RESUMO
The present study describes a 19-year-old woman with systemic herpes simplex virus (HSV)-1 infection and hemophagocytic lymphohistiocytosis (HLH) postpartum, and a fatal course of neonatal herpesvirus infection. Functional investigation of cells from the mother demonstrated significantly impaired induction of antiviral interferons and cytokines in the context of normal activation of the transcription factors NF-κB and IRF3. Whole-exome sequencing did not reveal any functionally validated genetic variants. We suggest that the functionally impaired antiviral responses, potentially caused by a variant in CASP8 or other variants in noncoding regions of the genome, contributed to the unusually severe disease course observed in two generations.
Assuntos
Herpes Simples/diagnóstico , Herpesvirus Humano 1/isolamento & purificação , Linfo-Histiocitose Hemofagocítica/complicações , Antivirais/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Citocinas , Feminino , Herpes Simples/complicações , Herpes Simples/tratamento farmacológico , Herpes Simples/mortalidade , Herpesvirus Humano 1/genética , Humanos , Imunidade Inata , Transmissão Vertical de Doenças Infecciosas , Interferons/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Período Pós-Parto , Complicações Infecciosas na Gravidez , Sequenciamento do Exoma , Adulto JovemRESUMO
Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.
Assuntos
Sequenciamento do Exoma , Herpes Simples , Meningite , Herpes Simples/genética , Herpesvirus Humano 2 , Humanos , Interferons , Linfócitos , Meningite/genética , Meningite/virologia , RecidivaRESUMO
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.
Assuntos
Interferon Tipo I , Poliomielite , Poliovirus , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Humanos , Neurônios , Poliomielite/genética , Poliomielite/prevenção & controle , Poliovirus/genéticaRESUMO
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.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Autofagia , Cisteína Endopeptidases/genética , Resistência à Doença , Herpesvirus Humano 2/imunologia , Meningite Viral/etiologia , Proteínas Associadas aos Microtúbulos/genética , Mutação , Idoso , Autofagia/genética , Autofagia/imunologia , Células Cultivadas , Resistência à Doença/genética , Resistência à Doença/imunologia , Suscetibilidade a Doenças , Feminino , Fibroblastos , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Proteínas de Membrana/metabolismo , Meningite Viral/diagnóstico , Pessoa de Meia-Idade , Recidiva , Transdução de Sinais , Carga Viral , Replicação ViralRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fumarato de Dimetilo/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacologia , Betacoronavirus/metabolismo , COVID-19 , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Betacoronavirus , Infecções por Coronavirus , Predisposição Genética para Doença , Pandemias , Pneumonia Viral , Betacoronavirus/genética , Betacoronavirus/imunologia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor proposed to act in the cyclic GMP-AMP synthase-stimulator of IFN genes pathway. Because mice do not have a clear ortholog of IFI16, this system is not suitable for genetic studies of IFI16. In this study, we have compared the dependency on IFI16, cyclic GMP-AMP synthase, and stimulator of IFN genes for type I IFN induction by a panel of pathogenic bacteria and DNA viruses. The IFN response induced by HSV-2 was particularly dependent on IFI16. In a cohort of patients with genital herpes and healthy controls, the minor G allele of the IFI16 single nucleotide polymorphism rs2276404 was associated with resistance to infection. Furthermore, the combination of this allele with the C allele of rs1417806 was significantly overrepresented in uninfected individuals. Cells from individuals with the protective GC haplotype expressed higher levels of IFI16 and induced more IFN-ß upon HSV-2 infection. These data provide genetic evidence for a role for IFI16 in protection against genital herpes.