RESUMEN
Paralytic poliomyelitis is a rare disease manifestation following poliovirus (PV) infection. The disease determinants remain largely unknown. We used whole exome sequencing to uncover possible contributions of host genetics to the development of disease outcome in humans with poliomyelitis. We identified a patient with a variant in ATG7, an important regulatory gene in the macroautophagy/autophagy pathway. PV infection did not induce a prominent type I interferon response, but rather activated autophagy in neuronal-like cells, and this was essential for viral control. Importantly, virus-induced autophagy was impaired in patient fibroblasts and associated with increased viral burden and enhanced cell death following infection. Lack of ATG7 prevented control of infection in neuronal-like cells, and reconstitution of patient cells with wild-type ATG7 reestablished autophagy-mediated control of infection. Collectively, these data suggest that ATG7 defect contributes to host susceptibility to PV infection and propose autophagy as an unappreciated antiviral effector in viral infection in humans.
Asunto(s)
Interferón Tipo I , Poliomielitis , Poliovirus , Autofagia/genética , Proteína 7 Relacionada con la Autofagia/genética , Humanos , Neuronas , Poliomielitis/genética , Poliomielitis/prevención & control , Poliovirus/genéticaRESUMEN
Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Autofagia , Cisteína Endopeptidasas/genética , Resistencia a la Enfermedad , Herpesvirus Humano 2/inmunología , Meningitis Viral/etiología , Proteínas Asociadas a Microtúbulos/genética , Mutación , Anciano , Autofagia/genética , Autofagia/inmunología , Células Cultivadas , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Susceptibilidad a Enfermedades , Femenino , Fibroblastos , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Proteínas de la Membrana/metabolismo , Meningitis Viral/diagnóstico , Persona de Mediana Edad , Recurrencia , Transducción de Señal , Carga Viral , Replicación ViralRESUMEN
Coronavirus disease-19 (COVID-19) describes a set of symptoms that develop following infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whilst COVID-19 disease is most serious in patients with significant co-morbidities, the reason for healthy individuals succumbing to fulminant infection is largely unexplained. In this review, we discuss the most recent findings in terms of clinical features and the host immune response, and suggest candidate immune pathways that may be compromised in otherwise healthy individuals with fulminating COVID-19. On the basis of this early knowledge we reason a potential genetic effect on host immune response pathways leading to increased susceptibility to SARS-CoV-2 infection. Understanding these pathways may help not only in unraveling disease pathogenesis, but also in suggesting targets for therapy and prophylaxis. Importantly such insight should instruct efforts to identify those at increased risk in order to institute preventative measures, such as prophylactic medication and/or vaccination, when such opportunities arise in the later phases of the current pandemic or during future similar pandemics.
