Abstract
Bovine neosporosis is currently considered one of the main causes of abortion in cattle worldwide and the outcome of the infection is, in part, determined by Neospora caninum isolate virulence. However, the dam and foetal immune responses associated with this factor are largely unknown. We used a model of bovine infection at day 110 of gestation to study the early infection dynamics (10- and 20-days post-infection, dpi) after experimental challenge with high- and low-virulence isolates of N. caninum (Nc-Spain7 and Nc-Spain1H, respectively). In the present work, dam peripheral cellular immune responses were monitored twice a week from -1 to 20 dpi. At different time points, IFN-γ and IL-4 production was investigated in stimulated dam blood and the percentage of monocytes, NK cells, B cells and T cells (CD4+, CD8+ and γδ) in peripheral blood mononuclear cells (PBMC) were determined by flow cytometry. In addition, maternal iliofemoral lymph nodes and foetal spleen and thymus were collected at 10 and 20 dpi for the study of the same cell subpopulations. Peripheral immune response dynamics were similar after the infection with both isolates, with a significant increase in the percentage of CD4+ T cells at 6 and 9 dpi in PBMC, coincident with the higher levels of IFN-γ and IL-4 release. However, the levels of IFN-γ were significantly higher and an increase in CD8+ T cells at 9, 13 and 20 dpi was observed in the dams infected with Nc-Spain7. Nc-Spain1H infection induced higher IL4 levels in stimulated blood and a higher CD4+/CD8+ ratio in PBMC. The analysis of the maternal iliofemoral lymph node showed a significant enhancement in the percentage of NK, CD4+ and CD8+ T cells for the animals infected with the highly virulent isolate and euthanized at 20 dpi. Regarding the foetal responses, the most remarkable result was an increase in the percentage of monocytes at 20 dpi in the spleen of foetuses from both infected groups, which suggests that foetuses were able to respond to N. caninum infection at mid gestation. This work provides insights into how isolate virulence affects the maternal and foetal immune responses generated against N. caninum, which may influence the course of infection.
Highlights
Neospora caninum infection is a major cause of bovine abortion worldwide
The levels of IFN-g and IL-4 were measured in stimulated blood by ELISA, and there was no antigen-specific IFN-g or IL-4 secretion in the peripheral blood mononuclear cells (PBMC) of the control animals (Figure 1)
Regarding gd-T cells, previous in vitro studies have suggested that these cells may act as a short-term or innate response to N. caninum infection based on the capability of these cells to kill infected target cells upon cytokine stimulation (Peckham et al, 2014)
Summary
Neospora caninum infection is a major cause of bovine abortion worldwide. Over the last few years, bovine neosporosis has been studied intensively, but the pathogenesis is complex and poorly understood. In vivo studies in pregnant cattle carried out by our group have shown a high percentage of abortion upon Nc-Spain infection with foetal death estimated to occur between 24 and 49 dpi (Caspe et al, 2012; Regidor-Cerrillo et al, 2014; Vázquez et al, 2019). With the aim of exploring in more depth the mechanisms involved in the pathogenesis of abortion or vertical transmission, we used a pregnant bovine model of infection at mid-gestation, in which early infection dynamics (10- and 20-days post-infection, dpi) were compared after inoculation with the high-virulence Nc-Spain and the lowvirulence Nc-Spain1H isolates. NcSpain1H infection did not result in lesion development or foetal death (Jiménez-Pelayo et al, 2019) These results were associated with a differential pattern in the local immune response at the placental level, in the early stages of infection. The low-virulence isolate Nc-Spain1H elicited an early and robust immune response characterized by a mixed Th1/Th2 profile, whereas a more predominantly pro-inflammatory Th1-based response was induced in Nc-Spain7-infected placentomes (Jiménez-Pelayo et al, 2020)
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