The Neospora caninum Paradox: Comparative Biology of Cattle and Water Buffalo Reveals Pathways to Control Bovine Neosporosis

Neospora caninum is a major cause of reproductive failure in cattle, responsible for epidemic abortion outbreaks that inflict annual billion-dollar losses on the global livestock industry. In water buffaloes (Bubalus bubalis), however, a phylogenetically close relative often raised in the same environments, the same parasite typically establishes a subclinical persistent infection with markedly lower rates of clinical abortion. This review inverts the traditional narrative by arguing that the key to next-generation control strategies lies in understanding the tolerant host (buffalo) rather than solely the susceptible host (cattle). By dissecting this “Neospora paradox”, we explore the molecular and immunological crosstalk that dictates pregnancy outcomes. We examine the parasite’s invasion proteins, revealed by CRISPR-Cas9 screens, and the maternal–fetal interface, where the balance between immune tolerance and parasite control determines the fate of pregnancy. We also compare N. caninum with the related zoonotic parasite Toxoplasma gondii to highlight how differential host immune recognition shapes infection outcomes. Finally, we propose that deciphering the buffalo’s successful equilibrium with N. caninum can illuminate novel pathways for vaccines and immunotherapeutic strategies, transforming the management of neosporosis worldwide.