Host genetics, innate immune responses, and cellular death pathways in poliomyelitis patients

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Host genetics, innate immune responses, and cellular death pathways in poliomyelitis patients. / Andersen, Nanna Sophie B.; Larsen, Simon M.; Nissen, Sara K.; Jørgensen, Sofie E.; Mardahl, Maibritt; Christiansen, Mette; Kay, Lise; Mogensen, Trine H.

In: Frontiers in Microbiology, Vol. 10, 1495, 07.2019.

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@article{d316404cf52b4f8d8f7fb9fbe225e13a,
title = "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.",
keywords = "Apoptosis, Autophagy, Innate immunity, Interferon, Paralytic poliomyelitis, Poliovirus, Whole exome sequencing",
author = "Andersen, {Nanna Sophie B.} and Larsen, {Simon M.} and Nissen, {Sara K.} and J{\o}rgensen, {Sofie E.} and Maibritt Mardahl and Mette Christiansen and Lise Kay and Mogensen, {Trine H.}",
year = "2019",
month = "7",
doi = "10.3389/fmicb.2019.01495",
language = "English",
volume = "10",
journal = "Frontiers in Microbiology",
issn = "1664-302X",
publisher = "Frontiers Media S.A",

}

RIS

TY - JOUR

T1 - Host genetics, innate immune responses, and cellular death pathways in poliomyelitis patients

AU - Andersen, Nanna Sophie B.

AU - Larsen, Simon M.

AU - Nissen, Sara K.

AU - Jørgensen, Sofie E.

AU - Mardahl, Maibritt

AU - Christiansen, Mette

AU - Kay, Lise

AU - Mogensen, Trine H.

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Autophagy

KW - Innate immunity

KW - Interferon

KW - Paralytic poliomyelitis

KW - Poliovirus

KW - Whole exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85069528126&partnerID=8YFLogxK

U2 - 10.3389/fmicb.2019.01495

DO - 10.3389/fmicb.2019.01495

M3 - Journal article

VL - 10

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

SN - 1664-302X

M1 - 1495

ER -