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Interferon system deficiencies exacerbating severe pandemic virus infections.

ABSTRACT: Pandemics are caused by novel pathogens to which pre-existing antibody immunity is lacking. Under these circumstances, the body must rely on innate interferon-mediated defenses to limit pathogen replication and allow development of critical humoral protection. Here, we highlight studies on disease susceptibility during H1N1 influenza and COVID-19 (SARS-CoV-2) pandemics. An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled virus replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with autoantibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. We discuss key questions surrounding how such autoantibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.

SUBMITTER: Stertz S

PROVIDER: S-EPMC7980109 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Interferon system deficiencies exacerbating severe pandemic virus infections.

Stertz Silke S Hale Benjamin G BG

Trends in microbiology 20210320 11

Pandemics are caused by novel pathogens to which pre-existing antibody immunity is lacking. Under these circumstances, the body must rely on innate interferon-mediated defenses to limit pathogen replication and allow development of critical humoral protection. Here, we highlight studies on disease susceptibility during H1N1 influenza and COVID-19 (SARS-CoV-2) pandemics. An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled virus rep ...[more]

PMID: 33757684

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Project description:BackgroundVentriculitis, a dreaded complication of brain abscess, meningitis, and various neurosurgical procedures, has attracted limited attention in the medical literature.MethodsThis is a retrospective, single-center study. We screened the medical files of all patients who had a brain imaging report that included the word "ventriculitis" during years 2005-2019. Only patients with clinical, microbiological, and imaging features of ventriculitis were included. Data were collected through a standardized questionnaire.ResultsNinety-eight patients fulfilled inclusion criteria: 42 women and 56 men, and the median age was 60 years (interquartile range, 48-68). The primary mechanism for ventriculitis was classified as follows: brain abscess (n = 29, 29.6%), meningitis (n = 27, 27.6%), intraventricular catheter-related (n = 17, 17.3%), post-neurosurgery (n = 13, 13.3%), and hematogenous (n = 12, 12.2%). The main neuroimaging features were intraventricular pus (n = 81, 82.7%), ependymal enhancement (n = 70, 71.4%), and intraventricular loculations (n = 15, 15.3%). The main pathogens were streptococci (n = 44, 44.9%), Gram-negative bacilli (n = 27, 27.6%), and staphylococci (n = 15, 15.3%). In-hospital and 1-year mortality rates were 30.6% (n = 30) and 38.8% (n = 38), respectively. Neurological sequelae were reported in 34 of 55 (61.8%) survivors, including cognitive impairment (n = 11), gait disturbances (n = 9), paresis (n = 7), behavior disorder (n = 6), and epilepsy (n = 5). On multivariate analysis, age >65 years, Glasgow Coma Scale score <13 at initial presentation, status epilepticus, hydrocephalus, and positive cerebrospinal fluid culture were associated with 1-year mortality. We built a scoring system to stratify patients with ventriculitis into low risk (12.5%), intermediate risk (36.5%), and high risk (71.4%) of death.ConclusionsVentriculitis is a severe complication of brain abscess, meningitis, or neurosurgery, with an in-hospital mortality rate of 30% and neurological sequelae in 60% of survivors.

Project description:Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-γ (IFN-γ) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-γ on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-γ responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-γ on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-γ responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-γ. THP-1 cells showed a dose dependent effect of IFN-γ on cytokine responses to endotoxin. For PBMC, IFN-γ enhanced interleukin (IL)-1β, IL-6, and tumor necrosis factor-α responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-γ. There was no effect of gender or genotype on IFN-γ responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.

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Interferon system deficiencies exacerbating severe pandemic virus infections.

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Interferon system deficiencies exacerbating severe pandemic virus infections.

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