The life cycle of N. caninum is depicted in Figure 62.1. Neospora caninum has a facultative heteroxenous life cycle, meaning that the organism may use more than one host during its life cycle.^22,23 Unsporulated oocytes (10–14 μm) are shed in the feces of definitive hosts (i.e., dog or wild canid).²⁴ The oocytes sporulate within 24 hours to the infective form. Each sporulated oocyte contains two sporocysts, and each sporocyst contains four sporozoites. When consumed by cattle or a wide range of other warm-blooded animals which can serve as intermediate hosts, eight sporozoites are released into the gastrointestinal tract for each oocyte consumed.¹ The sporozoites differentiate into tachyzoites (5–7 μm), which subsequently invade the epithelial cells of the gastrointestinal tract. The tachyzoites replicate rapidly via asexual endodyogeny.²⁵ Endodyogeny is a form of asexual reproduction that involves an unusual process where two daughter cells are produced inside a mother cell, which is then consumed by the offspring prior to their separation.²⁶ Replication occurs rapidly within cells and tachyzoites may spread hematogenously within mononuclear phagocytes²⁷ to infect many cell types including neural cells, vascular endothelial cells, myocytes, hepatocytes, renal cells, alveolar macrophages, and placental trophoblasts.^28–30 Tachyzoites differentiate into bradyzoites which are the slowly replicating encysted stage of the parasite. Each cyst may contain hundreds of bradyzoites.²³ In congenitally infected bovine fetuses and calves, tissue cysts are found in the brain and spinal cord.³¹ A few thin-walled cysts have been found in skeletal muscle of two naturally infected 2-day-old calves.³² Bradyzoites are thought to persist for the duration of the host’s life and be responsible for persistent infection, although tissue cysts have not been observed in histological sections of naturally infected cattle older than 2 months.^23,28 Bradyzoites are believed to reactivate and differentiate back into tachyzoites, thereby establishing persistent infection.²³ Bradyzoites can be differentiated in tissue sections from tachyzoites by labeling with a specific antibody.³³ The cycle continues when tissue cysts shed by the intermediate host (cattle) are consumed by the definitive host (canids).¹

Transmission

Neospora can be transmitted vertically or horizontally with both routes being vital to long-term survival of the parasite.²³ Vertical transmission takes place when tachyzoites migrate transplacentally from dam to fetus during pregnancy.^1,24 Neospora caninum is one of the most efficiently transplacentally transmitted parasites among all known microbes in cattle.¹ The terms “endogenous transplacental transmission” and “exogenous transplacental transmission” have been used to more precisely describe the origin and route of fetal infection (Figure 62.2).²² Endogenous transplacental transmission occurs in a persistently infected dam when the infection crosses the placenta and enters the fetus.²² The endogenous form has a higher rate of associated abortion.³⁴ Exogenous transplacental transmission occurs when a previously noninfected dam ingests infective oocysts while pregnant and her fetus subsequently also becomes infected in utero.

Vertical transmission can result in abortion but in most cases the calf is congenitally infected but asymptomatic with no evidence of deleterious effects on subsequent calf health.³⁵ If the infection occurs during the second or third trimester when immunocompetence of the fetus is greater, the most likely outcome will be a liveborn but persistently infected calf.²³ Once infected, cattle are presumed to be infected for life³⁶ and females can transmit the infection to successive generations.^37,38 Although not every pregnancy results in transmission of the disease, it has been reported that the rate of transmission is as high as 75–100%.¹⁶ In the case of exogenous transplacental transmission, the number of oocysts ingested by the dam and stage of gestation influence pregnancy outcome.^24,39 There is a report indicating that in persistently infected cattle, vertical transmission is more efficient in younger than older cows.⁴⁰ Also, transplacental infection may be more likely to occur in dams that were themselves prenatally infected compared with postnatally infected dams.⁴¹ The risk of abortion was positively correlated with N. caninum-specific antibodies in individual animals⁴² and severity of fetal Neospora-associated lesions also increased with higher maternal seropositivity.⁴³ Cows with high antibody titers (≥400) showed higher vertical transmission frequency (94.8%) than cows with low antibody titers of 25–200 (14.8%).⁴⁴ Occasionally, a seronegative dam will give birth to a seropositive calf.^45,46 This can occur when the dam has a long-standing infection with low antibody titer and she was wrongly diagnosed as uninfected.¹

Horizontal transmission is less common than vertical transmission.¹⁶ The ingestion of sporulated oocysts from the environment is the only demonstrated natural mode of postnatal infection in cattle (Figure 62.2).^47,48 Both domestic and wild dogs are frequently implicated in horizontal transmission. This is attributed to canids consuming infected bovine placentas or fetuses and subsequently defecating in the environment where the oocytes are ingested by cattle.⁴⁹ There has been no horizontal cow-to-cow transmission reported at this time.³⁷ Experimentally, calves may become infected through ingestion of milk contaminated with tachyzoites^50,51 and N. caninum DNA has been detected in colostrum of seropositive cows.⁵² However, it remains doubtful that lactogenic transmission occurs naturally.⁴⁹ Since N. caninum DNA was reported in fresh and frozen semen from naturally infected bulls,⁵³ the possibility of venereal transmission was investigated. Intrauterine inoculation of nine heifers with 107 N. caninum tachyzoites reacted with seroconversion and a specific interferon (IFN)-γ response. Also, N. caninum DNA was demonstrated in the blood and tissues of all nine heifers.⁵⁴ However, the numbers of tachyzoites used to test the venereal route of infection are higher than those previously found in semen of naturally infected bulls, which range from 1 to 10 organisms per milliliter associated with the cell fraction of semen.^55,56 Therefore, it seems unlikely that venereal transmission is significant under natural conditions.

Pathogenesis of abortion

Neosporosis is primarily a disorder of the fetoplacental unit that occurs subsequent to maternal parasitemia resulting either from exogenous or endogenous infection.²³ In the case of exogenous infection, the ingested oocytes excyst in the small intestine and presumably release sporozoites which parasitize the maternal intestinal epithelium and transform into tachyzoites which, in turn, multiply in the mesenteric lymph nodes.²³ The tachyzoites are released into the blood and have been detected in the leukocyte fraction²⁷ of naturally infected cattle. The parasitemia results in dissemination throughout the body including the gravid uterus. The endogenous (vertical) route of transmission is most common.^37,57 It is suspected that latent infections are reactivated due to the immunosuppression associated with mid-gestation pregnancy.⁵⁸ It is also reported that endogenous transplacental transmission is more likely in cattle that were themselves infected in utero.^59,60

The mechanism by which N. caninum actually causes abortion is a topic of ongoing investigation and multiple hypotheses have been proposed. First, since the parasite is able to establish itself in the caruncular septum before crossing to the fetal placental villi,^61,62 the resultant placental damage may result in fetal death due to placental insufficiency.²³ Placental insufficiency, because it causes fetal stress and release of adrenocorticotropin, could also cause premature delivery of either viable or compromised calves. Second, infection by N. caninum stimulates cell-mediated immune responses associated with cytokine release from the damaged placenta, resulting in fetal rejection by the maternal immune system culminating in fetal expulsion.^23,63,64 Finally, the placental damage may result in endometrial prostaglandin (PG)F_2α release causing luteolysis and abortion as has been demonstrated in goats with toxoplasmosis.⁶⁵ However, cows with high Neospora antibody titers have higher plasma progesterone levels throughout gestation than seronegative cows or cows with low antibody titers;⁶⁶ in a study in which exogenous progesterone was administered during the mid-gestation period, the risk of abortion increased dramatically in cows with high levels of antibodies against N. caninum.⁶⁷ It seems most likely that all three of the proposed mechanisms play a part in inducing Neospora-associated abortion in cattle.

The first-trimester fetus seems particularly susceptible to damage by invading N. caninum since it is not immunocompetent⁶⁸ and unlikely to survive infection. In the middle trimester the fetus may be able to mount an immune response to N. caninum challenge, although the response may not be robust enough to preclude fetal death.^58,69,70 By the third trimester the fetus is capable of mounting an immune response of sufficient magnitude that it is likely to survive N. caninum infection, leading to birth of clinically normal but infected calves. In beef cows experimentally infected with N. caninum at various times during gestation by either subcutaneous or intravenous routes, transplacental infection rate increased with gestational age and cows infected during later gestation generally delivered normal but infected calves.³⁹

In cows experimentally infected with N. caninum the most severe lesions are found in the placenta and the fetal brain.^39,69 Lesions consist of a nonsuppurative inflammatory response.⁶² The associated inflammatory cells have been shown capable of producing INF-γ,⁵⁸ which suggests fetal death may be more a consequence of the maternal immune response rather than direct effects of the parasite.⁵⁸ At the time of placental invasion the parasite also enters the fetal bloodstream with a predilection for the central nervous system,⁶² where it is located perivascularly,²⁹ and in younger fetuses causes widespread destruction of neuropil with very little inflammatory response.⁷¹ When fetuses later in gestation become infected with N. caninum the tissue reaction is more moderate, with areas of necrosis restricted to small foci surrounded by intense inflammatory infiltrate in brain tissue^18,72 and sometimes, mild meningitis.⁷³ Neospora caninum fetal infection also causes characteristic lesions of inflammation and necrosis in tissues such as liver and heart.¹⁸

Clinical signs

Neospora caninum infection causes abortion in both beef and dairy cattle. Abortion may occur from 3 months of gestation to term but typically occurs at 5–6 months of gestation.^4,18,74,75 Possible outcomes of infection include fetal death followed by resorption,⁷⁶ mummification,⁷⁷ autolysis,⁷⁸ stillbirth,⁷⁹ born with clinical signs,⁷⁸ or born clinically normal³⁵ but persistently infected. Fetuses dying in utero between 3 and 8 months are usually expelled with evidence of moderate autolysis while those dying before 5 months of gestation are more likely to mummify.²³

Stay updated, free articles. Join our Telegram channel

Join