Parasitology
Neosporosis: looking at the host parasite relationship
Dr Lee Innes
Figure 1: Neospora caninum parasites multiplying within host cells. |
Neospora caninum is a protozoan parasite, closely related to Toxoplasma gondii, that has emerged as a major cause of reproductive failure in cattle worldwide. Cattle infected with the parasite are 3-7 times more likely to abort than uninfected cattle, with infected heifers at the highest risk. Economic losses associated with the disease include costs incurred due to neonatal mortality, early foetal death (which may present as a return to service and/or increased calving interval), reduced milk production, reduced value of breeding stock and increased likelihood of culling.
The dog is a definitive host of the parasite and oocysts may be shed in the faeces of acutely infected dogs that acquire the infection following the consumption of infected cattle tissue. These oocysts can persist in the environment and are a source of infection for cattle through contaminated feed or water. Cattle may also become infected through vertical transmission from dam to calf during pregnancy. This method of congenital transmission is highly efficient and can occur over several generations and in successive pregnancies thus providing a very effective route for the parasite to be maintained within a herd.
To enable the development of effective control strategies against bovine neosporosis there is a need to understand more about how the parasite causes disease and how the host immune system fights the infection.
Neospora caninum, in common with other obligate intracellular parasites, can only multiply within the cells of the host organism (Figure 1). Activated T-lymphocytes (T-cells) can recognise and respond to parasite-infected cells. Through direct action or the production of soluble factors (cytokines), such as interferon gamma (IFN ), T-cells can significantly inhibit parasite multiplication, thus contributing to protection of the host. In the pregnant animal there is a natural modulation of the immune response to allow the mother to carry what is essentially a foreign tissue graft (the foetus) without immunological rejection taking place. Studies examining cytokine regulation in pregnancy have shown that the environment in the placenta favours more regulatory cytokines such as interleukin 10 (IL-10) and transforming growth factor beta (TGF-b) whose role is to counteract the inflammatory cytokines such as IFN . In addition, inflammatory cytokines, known to be protective against N. caninum, can, when present in placental tissues, compromise the pregnancy resulting in foetal death.
Therefore N. caninum infection presents a dilemma for the pregnant cow since the natural immunomodulation occurring during pregnancy may alter her ability to effectively control the infection, while the immune response made to fight the infection may in itself compromise the pregnancy.
Figure 2: Cross section through placenta. Neospora caninum parasites (stained brown) mainly in foetal area. |
To help us understand why some infected cattle abort their foetuses while others do not, recent studies at Moredun have compared maternal immune responses in N. caninum infected cattle, where foetal death has occurred, with those infected cattle carrying live foetuses (Figure 2). Preliminary data has shown the presence of inflammatory cells including CD4+, CD8+ and d T-cells and cytokines such as IFN associated with lesions in placental tissues from dams carrying dead foetuses. These immune responses were not seen in infected cattle carrying live foetuses. In addition, the N. caninum infected cows carrying live foetuses had significantly greater antigen specific IFN responses in local and peripheral lymph nodes compared to those carrying dead foetuses (Figure 3).
As pregnancy progressed the ability of the dam to mount an antigen-specific IFN response was found to decrease. This down-regulation of IFN may be a contributing factor in causing recrudescence of parasite activity in persistently infected animals, allowing vertical transmission to the foetus. Most abortions associated with N. caninum infection occur between 4-6 months of gestation.
Figure 3: IFN response in lymph nodes taken from infected dams carrying live (blue squares) or dead (pink squares) foetuses. |
These results illustrate how immune cytokines may have both a beneficial and a detrimental effect depending on their concentration and tissue location.
Another important factor influencing disease outcome is the gestational age of the foetus at the time of infection. The immune system of the foetus becomes increasingly competent as gestation progresses. During the first trimester of pregnancy the foetus is vulnerable to infection and can only mount primitive immune responses. Between 4- 6 months of gestation the foetus is able to make antigen-specific cell proliferation responses, IFN and antibodies to fight against parasite infection. The timing of placental, and hence foetal, infection in gestation is an important factor in determining the outcome. Infection occurring earlier in gestation is more likely to have severe consequences to the foetus.
Further studies to investigate the changing dynamics of the maternal and foetal immune responses throughout gestation and their consequential effect on parasite multiplication is essential in determining the factors involved in disease progression or resolution. Is the decrease in disease severity as pregnancy progresses due to the foetus being increasingly able to defend itself, or are the regulatory cytokines necessary to maintain the pregnancy damping down the potentially destructive inflammatory responses?
The host-parasite relationship in pregnant cattle infected with N. caninum is a fascinating dynamic interaction between the maternal immune response, the developing foetal immune response and the parasite; with the interaction between the three changing throughout gestation. A better understanding of how the parasite exploits the natural immunomodulation, occurring in pregnancy, to transmit to the foetus will aid in the development of effective control strategies against this important disease.
This research is funded by SEERAD.