Toxoplasmosis

Definition

Toxoplasmosis refers to symptomatic disease, whereas T. gondii infection refers to latent, asymptomatic disease. Toxoplasma gondii is a ubiquitous protozoan parasite. Although felids are T. gondii ’s only definitive host (i.e., where parasitic sexual reproduction occurs), the parasite’s intermediate hosts include most warm blooded animals, from birds to humans. In both the definitive and intermediate hosts, T. gondii causes an acute infection followed by the establishment of a long-term persistent or latent infection. The initial acute infection can be symptomatic, but T. gondii is predominantly known for causing congenital disease in children of mothers with a primary infection during pregnancy and encephalitis in persons with severe acquired immune deficiencies.

The Pathogen

T. gondii has a sexual and asexual life cycle. During the sexual life cycle, which occurs in felid enterocytes, the parasite differentiates into male and female gametocytes, which fuse to form a diploid zygote. This diploid form is surrounded by a protective wall, which collectively forms the unsporulated oocyst that is expelled into the environment via felid feces ( Fig. 320-1A ). After being expelled, the oocysts sporulate to form haploid sporozoites, which are infectious if ingested. These oocysts, which are extremely hardy, can potentially survive for years in the environment. Felids apparently are the only definitive host because only their enterocytes have the excess levels of linoleic acid that are required for sexual reproduction owing to their lack of the delta-6-desaturase enzyme, which helps convert linoleic acid to arachidonic acid.

In the asexual life cycle, which is subdivided into lytic and latent stages, T. gondii replicates its haploid genome and divides into two daughter cells via a process called endodyogeny, by which the two daughter cells form within the mother, and then the mother cell dissolves. During the lytic cycle, parasites are in a fast-replicating form called a tachyzoite (see Fig. 320-1B ). As tachyzoites rapidly expand in number and disseminate throughout the body, they generate a robust immune response. As the immune response clears tachyzoites, the tachyzoites convert to bradyzoites, which are a slow-replicating form of T. gondii that forms tissue cysts in certain organs and cell types, especially neurons and striated muscle (see Fig. 320-1C ). These tissue cysts, which can contain hundreds or even thousands of bradyzoites, typify the latent stage of the life cycle. At this stage, the organism can evade the host’s immune system, thereby enabling long-term infection. This long-term latent infection is essential for passage of T. gondii between intermediate hosts, a process thought to underlie T. gondii ’s success as a parasite (geographically ubiquitous and with a broad intermediate host range).

Epidemiology

Humans become infected with T. gondii via the ingestion of undercooked meat that contains tissue cysts (both commercial and game) or oocyst-contaminated water or food ^, ; vertical transmission from mother to child; rarely from solid organ transplantation; and potentially from transfusions. Infection from a cat occurs when oocysts or cat feces contaminate food or water, or when caretakers use poor hand-hygiene when exposed to cat feces (i.e., cleaning kitty litter). Thus, risk of infection depends on a variety of parameters such as cultural habits (e.g. having cats as pets, drinking unpasteurized goat’s milk) and access to clean water and hygiene, which often correlate with geography and socioeconomic status.

As estimated by seropositivity surveys, rates of infection with T. gondii vary in different countries and within a single country. For example, although the overall U.S. seropositivity rate is estimated to be about 11%, the seropositivity among the Old Order Amish in Lancaster County, Pennsylvania is over 50%. Similarly, people living in the former East Germany have a higher T. gondii seroprevalence than people who live in the former West Germany, a distinction that is postulated to arise from the East German tradition of eating raw minced beef and pork. In developed nations, T. gondii seroprevalence is higher in rural populations compared with urban populations; but in Brazil, urban populations have a higher seroprevalence. Although seropositivity often increases with age, presumably owing to increased exposure over a lifetime, high levels of seropositivity are seen even at a young age in urban areas in Brazil.

In the era before highly active anti-retroviral therapy, approximately 30 to 50% of patients who were seropositive for human immunodeficiency virus (HIV) and had the acquired immunodeficiency syndrome (AIDS) developed toxoplasmic encephalitis, but that risk is now very low in patients who are on effective therapy. Both primary and reactivation disease has been seen in patients who are taking immunosuppressive drugs (e.g., anti-TNF therapy, rituximab, and mycophenolate mofetil), but these risks are relatively rare compared with HIV/AIDS patients with low CD4 counts.

Patients who undergo hematopoietic stem cell transplants ( Chapter 163 ) or solid organ transplantation are at risk for toxoplasmosis. The risk of toxoplasmosis is highest for allogenic hematopoietic stem cell transplants when the recipient is seropositive for toxoplasmosis and the donor is seronegative; in this situation, the recipient has a high likelihood of latent T. gondii infection, but the donor’s immune system lacks preexisting adaptive immunity to T. gondii . For recipients of solid organ transplants, the risk of symptomatic toxoplasmosis is just the opposite—highest when the recipient is seronegative but the donor is seropositive. The risk is highest in recipients of heart transplants, presumably because heart tissue is known to harbor persistent, encysted parasites. For other solid organ transplants, infection can be seen clinically months to years after transplantation, when it is difficult to determine whether the parasite came from the transplanted organ or whether the recipient developed a symptomatic primary or reactivation infection because of long-term immunosuppression.

Congenital toxoplasmosis most commonly occurs when a seronegative pregnant woman develops a primary infection. The likelihood of transmitting the infection to the fetus increases with gestational age, with a 6% or less risk for maternal seroconversion at less than 13 weeks of gestation and above 70% risk for seroconversion at 36 weeks or more. Infections in early gestation have a higher likelihood of severe infection compared to late infections. Mother-to-child infection is unusual in HIV patients who have a CD4 count above 200 cells/μL.

The genotype of the infecting T. gondii strain may also influence the severity of the primary infection in an immunocompetent host as well as vertical transmission of congenital disease and ocular infection in immunocompromised patients. Limited data from congenitally infected infants and their parents also suggest that human polymorphisms in nalp1/nlrp1 and alox12 may play a role in susceptibility to congenital toxoplasmosis. The mechanisms by which these polymorphisms contribute to this susceptibility are unknown, but differences in NLRP1-triggered pyroptosis determine the likelihood of T. gondii infection in different strains of rats.

Pathobiology

In postnatally acquired infection, most individuals become infected with T. gondii by ingesting either tissue cysts or oocysts. Once ingested, bradyzoites or sporozoites are released via digestive enzymes, followed by infection of epithelial cells. During this enteral stage, parasites convert to the tachyzoite stage, which disseminates throughout the body. The innate and adaptive immune response targets the tachyzoites, thereby controlling the infection in a manner that is highly dependent upon the production of interferon (IFN-γ) by immune cells, especially CD8 ⁺ effector T cells, and subsequent IFN-γ responses in hematopoietic and nonhematopoietic cells. Key innate immune cells include the antigen presenting dendritic cells, natural killer cells, neutrophils, tissue-infiltrating monocytes, and tissue macrophages such as microglia.

In the face of this stress, tachyzoites transition to encysting bradyzoites, which are not fully cleared from specific organs (e.g., eye, brain) thereby leading to long-term persistence. In hosts who become immunocompromised and occasionally even in immunocompetent individuals, these persistent parasites reactivate to cause symptomatic disease. The conversion to the bradyzoite/encysted stage, which includes changes in the parasite’s surface antigens, is thought to help parasites evade the tachyzoite-directed immune response. Although the human immune response to bradyzoites/cysts may be muted, some degree of a bradyzoite-directed immune response probably does occur.

Clinical Manifestations

T. gondii infections cause a wide range of symptoms, which vary from acute as compared with chronic infection and are different in immunocompetent individuals as compared with immunocompromised patients or patients with congenital infection ( Table 320-1 ).