TNFR2⁺ regulatory T cells protect against bacteremic pneumococcal pneumonia by suppressing IL-17A-producing γδ T cells in the lung.

Streptococcus pneumoniae is a pathogen of global morbidity and mortality. Pneumococcal pneumonia can lead to systemic infections associated with high rates of mortality. We find that, upon pneumococcal infection, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficient mice have compromised Treg cell responses and highly activated IL-17A-producing γδ T cell (γδT17) responses, resulting in significantly enhanced neutrophil infiltration, tissue damage, and rapid development of bacteremia, mirroring responses in Treg cell-depleted mice. Deletion of total Treg cells predominantly activate IFNγ-T cell responses, whereas adoptive transfer of TNFR2+ Treg cells specifically suppress the γδT17 response, suggesting a targeted control of γδT17 activation by TNFR2+ Treg cells. Blocking IL-17A at early stage of infection significantly reduces bacterial blood dissemination and improves survival in TNFR2-deficient mice. Our results demonstrate that TNFR2 is critical for Treg cell-mediated regulation of pulmonary γδT17-neutrophil axis, with impaired TNFR2+ Treg cell responses increasing susceptibility to disease

C-terminal PEGylation improves SAAP-148 peptide's immunomodulatory activities

Synthetic antibacterial and anti-biofilm peptide (SAAP)-148 was developed to combat bacterial infections not effectively treatable with current antibiotics. SAAP-148 is highly effective against antimicrobial-resistant (AMR) bacteria without inducing resistance, however challenges for further development of SAAP-148 include its cytotoxicity and short circulation half-life. To circumvent these drawbacks a library of SAAP-148 linked to polyethylene glycol (PEG) groups of various lengths was screened for in vitro antibacterial activity and hemolytic activity. Results indicated that PEGylated SAAP-148 variants combine antibacterial activities with reduced hemolysis compared to SAAP-148. Interestingly, pro-inflammatory immunomodulatory activities of SAAP-148 were enhanced upon C-terminal PEGylation, with SAAP-148-PEG27 showing most effect. SAAP-148-PEG27 enhanced SAAP-148’s capacity to chemoattract human neutrophils and was able to more efficiently (re)direct M-CSF-induced monocyte-macrophage differentiation towards type 1 macrophages compared to SAAP-148. Furthermore, dendritic cells with a stronger mature expression profile were produced if monocytes were exposed to SAAP-148-PEG27 during monocyte-immature dendritic cell differentiation in comparison to SAAP-148. Parameters that influenced the immunomodulatory activities of the peptide-PEG conjugate include i) the length of the PEG-group, ii) the position of PEG conjugation, and iii) the peptide sequence. Together, these results indicate that SAAP-148-PEG27 is highly effective in redirecting monocyte-macrophage differentiation towards a proinflammatory phenotype and promoting monocyte-mature dendritic cells development. Therefore, SAAP-148-PEG27 may be a promising agent to modulate inadequate immune responses in case of tumors and chronically infected wounds

Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models

Exposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely understood. Undifferentiated or differentiated primary bronchial epithelial cells were acutely/chronically exposed to whole CS (WCS) or CS extract (CSE) in submerged or air-liquid interface conditions. Abundance of key regulators controlling mitochondrial biogenesis, mitophagy and mitochondrial dynamics was assessed. Acute exposure to WCS or CSE increased the abundance of components of autophagy and receptor-mediated mitophagy in all models. Although mitochondrial content and dynamics appeared to be unaltered in response to CS, changes in both the molecular control of mitochondrial biogenesis and a shift toward an increased glycolytic metabolism were observed in particular in differentiated cultures. These alterations persisted, at least in part, after chronic exposure to WCS during differentiation and upon subsequent discontinuation of WCS exposure. In conclusion, smoke exposure alters the regulation of mitochondrial metabolism in airway epithelial cells, but observed alterations may differ between various culture models used. This article has an associated First Person interview with the joint first authors of the paper

Equalizing the Cost of Health Insurance

The Dutch government compensates health insurance companies when insuring individuals who are estimated to have high health care costs. This is necessary to avoid insurers not offering services to certain groups or not providing them with a high quality of service. It is, however, unknown to what extent the differences in health care expenses by different groups of people are truly due to a poorer or better health status. We explore several statistical approaches that facilitate explaining the cause of these differences

Equalizing the Cost of Health Insurance

The Dutch government compensates health insurance companies when insuring individuals who are estimated to have high health care costs. This is necessary to avoid insurers not offering services to certain groups or not providing them with a high quality of service. It is, however, unknown to what extent the differences in health care expenses by different groups of people are truly due to a poorer or better health status. We explore several statistical approaches that facilitate explaining the cause of these differences