Feline panleukopenia virus in cerebral neurons of young and adult cats

Abstract

BackgroundPerinatal infections with feline panleukopenia virus (FPV) have long been known to be associated with cerebellar hypoplasia in kittens due to productive infection of dividing neuroblasts. FPV, like other parvoviruses, requires dividing cells to replicate which explains the usual tropism of the virus for the digestive tract, lymphoid tissues and bone marrow in older animals.ResultsIn this study, the necropsy and histopathological analyses of a series of 28 cats which died from parvovirus infection in 2013 were performed. Infections were confirmed by real time PCR and immunohistochemistry in several organs. Strikingly, while none of these cats showed cerebellar atrophy or cerebellar positive immunostaining, some of them, including one adult, showed a bright positive immunostaining for viral antigens in cerebral neurons (diencephalon). Furthermore, infected neurons were negative by immunostaining for p27Kip1, a cell cycle regulatory protein, while neighboring, uninfected, neurons were positive, suggesting a possible re-entry of infected neurons into the mitotic cycle. Next-Generation Sequencing and PCR analyses showed that the virus infecting cat brains was FPV and presented a unique substitution in NS1 protein sequence. Given the role played by this protein in the control of cell cycle and apoptosis in other parvoviral species, it is tempting to hypothesize that a cause-to-effect between this NS1 mutation and the capacity of this FPV strain to infect neurons in adult cats might exist.ConclusionsThis study provides the first evidence of infection of cerebral neurons by feline panleukopenia virus in cats, including an adult. A possible re-entry into the cell cycle by infected neurons has been observed. A mutation in the NS1 protein sequence of the FPV strain involved could be related to its unusual cellular tropism. Further research is needed to clarify this point.

Cell cycle S phase markers are expressed in cerebral neuron nuclei of cats infected by the Feline Panleukopenia Virus

“…10 This mutation was not present in the tested cats of the present series. It is thus unlikely that this mutation plays any role in the particular neuronal tropism of the FPV.…”

“…We observed FPV proteins expression in extracerebellar neurons in cats of 10 weeks (this study, an age when even the cerebellar cortex is adult-like) and FPV expression in extracerebellar neurons has been described in individuals up to 4.5 y. 10 Consequently, neuron immaturity and lack of trophic factors from the connected neurons (cerebellar granule cells) are not likely to be the major cause of their cell cycle reentry after FPV infection.…”

“…An outbreak with the KP769859 strain would better explain the repeated observation of the mutation in this previous study. 10 Expression of the SV40 T-antigen in developing Purkinje cells drove these neurons into cell cycle-associated death. 29 Viral proteins like the SV40 T-antigen that inactivate tumor suppressors of the retinoblastoma family (pocket proteins), free the E2F family transcription factors and might be able to launch neuronal cell cycle reentry.…”

“…5,7,8 Moreover, CPV was detected by immunohistochemistry in cerebral neurons of 18/100 cats submitted for necropsy, 9 and more recently, FPV protein expression was evidenced in cerebral neurons of 4/23 cats that presented enteritis. 10 In the latter study, the thalamus was the most affected area, and the cerebellum was spared. In the present study, we retrospectively investigated the whole brain of cats with FPVassociated, PCR-confirmed cerebellar hypoplasia.…”

“…5,7 For Cats #5, 7, 9-12, the same primers as those used in a previous study, 10 which reported FPV proteins in thalamic and brain stem neurons, were used to amplify a 357 bp product coding for the C-terminus of the FPV NS1 protein. For cat #12, no product was obtained and a different pair of primers was used to amplify a shorter, 206 bp product of the NS1 gene (Fig.…”