Persistent retroviral infection with MoMuLV influences neuropathological signature and phenotype of prion disease

Abstract

A fundamental step in pathophysiology of prion diseases is the conversion of the host encoded prion protein (PrP(C)) into a misfolded isoform (PrP(Sc)) that accumulates mainly in neuronal but also non-neuronal tissues. Prion diseases are transmissible within and between species. In a subset of prion diseases, peripheral prion uptake and subsequent transport to the central nervous system are key to disease initiation. The involvement of retroviruses in this process has been postulated based on the findings that retroviral infections enhance the spread of prion infectivity and PrP(Sc) from cell to cell in vitro. To study whether retroviral infection influences the phenotype of prion disease or the spread of prion infectivity and PrP(Sc) in vivo, we developed a murine model with persistent Moloney murine leukemia retrovirus (MoMuLV) infection with and without additional prion infection. We investigated the pathophysiology of prion disease in MoMuLV and prion-infected mice, monitoring temporal kinetics of PrP(Sc) spread and prion infectivity, as well as clinical presentation. Unexpectedly, infection of MoMuLV challenged mice with prions did not change incubation time to clinical prion disease. However, clinical presentation of prion disease was altered in mice infected with both pathogens. This was paralleled by remarkably enhanced astrogliosis and pathognomonic astrocyte morphology in the brain of these mice. Therefore, we conclude that persistent viral infection might act as a disease modifier in prion disease.

Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time

“…Again, we could not detect differences between animals infected with prions vs. those infected with prions + virus (Figure D). As previously reported, the clinical presentation of the prion disease of mice after intraperitoneal prion injection changes upon an additional retrovirus infection . However, changes were less pronounced in the intracerebrally infected when compared with intraperitoneally prion infected mice (data not shown).…”

Protease-sensitive prion species in neoplastic spleens of prion-infected mice with uncoupling of PrPSc and prion infectivity

“…Previously, we showed that persistent retroviral infection with Moloney murine leukemia retrovirus (MoMuLV) changed the neuropathological signature and phenotype of prion disease (Krasemann et al, 2012). In this study, a subset of mice were used that developed spleenomegaly (Fig.…”

“…All procedures involving animals were performed in accordance with the institutional guidelines from the animal facility of the University Medical Center Hamburg-Eppendorf and were in compliance with the Guide for the Care and Use of Laboratory Animals. Mice were inoculated with MoMuLV on post-natal day 5 with~7610 4 IU to achieve virus persistence (Krasemann et al, 2012;Rodenburg et al, 2007;Schwieger et al, 2002). For prion-only infection or infection with both pathogens (MoMuLV+prion), strain RML 5.0 prions (Prinz et al, 2003b) were injected on day 21.…”

Exosomes and the Prion Protein: More than One Truth

“…Further studies showed a link between release of retrovirus particles, presence of PrP Sc , and prion infectivity on both, exosomes and retroviral particles, thus it was proposed that retroviral infection could be a cofactor in the spreading of prion disease (Alais et al, 2012). However, subsequent in vivo studies by our group and others did not provide evidence for this, but rather showed that subclinical retroviral infection acts as a disease modifier, but does not enhance spreading of the disease (Alais et al, 2012; Krasemann et al, 2012; Muth et al, 2016). …”