Human pegivirus, an RNA virus in the flavivirus family, was identified in the brains and cerebrospinal fluid of patients with Parkinson’s disease, but not in matched control samples, according to a new study.
Researchers also found that human pegivirus (HPgV) infection was associated with altered immune signaling and gene expression profiles in both the central nervous system and peripheral blood. These effects differed based on LRRK2 genotype.
Using an unbiased sequencing platform and confirmatory qPCR, HPgV RNA was detected in 5 of 10 postmortem brain samples that had Parkinson’s disease (PD) and in 0 of 14 control brains (P = .020). HPgV NS5A protein was visualized in oligodendrocytes from 2 infected patients which suggested viral protein expression in glial cells. HPgV RNA was also found in cerebrospinal fluid from 3 PD cases, all of which had previously tested positive for HPgV in brain tissue.
All 5 patients with HPgV-positive PD showed advanced Braak staging that involved the limbic region, compared with 1 of 5 patients with HPgV-negative PD (P = .012). Additionally, Complexin-2 levels—a marker of excitatory neurotransmission—were elevated in infected patients (0.67 vs –0.34 log10 z-score; P = .008).
In a separate blood-based analysis from the Parkinson’s Progression Markers Initiative cohort (n = 1393), HPgV viremia was detected in 14 participants (1%), including 8 of 753 patients with PD (1.1%). Though prevalence was similar between PD and non-PD groups, patients with HPgV-positive PD had higher serum IGF-1 levels (177.85 ng/mL vs 138.40 ng/mL; P = .047) and lower levels of phosphorylated ubiquitin (pS65-Ub) (32.50 ng/mL vs 46.73 ng/mL; P = .005), a marker of mitophagy.
Transcriptomic analyses revealed suppression of interleukin-4 (IL-4) signaling in patients who had HPgV-positive PD. The direction of this immune signaling response varied by LRRK2 genotype: in patients with the mutation, IL-4 signaling decreased with higher HPgV titer, but increased in wild-type patients.
Gene network analysis identified YWHAB (14-3-3β) as a central hub gene that differentiates these genotype-specific responses. Its expression was associated with modulation of key immune and neuronal pathways, including NF-κB, STAT3, and TSC2. These pathways are linked to neuroinflammation, lysosomal function, and cortical neuron death.
HPgV also affected expression of small nucleolar RNAs (snoRNAs), and opposing patterns were identified in wild-type and LRRK2 PD subgroups. Longitudinal data showed that HPgV viremia could persist for over 2 years; approximately 45% of patients cleared the virus during follow-up.
Limitations of the study included the small sample size and reliability of detecting subtler effects of HPgV. Age differences in the brain tissue and blood cohorts may have introduced confounders.
HPgV has a potential role in modulating immune responses and gene networks in PD, the authors concluded. Further research is needed to clarify the temporal relationship and mechanistic impact of HPgV infection on disease progression, as well as central vs peripheral effects of HPgV in PD pathophysiology.
The authors reported no conflicts of interest.
Source: JCI Insight