Parasitology
Neospora caninum: A fascinating relationship between parasite and host
Dr Lee Innes
The protozoan parasite Neospora caninum was first recognised in the
1980s and has since emerged as an important cause of disease in dogs
and cattle. Infection with N. caninum has been strongly associated
with bovine abortion in both dairy and beef cattle worldwide. In many
countries and regions with an intensive dairy industry it is cited
as the most commonly diagnosed cause of abortion. Accumulating evidence
from epidemiology studies has shown that seropositive animals are
3-7 times more likely to abort than seronegative animals, with congenitally
infected heifers being of particularly high risk during the first
pregnancy.
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Fig 1. |
The majority of Neospora-associated abortions occur between 4-6 months of gestation and it is possible that the parasite may be responsible for early foetal loss which is more difficult to diagnose. Cattle may acquire infection through the ingestion of oocysts that are shed in the faeces of infected dogs, recently shown to be a definitive host of the parasite, or by congenital infection where the parasite passes from mother to foetus via the placenta. The consequences of infection in a pregnant animal may be abortion of the foetus, birth of a weak calf or birth of a clinically healthy but persistently infected calf. The parasite can be transmitted from mother to foetus over several generations and congenitally infected heifers can later transmit the parasite to their own offspring. Therefore, the parasite is spread very efficiently and can persist within an infected herd without the involvement of the definitive host.
Control measures
There are currently no effective control measures against the parasite. However, as it is now known that dogs can shed Neospora oocysts, it is important that dogs be kept away from cattle feed and water. They should also be prevented from eating aborted foetuses, placental tissue or dead calves which may harbour infection. Culling of seropositive animals has been suggested as a method of control due to the very high rates of vertical transmission observed in many countries, however this may not be practical where there is a high prevalence of infection. There is also accumulating evidence that cattle previously exposed to the parasite are less likely to abort than those undergoing a primary infection. This suggests that cattle are developing a degree of protective immunity which may be an important factor to consider in a culling programme of seropositive cattle.
The host/parasite relationship
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Fig 2 |
The main thrust of our research programme is to study the host/parasite relationship in both pregnant and non-pregnant animals to enable us to better understand the cause of disease, vertical transmission of the parasite and whether the host can develop protective immunity. Cattle generally show very few clinical symptoms following infection with the parasite and the parasite is thought to persist within cysts in the central nervous system of the host. It is known that cattle infected with N. caninum will respond by producing specific antibodies, which are often used as an aid to diagnosis and are a useful epidemiological tool. How effective antibodies are in development of protective immunity remains to be determined but a likely role would be to help control parasitaemia by responding to the extracellular tachyzoite stage of the parasite. However, N. caninum is an obligate intracellular parasite and can only multiply within the cells of the host. Therefore the parasite will spend most of the time inside the host cells and will only be extracellular in a free living form for a limited time. The intracellular location of N. caninum means that cell-mediated immune responses are also likely to be important in protective immunity. Evidence of the importance of cell-mediated immunity came initially from in vitro studies showing that treatment of cells with recombinant interferon gamma (IFNg), a cytokine produced by activated T-lymphocytes, would inhibit significantly intracellular multiplication of N. caninum. The parasite and host can co-exist for lengthy periods in relative harmony until the host becomes pregnant. The changes in the immune system, which occur naturally in order to support the pregnancy, create an imbalance in the host-parasite relationship which may help to explain the pathogenesis of neosporosis in cattle.
Pregnancy and the immune system
In the 1950s Peter Medawar described how experimental work involving exchange of skin grafts between allogenic- and identical-twin cattle led to the important realisation that the ability to distinguish between self and non-self was an acquired characteristic of the immune system. He went on also to discuss the "riddle of the foetal allograft" where the foetus inherits half of its genetic material from the father and therefore would be expected to be rejected by the mother as a semi-allogenic tissue graft. The reasons why the immune system of the mother tolerates the foetus are not fully understood but recent research into cytokine regulation during pregnancy has shown that certain cytokines at the materno-foetal interface are beneficial for pregnancy whereas others are very harmful. Pro-inflammatory cytokines such as IFNg, interleukins 2 and 12 and tumour necrosis factor alpha (TNFa) can be detrimental to a successful pregnancy and may compromise foetal survival. In contrast, regulatory cytokines, such as interleukin 10 which will counteract the effect of the pro-inflammatory cytokines are upregulated during pregnancy and are produced locally at the materno-foetal interface. This natural immunoregulation occurring during pregnancy has important implications for the host-parasite relationship in N. caninum infected cattle.
Pregnancy and the parasite
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Fig 3. |
Neospora caninum lives and multiplies within host cells and it is known that cell-mediated immune responses, involving pro-inflammatory cytokines, are important in protective immunity. If these immune responses are down-regulated during pregnancy, does this result in an imbalance of the host-parasite relationship allowing the parasite to become active again within the host? In addition, might the activity of the parasite within the host induce the host-protective pro-inflammatory response which may be directly detrimental to the pregnancy?
Recent work conducted at Moredun examined changes in the maternal immune system during pregnancy and showed that there was a significant down-regulation of specific cell-mediated immune responses, including IFNg, occurring around mid-gestation. This quantifiable change in the immune response may be a contributing factor in triggering recrudescence of infection within the host and may facilitate successful transmission of N. caninum from mother to calf. The foetus is very vulnerable to infectious agents during its development in utero and clearly the gestational age and immunocompetence of the foetus at the time of exposure to the parasite is critical in determining severity of disease. The earlier in gestation that a parasitaemia occurs the more severe the consequences to the foetus. A parasitaemia later in gestation is likely to result in the birth of a clinically normal calf which is infected with the parasite. Congenitally-infected calves are very likely to pass the parasite on to their progeny in subsequent pregnancies thus increasing the numbers of infected animals which have a significantly increased likelihood of aborting.
Induction of protective immunity?
Therefore, the objective in developing an effective control strategy against N. caninum must be not only to prevent abortion in cattle but to prevent vertical transmission as well.
In a recent study at Moredun, cattle were experimentally infected with N. caninum parasites prior to pregnancy and were then re-challenged with the parasite at mid-gestation. The cattle gave birth to clinically-normal calves which were not infected with the parasite. In contrast, a group of cattle, naïve to the parasite, were also challenged at mid-gestation and they gave birth to N. caninum infected calves. This study showed that it is possible to induce protective immunity in cattle to prevent vertical transmission of N. caninum, which is an important step towards the goal of developing an effective vaccine against the disease.
This result also raises interesting questions on why naturally-infected cattle do not readily develop protective immunity against vertical transmission, often passing the parasite to their offspring over several generations. Perhaps the answer lies in the relative maturity of the immune system at the time of first exposure to the parasite. The majority of naturally infected cattle first experience the parasite in utero while their immune systems are still developing. Does this compromise immune recognition of the parasite later in life?
The relationship between Neospora caninum and its bovine host is finely balanced. The immunomodulation which occurs naturally during pregnancy allows the parasite to invade the placenta and infect the foetus. The timing of infection in gestation is critical in determining survival of the foetus. Any immunological intervention to generate pro-inflammatory responses, which we believe to be host protective, during gestation may itself cause the pregnancy to fail. Therefore our challenge in vaccine design is to intervene in a manner that will tip the host parasite balance in favour of the host without compromising the pregnancy.
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Fig 4. |
