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Mechanisms to control the immune response are important to pathogen evasion and host defense. Gram-negative bacteria are common pathogens that can activate host immune responses through their outer membrane component, LPS. Macrophage activation by LPS induces cell signals that promote hypoxic metabolism, phagocytosis, Ag presentation, and inflammation. Nicotinamide (NAM) is a vitamin B(3) derivative and precursor in the formation of NAD, which is a required cofactor in cellular function. In this study, treatment of human monocyte-derived macrophages with NAM promoted posttranslational modifications that antagonized LPS-induced cell signals. Specifically, NAM inhibited AKT and FOXO1 phosphorylation, decreased p65/RelA acetylation, and promoted p65/RelA and hypoxia-inducible transcription factor-1α (HIF-1α) ubiquitination. NAM also increased prolyl hydroxylase domain 2 (PHD2) production, inhibited HIF-1α transcription, and promoted the formation of the proteasome, resulting in reduced HIF-1α stabilization, decreased glycolysis and phagocytosis, and reductions in NOX2 activity and the production of lactate dehydrogenase A. These NAM responses were associated with increased intracellular NAD levels formed through the salvage pathway. NAM and its metabolites may therefore decrease the inflammatory response of macrophages and protect the host against excessive inflammation but potentially increase injury through reduced pathogen clearance. Continued study of NAM cell signals in vitro and in vivo may provide insight into infection-associated host pathologies and interventions.

BackgroundData on cellular immune responses in persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following vaccination are limited. The evaluation of these patients with SARS-CoV-2 breakthrough infections may provide insight into how vaccinations limit the escalation of deleterious host inflammatory responses.MethodsWe conducted a prospective study of peripheral blood cellular immune responses to SARS-CoV-2 infection in 21 vaccinated patients, all with mild disease, and 97 unvaccinated patients stratified based on disease severity.ResultsWe enrolled 118 persons (aged 50 years [SD 14.5 years], 52 women) with SARS-CoV-2 infection. Compared to unvaccinated patients, vaccinated patients with breakthrough infections had a higher percentage of antigen-presenting monocytes (HLA-DR+), mature monocytes (CD83+), functionally competent T cells (CD127+), and mature neutrophils (CD10+); and lower percentages of activated T cells (CD38+), activated neutrophils (CD64+), and immature B cells (CD127+CD19+). These differences widened with increased disease severity in unvaccinated patients. Longitudinal analysis showed that cellular activation decreased over time but persisted in unvaccinated patients with mild disease at 8-month follow-up.ConclusionsPatients with SARS-CoV-2 breakthrough infections exhibit cellular immune responses that limit the progression of inflammatory responses and suggest mechanisms by which vaccination limits disease severity. These data may have implications for developing more effective vaccines and therapies.Clinical Trials Registration . NCT04401449.

Additional file 4. Extraction form utilitzed by authors for O2 only studies and O2 with non-O2 studies.

Additional file 3. Search strategy used for PUBMED, Web of Science, and EMBASE.

Additional file 1: Figure S1. Flow diagram for the literature search. Figure S2. Effects of FiO2 ≤ 0.60 and > O.21 (FiO2 ≤ 0.60/ > O.21) (upper panel) or FiO2 ≥ 0.60 (lower panel) vs. FiO2s = 0.21 (controls) on the odds ratios of survival (95%CIs) (OR) in studies [author (y)] that also administered an infectious or noninfectious inflammatory challenge in animals. These were studies that included more than one regimen of oxygen or dose of an inflammatory challenge and these groups are shown individually here. Animal type, increased FiO2 level and duration, inflammatory challenge route and type employed and the numbers of surviving and total animals challenged in oxygen or control groups are shown. Open circles show ORs for groups within studies and solid circles show the overall OR for a study when groups could be pooled (I2 level of significance, p ≥ 0.10). These pooled ORs were then employed for overall analysis (Fig. 1). IP intraperitoneal, CLP cecal ligation and puncture, IT intratracheal, L. p. Legionella pneumoniae, LPS lipopolysaccharide, LD low dose, HD high dose. Table S1. Animal numbers for O2 + nonO2 inflammatory challenge studies. Table S2. Results of lung injury measures reported in O2 + nonO2 inflammatory challenge studies for groups exposed to FiO2s≤0.60 and >0.21 or FiO2=0.21. Table 3. Results of lung injury and immune response measures reported in O2 + nonO2 inflammatory challenge studies for groups exposed to FiO2 >0.60 or FiO2=0.21. Table S4. Results of immune response measures reported in O2 + nonO2 inflammatory challenge studies for groups exposed to FiO2s≤0.60 and >0.21. Table S5. Animal numbers for O2 only studies. Table S6. Body weights following oxygen exposure for O2 only studies. Table S7. Results of lung injury measures reported in O2 only studies for groups exposed to FiO2s≤0.60 and >0.21 or FiO2=0.21. Table S8. Results of immune response measures reported in O2 only studies for groups exposed to FiO2s≤0.60 and >0.21 or=0.21. Table S9. Results of lung injury and immune response measures reported in O2 only studies for groups exposed to FiO2s>0.60 or FiO2=0.21. Table S10. Quality of evidence, adapted from SYRCLE.

Additional file 2. 27-item PRISMA Checklist for Systematic Reviews.

Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.