Abstract
PurposePoliovirus (PV) is one of the most studied viruses. Despite efforts to understand PV infection within the host, fundamental questions remain unanswered. These include the mechanisms determining the progression to viremia, the pathogenesis of neuronal infection and paralysis in only a minority of patients. Because of the rare disease phenotype of paralytic poliomyelitis (PPM), we hypothesize that a genetic etiology may contribute to the disease course and outcome.MethodsWe used whole-exome sequencing (WES) to investigate the genetic profile of 18 patients with PPM. Functional analyses were performed on peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MdMs).ResultsWe identified rare variants in host genes involved in interferon signaling, viral replication, apoptosis, and autophagy. Upon PV infection of MdMs, we observed a tendency toward increased viral burden in patients compared to controls, suggesting reduced control of PV infection. In MdMs from patients, the IFNβ response correlated with the viral burden.ConclusionWe suggest that genetic variants in innate immune defenses and cell death pathways contribute to the clinical presentation of PV infection. Importantly, this study is the first to uncover the genetic profile in patients with PPM combined with investigations of immune responses and viral burden in primary cells.
Highlights
Paralytic poliomyelitis (PPM) is a rare disease presentation following poliovirus (PV) infection
Following the ingenuity variant analysis (IVA) filtering described in Figure 1, the section “Materials and Methods” and Supplementary Method 1, we sorted out 160 variants in 163 genes
To illustrate to what extent the 36 genes included in the PPM cohort represented a genuine enrichment, we analyzed the PPI enrichment p-value 50 times in random sets of 36 proteins generated from the biological filter list (Supplementary Table S2)
Summary
Paralytic poliomyelitis (PPM) is a rare disease presentation following poliovirus (PV) infection. In 1988, The global polio eradication initiative (GPEI) launched a program in which global expansion of the PV vaccine resulted in reduction of PPM from an annual level of at least 350,000 cases to only 22 cases caused by wild poliovirus (WPV) in 2017. These cases were identified in the two endemic countries Afghanistan and Pakistan with 14 and 8 cases, respectively (Khan et al, 2017). In 2019, the year-to-date of WPV is almost twice the size of the year-to-date in 2018 (The Global Polio Eradication Initiative [GPEI], 2018). The failing achievement of stopping PV transmission challenges global eradication
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