Host Genetics, Innate Immune Responses, and Cellular Death Pathways in Poliomyelitis Patients

Abstract

Purpose Poliovirus (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. Methods We 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). Results We 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. Conclusion We 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.

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

“…Host genetics and profile of immune responses affect the course of PV infection, determining if a particular individual will have neurological impairment (Andersen et al, 2019). Considering that CCR5 affects the course of other neuroinvasive viral infections such as TBEV and WNV, it was hypothesized that CCR5Δ32 could influence the development of neurological impairment associated with PV infection, as this only occurs in a portion of infected individuals (Rosenberg et al, 2013).…”

Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants

“…Genetic variants in apoptosis-related genes were previously identified in poliomyelitis and a Mollaret meningitis cohort (Andersen et al, 2019;Hait et al, 2021); however, the present study represents the first description of major variants related to apoptosis in patients with VZV infection. Considering how herpesviruses establish latency in their hosts it seems plausible that a careful regulation of cell death pathways is of central importance.…”

“…Evolutionary conservation of this pathway has been described in Drosophila melanogaster (Hura et al, 2022), further underlining the essential role of this biological pathway, possibly also in antiviral defense against VZV infection of ocular tissue. Of note, Q10-related variants have not previously been identified in any other WES studies (Andersen et al, 2019;Hait et al, 2021;Thomsen et al, 2021), underlining a potential specificity of COQ10 biology for ARN development.…”

Genetic susceptibility to viral disease in humans

“…Based on this work, it may be hypothesized that autophagy plays a particularly important role in antiviral defenses in the CNS, an organ vulnerable to immunopathology and excessive IFN production, explaining why defective autophagy may represent a rare IEI associated with susceptibility to viral neuro-infections (17). This idea is further supported by another study on human immunogenetics of individuals suffering from severe poliomyelitis during the large poliovirus epidemics in the 1950's implicated autophagy defects in ATG7 and possibly other autophagy-related genes in the pathogenesis of rare cases of poliomyelitis (19,20).…”