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Microbiome-dependent Serp-1 and S-7 efficacy is associated with pulmonary inflammation and increased occupancy of CD3+ and CD8+ cells (A) Representative H&E sections of mouse lungs at 3 days follow-up after MHV-68 infection without antibiotic pre-treatment (top row) or after antibiotic pre-treatment (bottom row) and with saline, Serp-1 or S-7 treatment. Scale bar is 100 µm. (B) Alveolar wall thickness and (C) Alveolar lumen area of mouse lungs at 3 days follow-up as in (A). (D) Representative CD3 IHC micrographs of mouse lungs at 3 days follow-up after MHV-68 infection without antibiotic pre-treatment (top row) or after antibiotic pre-treatment (bottom row) and with saline, Serp-1 or S-7 treatment. Scale bar is 20 µm. (E) Quantification of CD3+, CD4+ and CD8+ cells per 40× field from 3-6 fields per mouse. Statistics in panels B, C and E performed by Two-Way ANOVA with Fisher's LSD post-hoc analysis. *p < 0.05, **p < 0.01, ***p < 0.001; n.s. is not significant. N = 3 for all conditions.

Microbiome-dependent Serp-1 and S-7 efficacy is associated with pulmonary inflammation and increased occupancy of CD3+ and CD8+ cells (A) Representative H&E sections of mouse lungs at 3 days follow-up after MHV-68 infection without antibiotic pre-treatment (top row) or after antibiotic pre-treatment (bottom row) and with saline, Serp-1 or S-7 treatment. Scale bar is 100 µm. (B) Alveolar wall thickness and (C) Alveolar lumen area of mouse lungs at 3 days follow-up as in (A). (D) Representative CD3 IHC micrographs of mouse lungs at 3 days follow-up after MHV-68 infection without antibiotic pre-treatment (top row) or after antibiotic pre-treatment (bottom row) and with saline, Serp-1 or S-7 treatment. Scale bar is 20 µm. (E) Quantification of CD3+, CD4+ and CD8+ cells per 40× field from 3-6 fields per mouse. Statistics in panels B, C and E performed by Two-Way ANOVA with Fisher's LSD post-hoc analysis. *p < 0.05, **p < 0.01, ***p < 0.001; n.s. is not significant. N = 3 for all conditions.

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Immunopathogenesis in systemic viral infections can induce a septic state with leaky capillary syndrome, disseminated coagulopathy, and high mortality with limited treatment options. Murine gammaherpesvirus-68 (MHV-68) intraperitoneal infection is a gammaherpesvirus model for producing severe vasculitis, colitis and lethal hemorrhagic pneumonia in...

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... analyses of lungs at an early, 3-day follow-up after infection. In the absence of antibiotics, considerable early pulmonary consolidation and inflammation was observed in MHV-68-infected lung tissue in IFNγR −/− mice treated with control saline alone. This severe pulmonary pathology was considerably reduced by Serp-1 or S-7 peptide treatment (Fig. 4A) 10 . Early lung pathology was markedly worse after antibiotic treatment in all conditions (saline, Serp-1 or S-7), with most animals in the saline group also showing hemorrhage in affected ...
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... lumen area are reliable indicators of pulmonary inflammation in acute laboratory models [37][38][39] . In this study, quantitative morphometry of the lungs revealed a significant reduction in alveolar wall thickness in MHV-68-infected mice treated with Serp-1 or S-7 versus saline-treated controls that was lost after treatment with antibiotics (Fig. 4B). Without antibiotic pre-treatment and when compared to saline-treated controls, alveolar lumen area was significantly increased in mice treated with S-7 (p = 0.0067) with a trend toward an increase in mice treated with Serp-1. Antibiotic treatment nullified any level of protection by treatment with S-7 (Fig. 4C). No diagnostic ...
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... after treatment with antibiotics (Fig. 4B). Without antibiotic pre-treatment and when compared to saline-treated controls, alveolar lumen area was significantly increased in mice treated with S-7 (p = 0.0067) with a trend toward an increase in mice treated with Serp-1. Antibiotic treatment nullified any level of protection by treatment with S-7 (Fig. 4C). No diagnostic pathology nor significant changes in inflammatory cell infiltrates on histological analysis was noted in the gut or aorta at this early, 3-day follow-up time (not shown). These results indicate that immune protection against pulmonary inflammation and early stage hemorrhage promoted by Serp-1 and S-7 treatment are ...
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... responses play a crucial role in limiting active infection and have been reported as central mediators for managing chronic MHV-68 infection [40][41][42] . Hence, we examined early, acute phase CD3+ T-cell recruitment to the lungs in MHV-68 infections. Antibiotic treatment significantly reduced CD3+ cells in the lungs of saline-treated mice (Fig. 4E, p = 0.0155). Further, S-7 significantly increased, and Serp-1 trended towards increasing, the detectable CD3+ cells in the lungs of infected mice (Fig. 4D,E), indicating that the serpin-mediated protection against MHV-68 induced disease is closely associated with increased pulmonary T-cell activity. Further staining indicates no ...
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... . Hence, we examined early, acute phase CD3+ T-cell recruitment to the lungs in MHV-68 infections. Antibiotic treatment significantly reduced CD3+ cells in the lungs of saline-treated mice (Fig. 4E, p = 0.0155). Further, S-7 significantly increased, and Serp-1 trended towards increasing, the detectable CD3+ cells in the lungs of infected mice (Fig. 4D,E), indicating that the serpin-mediated protection against MHV-68 induced disease is closely associated with increased pulmonary T-cell activity. Further staining indicates no appreciable effect of Serp-1 and S-7 on pulmonary CD4+ cells (Fig. 4F), while CD8+ staining showed significant increases with S-7 (p = 0.0312) and a strong trend ...
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... and Serp-1 trended towards increasing, the detectable CD3+ cells in the lungs of infected mice (Fig. 4D,E), indicating that the serpin-mediated protection against MHV-68 induced disease is closely associated with increased pulmonary T-cell activity. Further staining indicates no appreciable effect of Serp-1 and S-7 on pulmonary CD4+ cells (Fig. 4F), while CD8+ staining showed significant increases with S-7 (p = 0.0312) and a strong trend towards increase with Serp-1 (p = 0.1734) treatment www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 4G). Remarkably, antibiotic treatment that depleted the gut microbiome led to a loss of this observed CD3 ...
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... increased pulmonary T-cell activity. Further staining indicates no appreciable effect of Serp-1 and S-7 on pulmonary CD4+ cells (Fig. 4F), while CD8+ staining showed significant increases with S-7 (p = 0.0312) and a strong trend towards increase with Serp-1 (p = 0.1734) treatment www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 4G). Remarkably, antibiotic treatment that depleted the gut microbiome led to a loss of this observed CD3 infiltration-promoting effects and a loss of CD8 bias of both Serp-1 and S-7 ( Fig. 4E-G). Taken together, these results suggest protection from MHV-68 induced disease via CD3 recruitment and surveillance in the lungs, with a CD8 bias, ...
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... S-7 (p = 0.0312) and a strong trend towards increase with Serp-1 (p = 0.1734) treatment www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 4G). Remarkably, antibiotic treatment that depleted the gut microbiome led to a loss of this observed CD3 infiltration-promoting effects and a loss of CD8 bias of both Serp-1 and S-7 ( Fig. 4E-G). Taken together, these results suggest protection from MHV-68 induced disease via CD3 recruitment and surveillance in the lungs, with a CD8 bias, enhanced by Serp-1-or S-7, proceeds via a microbiome-dependent mechanism. www.nature.com/scientificreports www.nature.com/scientificreports/ Serp-1 and S-7 reduce pulmonary MHV-68 levels in a ...
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... by Serp-1 or S-7 10 . Microbiome ablation completely abolished treatment efficacy and improved survival (Fig. 1B). Probing further, we found that Serp-1 and S-7 facilitated protection against lung inflammation and consolidation associated with an increase in CD3+ cell invasion (with a CD8+ bias) and a reduction of MHV-68 staining in the lungs (Figs. 4 and 5). This finding is in agreement with previous reports that T-cell surveillance (effected by CD8+ cells) is critical for limiting acute GHV infection and that a progressive loss of T-cells is associated with worsened GHV disease 40-42 . The loss of Serp-1-based treatment efficacy was not expected to be due to direct interactions between ...
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... analyses were first performed compared Serp-1 (no Abx) to saline (no Abx) mice, S-7 (no Abx) to saline (no Abx) mice, and finally as a combined group of Serpin-treated mice [Serp-1 (no Abx) and S-7 (no Abx)] to saline (no Abx mice). Discriminant ASVs identified in these analyses were pooled and validated in heatmap and abundance analyses (Fig. ...

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Chapter
Viruses have devised highly effective approaches that modulate the host immune response, blocking immune responses that are designed to eradicate viral infections. Over millions of years of evolution, virus-derived immune-modulating proteins have become extraordinarily potent, in some cases working at picomolar concentrations when expressed into surrounding tissues and effectively blocking host defenses against viral invasion and replication. The marked efficiency of these immune-modulating proteins is postulated to be due to viral engineering of host immune modulators as well as design and development of new strategies (i.e., some derived from host proteins and some entirely unique). Two key characteristics of viral immune modulators confer both adaptive advantages and desirable functions for therapeutic translation. First, many virus-derived immune modulators have evolved structures that are not readily recognized or regulated by mammalian immune pathways, ensuring little to no neutralizing antibody responses or proteasome-mediated degradation. Second, these immune modulators tend to target early steps in central immune responses, producing a powerful downstream inhibitory “domino effect” which may alter cell activation and gene expression.