Lethal immunity

A battle for survival between mother and child

A parasitic infection of cattle triggers abortion. Finding out why could mean fewer deaths and provide insight into the interactions between cow and calf.

"When purchasing cattle, dairy farmers often select particular lines or families of animals that have been bred for milk production, genetic merit, perhaps certain behavioural characteristics, with the intention of breeding more such animals," explains Dr Diana Williams at the Liverpool School of Tropical Medicine. Unknowingly, however, they may be selecting a line of cattle infected with a parasite that will cause many pregnancies to end in abortion, with severe economic implications for their farms.

According to Dr Williams, the parasite Neospora caninum is the most frequently diagnosed infectious cause of abortion in dairy cattle in the UK. First identified as recently as 1984 in Norwegian dogs, Neospora has now emerged as an important veterinary problem. "In this country around 6 per cent of dairy cows are infected and epidemiological studies we've done have shown that of all dairy abortions that occur, about 13 per cent of them are attributable to Neospora. That means there are probably about 6000 abortions a year due to Neospora in this country. In the USA it's one of their leading causes of abortion. You find it everywhere in the world."

There is at present no cure for Neospora and there are no vaccines in this country. "The only control methods that we can advise farmers is culling to remove the animals from the herd, or not to breed dairy replacement calves from it, and that means a big loss, particularly if you've got a valuable animal."

Dr Williams has received a Wellcome Trust project grant to study the impact of the parasite in cattle more closely. A fundamental question is how infection leads to abortion. "We know that the parasite is transmitted from mother to offspring in the uterus, across the placenta. And we know this happens repeatedly; an infected animal can infect any number, or all, of its offspring. But although 95 per cent of affected animals do infect their fetuses, the infection doesn't always result in an abortion. So we would like to look closely at what is going on here, and find out why some of these animals abort and others don't."

Awakening infection

Dr Williams and her colleagues believe that the Neospora parasite has a latent stage, in the form of cysts that lie dormant in the animal's brain. During pregnancy, the cysts are activated and the parasites spread through the body of the animal; then, after pregnancy, they become latent again. Meanwhile the calf, if it is not aborted, is born with the infection, but appears perfectly healthy. However, when that calf becomes an adult and becomes pregnant, she can pass the infection onto her progeny.

Dr Williams believes that this activation of the parasite during pregnancy, and its suppression again after pregnancy, is related to changes in the maternal immune system during pregnancy.

"Back in the 1950s it was pointed out that a pregnant mammal is immunologically very unusual in that she is carrying a fetus which is expressing 'foreign' (paternal) proteins yet nevertheless survives in an immunologically competent mother. It's an evolutionary dilemma between the mother rejecting the fetus as immunologically foreign, and keeping it in order to reproduce. There are many different theories as to how this happens. But one idea that has been gaining some credence over the last few years is that the fetus itself is modulating the maternal immune response."

According to the model, the fetal immune system starts producing a set of signalling molecules, known as type 2 cytokines, which dampen down the mother's immune response. Their main effect is to suppress the mother's 'type 1' or 'killer' immune response, which is capable of destroying foreign tissues - potentially even those of the fetus. The result is a delicate balance between the type 2 immune response of the fetus and the type 1 immune response of the mother, which in normal pregnancies allows the fetus to grow undamaged by the maternal immune system while still enabling the mother to fight off infection.

However, the presence of the parasite may upset this balance. "One hypothesis is that, during pregnancy, the modulation of the maternal immune response by the fetal type 2 cytokines means that the parasite is no longer suppressed, and that's why it reactivates and starts to replicate. That may lead to a stimulation of the maternal type 1 response, to control the parasite growth, which would jeopardise the delicate balance between the fetal and maternal immune systems. Since it's obviously in the mother's interest not to be killed by the activation of the parasite, we think the fetus loses the battle and dies, leading to abortion. This is the hypothesis we're testing."

Support for this theory comes from studies in other pregnant mammals. Mice infected with the Leishmania parasite, for example, normally show a strong type 1 response which controls the infection, but if the infected mice are pregnant, then either the protective type 1 response is lower, or the infection results in more fetal deaths than in uninfected mice. In humans as well there is evidence that pregnant women are more susceptible to infections such as malaria or chlamydia.

There could be another explanation, however. "We've focused particularly on the balance between the maternal and fetal immune systems," says Dr Williams. "But another hypothesis is that the fetal immune system only develops during the second half of the pregnancy. This would mean a fetus exposed to parasites very early on has no way of controlling their growth and it could be the sheer number of parasites infecting the fetus, as opposed to the mother's immune response, which are causing the abortions."

Exploring infection

To shed light on these questions, Dr Williams and her team are attempting to identify exactly what is going on in the infected uterus. "We want to focus on what is happening at the interface between the maternal tissues and the fetal tissues in the uterus. We need to establish what cells and cytokines are present in both tissues, and in particular look at the nature of the balance between the type 1 and type 2 cytokines. We need to describe exactly what cytokines are present, how much is being produced, and when."

During background work, Dr Williams and her colleagues developed a powerful experimental system to enable them to address these questions, focusing on the cytokines that are produced early in pregnancy. They will be helped by collaborators at the Institute of Animal Health at Compton, who have developed novel methods to quantify the cytokines in cattle tissues. Collaborators at the Royal Veterinary College in London will be looking at the fetal immune response.

"Our aim is to increase our understanding of this dynamic interaction between fetus and mother in the face of an infectious challenge," explains Dr Williams. "In the end it may lead to some form of control, perhaps through vaccination, or by stimulating the immune system in some other way which would protect the fetus but allows the cow to deal with the growth of the parasite at the same time."

As well as having huge economic implications for the farming industry and animal welfare, the project is also likely to increase our understanding of all mammalian pregnancies - including the relationship between mother and fetus in humans - and thus has important medical implications as well.

Lethal immunity

A battle for survival between mother and child

Awakening infection

Exploring infection

See also

Further reading