Five years of porcine circovirus 3: What have we learned about the clinical disease, immune pathogenesis, and diagnosis

Porcine circovirus type 3 (PCV3) is a non-enveloped, circular, single-stranded DNA virus in the family Circoviridae. This member of the genus Circovirus was initially described as affecting swine in 2016, and new research has provided further insight into its structural characteristics, disease presentations, pathogenesis, and immune response following infection. Therefore, this review aims to summarize advances in PCV3-related research about genomic characteristics epidemiology, pathogenesis, immune response, and the development of diagnostics. PCV3 has been detected globally and retrospectively in pigs of all ages and is associated with a range of clinical presentations, including multisystemic inflammatory syndrome, reproductive failure, porcine dermatitis and nephropathy syndrome, and subclinical infection. Experimental studies have successfully reproduced multisystemic inflammation but have not detected clinical disease. These findings, coupled with a large number of reports of coinfections coinciding with PCV3, may suggest that PCV3 infection alone may not be sufficient to cause evidenceable clinical disease. The pathogenesis of PCV3 has not been fully elucidated yet, and while receptors that facilitate cell-viral entry have not been identified, replication has been confirmed in a wide range of cell types, including trophoblasts, myocardiocytes, skin adipocytes, and neurons. PCV3 seems to evade the host immune response as evidenced by persistent viremia 42 days post-infection in experimental and longitudinal field studies despite a strong humoral response. Minimal differences in host cytokine profiles and peripheral cell-mediated responses have been observed, but certainly many questions still surround the mechanisms by which PCV3 evades the immune response. The epidemiology of PCV3 remains unclear, and the exact routes of transmission have not been described; but, PCV3 can be shed in oral fluids, nasal secretions, feces, colostrum, and semen, demonstrating the importance of lateral and vertical transmission. The detection of PCV3 in numerous domesticated and wild animal species, including cattle, dogs, mice, wild boar, chamois, roe deer, ticks, and mosquitoes, suggests the potential for multiple reservoirs and cross-species transmission. Current advances in PCV3 diagnostic tests have the ability to differentiate PCV3 from other PCVs and corroborate its presence within lesions. Given that the economic impact associated with PCV3 infection has not been assessed and the virus has the potential to emerge as a high-prevalence pathogen in the coming years, future research should focus on filling the knowledge gaps identified in this review.