations
of bleach. The cat sheds up to ten million oocysts in the faeces for up to two weeks, and this leads to contamination of the environment. Studies that have evaluated the prevalence ofT. gondiiin the cat population suggest that up to 80 per cent of cats are infected in the USA, and the estimate of contaminated cat faeces in the environment is in the tonnage! The ability ofToxoplasmato sur- vive outside the mammalian host in such a resistant form is a likely contributor to its success as a parasite. The oocyst can now cause infection via ingestion by grazing animals, or in humans through the consumption of unwashed fruit and vegetables.
Ingestion ofT. gondiiby any mammal other than a cat leads to the development of tissue cysts. These cysts are formed in muscle, heart, liver and brain, and they remain in the tissue for the lifetime of the host. Therefore, a second route of infection is the consumption of tissue cysts in under-cooked meat.
Following infection of an intermediate host, cysts rupture and sporozoites from oocysts or bradyzoites from tissue cysts will be released into the lumen. At this point, parasites convert to fast-replicating tachyzoites and invade cells of the small intestine. UnlikePlasmodiumspp., which spends most of its time in anu- cleated red blood cells, and where distinct life cycles and species require differ- ent host cells,T. gondiican replicate in any cell that has a nucleus. As it invades, it invaginates the host cell membrane, forming a protective parasitophorous vacuole (PV) isolating it from the inner workings of the cell – a process that takes less than 20 seconds. Tachyzoites proceed to divide within the PV approx- imately every eight hours. Continued replication results in cell lysis, and there- fore it is the proliferation of tachyzoites that is the primary cause of pathology associated with infection.
Generally, one week post-infection is the height of parasitaemia and the im- mune response, after which a contraction phase occurs (Figure 4.2). Tachy- zoites convert back to cyst-forming bradyzoites, a process that can be stimulated by stress conditionsin vitro(e.g. low pH). As it does not occur in immune-deficient animals, it is likely to be stimulated in part by the immune responsein vivo.
By three weeks post-infection, parasites are largely confined to the brain in cyst form. Here, continued reactivation of bradyzoites into tachyzoites necessitates a lifelong immune response in the central nervous system (CNS) to prevent Toxoplasmic encephalitis (TE). Although there are drugs that can inhibit the fast-replicating tachyzoites, none are yet available to remove the cyst form of the parasite. The cycle is completed following the ingestion of tissue contain- ing cysts by a feline, so in most cases (except on safari?),Toxoplasmainfection in humans represents a dead end for the parasite.
4.2.1 Clinical manifestations
One of the anomalies of T. gondii is that disease is rare, despite the high prevalence rates. Infection is generally asymptomatic in immune-competent individuals and may, at most, manifest as a non-specific swelling of the
CD4+
Th1 NK
cell
CD8+
Tc DC
CD4+
Th1 CD8+
Tc CD4+
Th1 CD8+
Tc
APC
chronic CNS infection acute systemic infection
CNS immune response
CNS immune response
day 7 day 14 day 21
APC
IFN-γ IL-12
IFN-γ
Figure 4.2 General immune response toToxoplasma gondii.Production of IL-12 by neutrophils, DCs and macrophages, and innate production of IFN-␥early following infection, controls parasite replication and initiates Th1 immune responses. During chronic infection, T cells and IFN-␥production are required to prevent parasite replication.
Abbreviations: APC, antigen presenting cell; DC, dendritic cell; IFN, interferon; IL, interleukin;
NK, natural killer; Tc, cytotoxic T cell; Th, T helper cell.
cervical lymph nodes and flu-like symptoms. However, when disease does oc- cur, it can be severe. Retinal toxoplasmosis is the uncontrolled replication of tachyzoites in the retina, and is one of the lead causes of blindness. Congeni- tally acquiredToxoplasmainfection remains one of the largest causes of foetal abnormalities, including hydrocephalus, intracranial calcification and mental retardation.
Historically, there was an increased focus of research onToxoplasmafollow- ing the advent of HIV and AIDS, which resulted in large numbers of patients with severe neurological conditions due to the reactivation of latentT. gondii cysts in the brain, causing TE. This patient population highlighted the re- quirements of the immune response in maintainingToxoplasmalatency. It is now recognised that all genetic or acquired immune-compromised patients are susceptible, and Toxoplasmosis is reported following organ transplant or chemotherapy.
The generalised immune response toT. gondiiis the production of interleukin (IL)-12, driving interferon (IFN)-␥production by Th1 cells and, subsequently, type 1 effector responses (Figure 4.2). In mouse models, the absence of IL-12, IFN-␥or T cells leads to a failure to control parasite replication, and mice suc- cumb to infection. In addition to the requirement for controlling and killing the parasite, susceptibility to infection is also apparent in the absence of immune molecules responsible for controlling the pro-inflammatory response.