Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). Lack of Mertk in Mertk-/- mice prevents induction of IL-10 and TGF-β, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.

The integrin associated protein (CD47) is a widely and moderately expressed glycoprotein in all healthy cells. Cancer cells are known to induce increased CD47 expression. Similar to cancer cells, all immune cells can upregulate their CD47 surface expression during infection. The CD47-SIRPa interaction induces an inhibitory effect on macrophages and dendritic cells (dendritic cells) while CD47-thrombospondin-signaling inhibits T cells. Therefore, the disruption of the CD47 interaction can mediate several biologic functions. Upon the blockade and knockout of CD47 reveals an immunosuppressive effect of CD47 during LCMV, influenza virus, HIV-1, mycobacterium tuberculosis, plasmodium and other bacterial pneumonia infections. In our recent study we shows that the blockade of CD47 using the anti-CD47 antibody increases the activation and effector function of macrophages, dendritic cells and T cells during viral infection. By enhancing both innate and adaptive immunity, CD47 blocking antibody promotes antiviral effect. Due to its broad mode of action, the immune-stimulatory effect derived from this antibody could be applicable in nonresolving and (re)emerging infections. The anti-CD47 antibody is currently under clinical trial for the treatment of cancer and could also have amenable therapeutic potential against infectious diseases. This review highlights the immunotherapeutic targeted role of CD47 in the infectious disease realm.

The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice (aly/aly, Map3k14^aly/aly, or Nik^aly/aly), which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169⁺ macrophages correlated with reduced immune activation in Map3k14^aly/aly mice. The transfer of wildtype B cells into Map3k14^aly/aly mice repopulated CD169⁺ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control.

Background/Objectives: CD47 is a cell surface glycoprotein moderately expressed in healthy cells and upregulated in cancer and viral infected cells. CD47’s interaction with signal regulatory protein alpha (SIRPα) inhibits phagocytic cells and its interaction with thrombospondin-1 inhibits T cell response. Experimental evidence has revealed that the blockade of CD47 resulted in the increased activation and function of both innate and adaptive immune cells, therefore exerting antitumoral and antiviral effects. Recent studies have shown that the combination of vaccines and immune checkpoint inhibitors could be a promising approach to increasing vaccine immunogenicity. Here, we investigated the vaccinal effect of anti-CD47 antibodies and discussed the possibilities of combining anti-CD47 treatments with vaccines. Methods: Using vesicular stomatitis virus (VSV), a widely used replication-competent vaccine vector, we evaluated the impact of the immunotherapeutic blockade of CD47 on cellular, humoral, and protective immunity. We infected C57BL/6 mice with VSV, treated them with anti-CD47 antibodies or an isotype, and evaluated the total immunoglobulin (Ig), IgG neutralizing antibodies, B cell activation, CD8+ T cell effector function, and survival of the mice. Results: We found that the treatments of anti-CD47 antibodies led to significantly increased Ig and IgG neutralizing antibody levels compared to the isotype treatment. Flow cytometric analysis of B cells revealed no difference in the number of circulating B cells; however, we observed an increased surface expression of CD80 and CD86 in B cells among anti-CD47-treated mice. Further analysis of the impact of CD47 blockade on T immunity revealed a significantly higher percentage of IFN-γ⁺ CD4 and IFN-γ⁺ CD8 T cells in anti-CD47-treated mice. Upon infecting mice with a lethal VSV dose, we observed a significantly higher survival rate among the anti-CD47-treated mice compared to control mice. Conclusions: Our results indicate that anti-CD47 treatment induces a stronger cellular and humoral immune response, leading to better protection. As such, immunotherapy by CD47 blockade in combination with vaccines could be a promising approach to improve vaccine efficacy.

Introduction: Glucocorticoids (GCs) such as dexamethasoneare widely used to treat allergies, autoimmune disorders, and chronic inflammatory conditions. However, their impact on antiviral immunity is complex and often contradictory. Clinically, dexamethasone can be beneficial in severe viral infections by suppressing excessive inflammation and limiting tissue injury. In contrast, during mild, early, or chronic infections, its immunosuppressive activity may delay viral clearance, promote viral replication or reactivation, and ultimately worsen disease outcomes. Reports describing both reduced and enhanced viral replication following GC treatment underscore the pleiotropic nature of GC action, yet the underlying mechanisms remain poorly understood. Methods: We investigated the effect of dexamethasone during persistent LCMV infection in wild-type ( Mertk ^+/+ ) and MerTK-deficient ( Mertk ^–/– ) mice (20-25g body weight). Animals were infected with 2 × 10 ⁴ PFU of the LCMV Docile strain intravenously and randomly assigned to two intervention arms, receiving either PBS or dexamethasone (2.5mg/kg, dose adjusted according to body weight) intraperitoneally every 48 hours.On day 8 post-infection, blood was collected prior to euthanasia, after which spleen and liver samples were harvested for flow-cytometric analysis. Viral titres were subsequently quantified in the spleen, liver, kidney, lung, and lymph nodes. Results: In Mertk ^+/+ mice, dexamethasone induced pronounced loss of CD8 ⁺ T cells and enhanced MerTK-dependent suppression of virus-specific CD8 ⁺ T cell responses, an effect largely absent in Mertk ^–/– animals. Functionally, dexamethasone substantially increases production of the anti-inflammatory cytokine IL-10 by macrophages and dendritic cells and elevates expression of the inhibitory checkpoint molecule PD-1 on LCMV-specific CD8 ⁺ T cells in Mertk ^+/+ mice. Moreover, expression of KLRG1, CD44, and CD127 on CD8 ⁺ T cells were substantially reduced, indicating impaired effector differentiation, whereas CD62L ⁺ CD8 ⁺ T cells were upregulated, suggesting retention in a naïve or central-memory–like state. Together, these changes promoted functionally impaired CD8 ⁺ T cell phenotype, weakened LCMV-specific immunity, and facilitated viral dissemination across multiple organs examined. Genetic ablation of MerTK mitigated these immunosuppressive effects, resulting in significantly improved viral control. Discussion: These findings demonstrate that the immunosuppressive effects of dexamethasone are critically dependent on the MerTK-mediated immunoregulatory axis. By identifying MerTK as a central node through which GCs reinforce inhibitory immune circuits, our study highlights MerTK as a potential target for future therapeutic intervention at the frontier of viral infections and inflammatory diseases. However, this therapeutic potential is currently supported solely by genetic loss-of-function evidence, and future studies employing pharmacological MerTK inhibition will be required to validate its efficacy and translational applicability.