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Efficient phagocytosis of pathogens is a key effector function of the innate immune system. Impaired phagocytic activity can result in uncontrolled pathogen proliferation and life-threatening infections. However, reliable methods to detect early dysfunction of the phagocytic system in vivo are limited. Here, we used a mouse model of Listeria monocytogenes infection to determine blood parameters which correlate with limited macrophage function. We found that lack of macrophages led to accumulation of nuclei in the blood. Further analysis of nuclei revealed that these nuclei were released from bone marrow-derived cells. Macrophage-depleted mice and interferon-gamma-deficient mice, which are known to have reduced phagocytotic capacity, showed increased amounts of free nuclei. This was associated with lethal outcome and occurrence of acute hepatopathy in these mice after Listeria monocytogenes infection. Our findings highlight a simple and noninvasive method to assess macrophage phagocytic function in vivo , which should be assessed in further murine and human studies as a tool for predicting host vulnerability to infection.

Neutralizing antibodies (nAbs) are pivotal in developing fast, broadly protective therapeutics against novel pandemic viruses. Despite their well-known direct neutralization capacity, their effector mechanisms via Fc receptors remain poorly understood. Identifying the types of effector cells engaged in antibody-mediated effector functions is essential for regulating their activities. Using the lymphocytic choriomeningitis virus (LCMV), we show that nAbs obtained from immune sera or monoclonal LCMV-specific nAbs show dependency on Fc receptors. We demonstrate that therapy with nAbs is highly protective in the presence of patrolling monocytes. These monocytes bind nAbs primarily via FcγRIV, targeting virus-infected cells, and thereby limiting virus propagation. Depleting patrolling monocytes or blocking FcγRIV resulted in a substantial loss of virus control by nAbs, indicating the pivotal role of patrolling monocytes in the antiviral activity of these antibodies. In conclusion, our findings highlight that, alongside direct neutralization, nAbs primarily exert their effects through the involvement of patrolling monocytes.

Malaria, caused by the parasite Plasmodium spp., remains the most prevalent and dangerous vector-borne infectious disease worldwide. Effective pathogen clearance during malaria hinges on the interplay between adaptive and innate immune responses, especially on T cells, B cells, antigen-presenting cells (APCs) and IFNγ response. In a previous study, we demonstrated that dendritic cell (DC) depletion resulted in impaired T cell responses. However, substantial CD4 + and CD8 + T cell activation was still detectable, suggesting that other APCs compensate for the lack of DCs. In the present study, we report an increase in splenic marginal zone macrophages (MZMΦ), and marginal metallophilic macrophages (MMMΦ) with an altered cytokine profile in DC-deficient mice upon P. yoelii infection. Ablation of macrophages by clodronate liposome (CL) application resulted in partially reduced T cell activation, which correlated with elevated parasitemia. To further elucidate the specific role of splenic macrophage subsets we studied P. yoelli infections in two transgenic C57BL/6 mouse lines. Treatment of CD169DTR mice with diphtheriatoxin (DT) efficiently depleted MMMΦ and MZMΦ, resulting in reduced IFNγ production by CD4 + T cells in P. yoelii -infected mice, though parasitemia progression was not modulated. In marked contrast, specific red pulp macrophages (RPMΦ) depletion in SpiC flox/flox x vav1cre mice resulted in elevated parasitemia. In conclusion, our data provide evidence that splenic macrophages located in or at the marginal zone contribute to CD4 + T cell activation, and that RPMΦs are indispensable for clearing of infected red blood cells (iRBCs) during P. yoelii infection.

Besides its robust antiviral activity, type I interferon (IFN-I) also exerts immunomodulatory effects and can even drive pathology during chronic viral infections. Mechanisms that regulate IFN-I induction during virus infection, thus strongly affecting the outcome of disease, remain to be defined. Here, using the lymphocytic choriomeningitis virus (LCMV) Docile strain, we identified acid ceramidase (aCDase, ) as a critical lipid-metabolic regulator of endosomal, nucleic acid-driven IFN-I responses and disease outcome during chronic virus infection. aCDase is highly expressed in plasmacytoid dendritic cells (pDCs) and required for robust early IFN-I production. aCDase deficiency resulted in ceramide accumulation, blunting IFN-α/β induction, impairing IFN-I-dependent upregulation of programmed death-ligand 1 (PD-L1) on antigen-presenting cells and preventing the exhaustion of virus-specific CD8 T cells, leading to severe immunopathology. This pathology is abrogated by CD8 T-cell depletion or by adoptive transfer of IFN-I-induced PD-L1-expressing macrophages. Conversely, limiting ceramide production in acid sphingomyelinase (Asm)-deficient mice prevented ceramide accumulation, and pDCs showed accelerated IFN-I induction. Mechanistically, ceramide abundance regulated IFN-I production by altering endosomal signaling microdomains. Collectively, our findings reveal ceramide homeostasis as a key determinant of IFN-I-driven CD8 T-cell exhaustion and immunopathology during chronic viral infection and highlight aCDase as a potential therapeutic target.

Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22-deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor–deficient ( Ifnar1 -deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN–dependent (IFN-I–dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.

Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by Fc[gamma]RIV, the homolog of human Fc[gamma]RIIIa. Fc[gamma]RIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of Fc[gamma]RIV on inflammatory monocytes, an effect absent in type I IFN receptor-deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, Fc[gamma]RIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN-dependent (IFN-I-dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fc[gamma] receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.

Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcyRIV, the homolog of human FcyRllla. FcyRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcyRIV on inflammatory monocytes, an effect absent in type | IFN receptor-deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcyRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type | IFN-dependent (IFN-I-dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcy receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.

Natural killer and CD8+ T cells are critical in the elimination of blood-borne viruses such as cytomegalovirus (CMV); however, the role of B cells in this process is less clear. Here, using the murine CMV (MCMV) infection model, we demonstrated that the B cell-deficient mice mounted a weaker primary virus-specific CD8+ T cell response than their wild-type counterparts, which was associated with increased viral transcription. Notably, we found that the contribution of B cells to the CD8+ T-cell-mediated anti-viral response was not associated with their ability to generate antibodies but with their ability to sustain Langerin+ type 1 conventional dendritic cells (cDC1s), a dendritic cells (DC) subset known for being involved in viral and bacterial clearance in the marginal zone of the spleen. Furthermore, we found that the presence of Langerin+ cDC1s is dependent on B cells expressing lymphotoxin beta to maintain CD169+ marginal metallophilic macrophages (MMMs). We further discovered, using ligand-receptor interaction analyses, that the communication between MMMs and Langerin+ cDC1s was mediated via VCAM1 - ITGA4/ITGB1 interaction. Thus, our data reveals that B cell regulate the development of MMMs in the spleen via lymphotoxin beta; expression and consequently sustain Langerin+ cDC1s homeostasis for effective initiation of an anti-viral CD8+ T cell response. Overall, our study offers a new perspective on how B cells maintain the homeostasis of antigen-presenting cells in the splenic marginal zone and thus indirectly affect the virus-specific CD8+ T cell response, which could potentially be extended to other infectious and autoimmune diseases as well as tumors.