13 However, the growth cycle can be slowed or arrested depending on intracellular nutrient availability, leading to bacterial persistence within host cells.14,15 This is a key survival feature of these organisms and is a major determinant of disease pathogenesis as discussed more fully in the following sections. C. abortus typically causes reproductive failure and abortion in ruminants and swine and has a world-wide distribution, with the exception of Australia and New Zealand. C. abortus is also a well-recognized and potentially

fatal zoonosis, presenting a major hazard to pregnant women who come in contact with livestock, particularly at lambing.16 Although OEA is a reproductive disease, the principal route of transmission to naïve sheep is thought to be via an oro-nasal route, most likely from heavily infected placentas from ewes that have aborted and contaminate the environment.17,18 A typical example R788 mouse of a placenta with characteristic thickened www.selleckchem.com/products/atezolizumab.html membranes from an ewe that aborted as a result of OEA is shown in Fig. 2. Abortion is thought to be because of inappropriate inflammatory cytokine and chemokine production in the placenta that leads to placentitis.18,19 The success of C. abortus as a reproductive pathogen in a species that is only pregnant for 5 months

and only gives birth once a year is because of its ability to establish a persistent, subclinical infection in non-pregnant sheep.20 Thus, when naïve, non-pregnant sheep are infected, protective immunity does not develop. Ewes then abort in the subsequent pregnancy. Sheep that have aborted do develop strong protective immunity (but not necessarily sterile immunity) and reproduce normally in subsequent pregnancies.20,21 The Adenylyl cyclase epidemiology and pathogenesis of OEA both indicate that a systemic phase of infection occurs after the primary infection of the oro-nasal mucosa. Neither the site of persistence of C. abortus nor the timing or duration of the systemic phase of infection has been identified. Therefore, the paradigms relating to reproductive immunology and to host immune control of intracellular bacteria are useful frameworks for addressing questions regarding

the pathogenesis of OEA. Furthermore, in addressing these paradigms in sheep, we can test their predictions and assess their relevance for a species other than mouse or human. In doing so, we should advance our knowledge of comparative immunology and reproduction. The first description of helper T-cell clones expressing distinctive cytokine profiles was made by Tim Mosmann, Robert Coffman and co-workers22 in 1986 in a paper that has had a profound impact on our understanding of how CD4+ve T cells orchestrate and regulate immune responses. They discovered that mitogen-activated murine CD4+ve T-cell clones were mutually exclusive in their expression of IL-2/IFN-γ (TH1) and what we now know to be IL-4 (TH2), whereas both sets of clones made IL-3.