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Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNβ, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNβ were evaluated for their therapeutic potential in genital HSV-1 infections. Respectivein vivostudies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNβ had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNβ led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

Mammalian seminal plasma contains a multitude of bioactive components, including lipids, glucose, mineral elements, metabolites, proteins, cytokines, and growth factors, with various functions during insemination and fertilization. The seminal plasma protein PDC-109 is one of the major soluble components of the bovine ejaculate and is crucially important for sperm motility, capacitation, and acrosome reaction. A hitherto underappreciated function of seminal plasma is its anti-microbial and antiviral activity, which may limit the sexual transmission of infectious diseases during intercourse. We have recently discovered that PDC-109 inhibits the membrane fusion activity of influenza virus particles and significantly impairs viral infections at micromolar concentrations. Here we investigated whether the antiviral activity of PDC-109 is restricted to Influenza or if other mammalian viruses are similarly affected. We focused on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 19 (COVID-19), thoroughly assessing PDC-109 inhibition with SARS-CoV-2 Spike (S)-pseudotyped reporter virus particles, but also live-virus infections. Consistent with our previous publications, we found significant virus inhibition, albeit accompanied by substantial cytotoxicity. However, using time-of-addition experiments we discovered a treatment regimen that enables virus suppression without affecting cell viability. We furthermore demonstrated that PDC-109 is also able to impair infections mediated by the VSV glycoprotein (VSVg), thus indicating a broad pan-antiviral activity against multiple virus species and families. Open Access Publication Fund of the University of Duisburg-Essen

Acute major tissue injury induces immune dysregulation that is characterized by the development of systemic sterile inflammation and an increased risk for opportunistic infections. Although the contribution of the innate immune system has been examined in detail, research on the impact of acute sterile tissue damage on the T cell compartment remains limited. In the current study, we used a clinically relevant mouse model for traumatic skeletal muscle injury to investigate the impact of sterile tissue damage on diverse subpopulations of CD4+ Th and CD8+ cytotoxic T cells in systemic and local lymphoid organs. For the first time, to our knowledge, we provide evidence that injury selectively induced the expression of the activation marker CD69 on naive and central/virtual memory CD8+ T cells in the lymph nodes but not in the spleen of male mice. CD4+ Th cells remained unaffected in both organs. The activation of CD8+ T cells was dependent on signaling through TLR4. Within a few hours, injury triggered the expression of IL-12 in the lymph nodes in a TLR4-dependent manner. Blocking of IL-12 prevented the activation of naive and central memory CD8+ T cells after injury. Thus, early after traumatic tissue damage, TLR4 transactivates naive and central/virtual memory CD8+ T cells through innate cytokines in local lymph nodes, where they might modulate forthcoming local immune responses.

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8⁺ T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10–13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8⁺ T cell responses were influenced to various extents by individual IFNα subtypes. IFNα4, 6, and 9 had the strongest effects on CD8⁺ T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFNα subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8⁺ T cells or DCs. Thus, precise modulation of virus-specific CD8⁺ T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFNα subtypes. OA Förderung 2019

Interferon alpha (IFNα) is commonly used for the treatment of chronic hepatitis B (CHB) patients. There are 13 different IFNα subtypes in humans, but only the subtype IFNα2 is used for clinical treatment. The antiviral activities of all other IFNα subtypes against HBV have not been studied. To obtain basic knowledge about the direct antiviral as well as the immunomodulatory effects of IFNα subtypes, we used the HBV hydrodynamic injection (HI) mouse model. Application of most IFNα subtype proteins inhibited HBV replication in vivo, with IFNα4 and IFNα5 being the most effective subtypes. Decreased viral loads after therapeutic application of IFNα4 and IFNα5 correlated with expanded effector cell populations of NK cells and T cells in both liver and spleen. Hydrodynamic injection of plasmids encoding for the effective IFNα subtypes (pIFNα) was even more potent against HBV than injecting IFNα proteins. The combination of pIFNα4 and pIFNα5 showed a synergistic antiviral effect on HBV replication, with a strong increase in NK cell and T cell activity. The results demonstrate distinct anti-HBV effects of different IFNα subtypes against HBV in the mouse model, which may be relevant for new therapeutic approaches.