IFNAR1 signaling in NK cells promotes persistent virus infection

Inhibition of type 1 interferon (IFN-I) signaling promotes the control of persistent virus infection, but the underlying mechanisms remain poorly understood. Here, we report that genetic ablation of Ifnar1 specifically in natural killer (NK) cells led to elevated numbers of T follicular helper cells, germinal center B cells, and plasma cells and improved antiviral T cell function, resulting in hastened virus clearance that was comparable to IFNAR1 neutralizing antibody treatment. Antigen-specific B cells and antiviral antibodies were essential for the accelerated control of LCMV Cl13 infection following IFNAR1 blockade. IFNAR1 signaling in NK cells promoted NK cell function and general killing of antigen-specific CD4 and CD8 T cells. Therefore, inhibition of IFN-I signaling in NK cells enhances CD4 and CD8 T cell responses, promotes humoral immune responses, and thereby facilitates the control of persistent virus infection.

Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis

Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections.

THE STATE OF THE IMMUNE SYSTEM IN WOMEN IN THE SECOND TRIMESTER OF PREGNANCY AT EXACERBATION OF CHRONIC SIMPLE BRONCHITIS CAUSED BY INFLUENZA A(H3N2)

The contents of anti-influenza antibodies, secretory immunoglobulin A (sIgA) and circulating immune complexes (CIC) were studied in 145 women in the second trimester of pregnancy. All women were divided into 5 groups. The first group included 30 women with the physiologic course of pregnancy. The second one consisted of 30 patients with chronic simple bronchitis (CB) in remission. The third group had 30 patients with the exacerbation of CB caused by influenza A(H3N2) (antibody titers were 1:16-1:64); the fourth group included 30 patients with CB, whose exacerbation was caused by influenza (antibody titers were 1:32-1:128). It was found out that in the second group there were higher concentrations of sIgA (7.34±0.37 mg/L) and CIC (0.191±0.006 units of optical density), than in the first group (5.86±0.43 mg/L, p<0.05 and 0.095±0.003 units of optical density, respectively, p<0.001). It can probably be explained by the stimulating influence of persistent virus infection on the local immunity and its important role in the development of autoimmune responses in pregnant women. In the fifth group unlike the third group there were registered minimal contents of sIgA: 3.86±0.25 mg/L (p<0.001) and maximal level of CIC: 0.232±0.006 units of optical density (p<0.001). The revealed changes suggested the decrease of local immune protection of airways and autoimmune alteration of a woman’s body caused by high intensity of humoral immunity to influenza virus A(H3N2) under exacerbation of chronic simple bronchitis in patients in the second trimester of gestation.

THE STATE OF THE IMMUNE SYSTEM IN WOMEN IN THE SECOND TRIMESTER OF PREGNANCY AT EXACERBATION OF CHRONIC SIMPLE BRONCHITIS CAUSED BY INFLUENZA A(H3N2)

The contents of anti-influenza antibodies, secretory immunoglobulin A (sIgA) and circulating immune complexes (CIC) were studied in 145 women in the second trimester of pregnancy. All women were divided into 5 groups. The first group included 30 women with the physiologic course of pregnancy. The second one consisted of 30 patients with chronic simple bronchitis (CB) in remission. The third group had 30 patients with the exacerbation of CB caused by influenza A(H3N2) (antibody titers were 1:16-1:64); the fourth group included 30 patients with CB, whose exacerbation was caused by influenza (antibody titers were 1:32-1:128). It was found out that in the second group there were higher concentrations of sIgA (7.34±0.37 mg/L) and CIC (0.191±0.006 units of optical density), than in the first group (5.86±0.43 mg/L, p<0.05 and 0.095±0.003 units of optical density, respectively, p<0.001). It can probably be explained by the stimulating influence of persistent virus infection on the local immunity and its important role in the development of autoimmune responses in pregnant women. In the fifth group unlike the third group there were registered minimal contents of sIgA: 3.86±0.25 mg/L (p<0.001) and maximal level of CIC: 0.232±0.006 units of optical density (p<0.001). The revealed changes suggested the decrease of local immune protection of airways and autoimmune alteration of a woman’s body caused by high intensity of humoral immunity to influenza virus A(H3N2) under exacerbation of chronic simple bronchitis in patients in the second trimester of gestation.