RESUMO
Both type I and type II interferons (IFNs) have been implicated in the host defense against varicella-zoster virus (VZV), a common human herpesvirus that causes varicella and zoster. The purpose of this study was to compare their contributions to the control of VZV replication, to identify the signaling pathways that are critical for mediating their antiviral activity, and to define the mechanisms by which the virus counteracts their effects. Gamma interferon (IFN-γ) was much more potent than IFN-α in blocking VZV infection, which was associated with a differential induction of the interferon regulatory factor (IRF) proteins IRF1 and IRF9, respectively. These observations account for the clinical experience that while the formation of VZV skin lesions is initially controlled by local immunity, adaptive virus-specific T cell responses are required to prevent life-threatening VZV infections.IMPORTANCE While both type I and type II IFNs are involved in the control of herpesvirus infections in the human host, to our knowledge, their relative contributions to the restriction of viral replication and spread have not been assessed. We report that IFN-γ has more potent activity than IFN-α against VZV. Findings from this comparative analysis show that the IFN-α-IRF9 axis functions as a first line of defense to delay the onset of viral replication and spread, whereas the IFN-γ-IRF1 axis has the capacity to block the infectious process. Our findings underscore the importance of IRFs in IFN regulation of herpesvirus infection and account for the clinical experience of the initial control of VZV skin infection attributable to IFN-α production, together with the requirement for induction of adaptive IFN-γ-producing VZV-specific T cells to resolve the infection.
Assuntos
Herpesvirus Humano 3/imunologia , Fator Regulador 1 de Interferon/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Interferon-alfa/imunologia , Interferon gama/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Replicação Viral/imunologiaRESUMO
BACKGROUND: COVID-19 infection is associated with D-dimer elevations, high rates of thrombus formation, and poor clinical outcomes. We sought to determine if empiric therapeutic anticoagulation (AC) affected survival in COVID-19 patients compared to standard prophylactic AC. METHODS: Retrospective analysis of 402 COVID-19 patients hospitalized between March 15 and May 31, 2020 was performed. Clinical outcomes were compared between 152 patients treated with therapeutic AC to 250 patients on prophylactic AC. An elastic net logistic regression was designed to first identify the important variables affecting mortality. These variables were then included as covariates to AC in standard multivariate logistic regression models studying the effect of AC on death. Nonparametric survival analysis was conducted, and Kaplan Meier curves were constructed. RESULTS: Increased mortality was associated with therapeutic AC [OR 3.42 (2.06, 5.67)]. The log-rank test was statistically significant at p = 0.001 showing higher mortality for patients treated with therapeutic AC compared to prophylactic AC. Subset analysis of critically ill and intubated patients had similar survival curves regardless of AC dose. The log-rank test was not significant even with Prentice modification. For non-ICU patients, the log rank test favoring prophylactic AC disappeared when the analysis was stratified by D-dimer level less or greater than 3 µg/mL. Approximately 9% of patients receiving therapeutic AC experienced clinically significant bleeding or thrombocytopenia, versus 3% in those receiving prophylactic AC. CONCLUSIONS: In our cohort, therapeutic anticoagulation provided no mortality benefit over thromboprophylaxis, independent of co-morbidities or disease severity. More adverse events were observed with therapeutic AC.