Vaping: Cell Damage at the Receiving ENDS Knapp, Sylvia
American journal of respiratory cell and molecular biology,
09/2020, Letnik:
63, Številka:
3
Journal Article
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Knapp discusses the the study of Serpa et al regarding the effects of electronic nicotine delivery systems (ENDS) on the viability of cells of the respiratory tract. Using an elegant system of in ...vitro ENDS-aerosol delivery of the main e-cigarette constituent propylene glycol and glycerol, the authors studied the effects of exposure to different types of human and murine respiratory epithelial cells. The main finding was that exposure to ENDS aerosol led to substantial cell death from apoptosis or secondary necrosis. Interestingly, the addition of nicotine aggravated cell death rates, whereas nicotine alone had no effect on epithelial cell viability. The report also found that macrophages responded to ENDS aerosol by undergoing pyroptosis, an inflammatory death pathway resulting in cell leakage and release of intracellular contents, further aggravating local inflammation. Interestingly, this event occurred independently of nicotine.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has been causing the COVID-19 pandemic since December 2019, with over 600 million infected persons worldwide and over six ...million deaths. We investigated the anti-viral effects of polyphenolic green tea ingredients and the synthetic resveratrol analogue 3,3',4,4',5,5'-hexahydroxy-
-stilbene (
), a compound with antioxidant, antitumor and anti-HIV properties. In the TCID
assay, four out of nine green tea constituents showed minor to modest cell protective effects, whereas HHS demonstrated the highest reduction (1103-fold) of the TCID
, indicating pronounced inhibition of virus replication.
was also a highly effective inhibitor of SARS-CoV-2 proliferation in VeroE6 cells with an IC
value of 31.1 µM.
also inhibited the binding of the receptor-binding domain (RBD) of the spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor (RBD-ACE2) binding with 29% at 100 µM and with 9.2% at 50 µM indicating that the SARS-CoV-2 inhibitory effect might at least in part be attributed to the inhibition of virus binding to ACE2. Based on the chemical similarity to other polyphenols, the oral bioavailability of
is likely also very low, resulting in blood levels far below the inhibitory concentration of
against SARS-CoV-2 observed in vitro. However, administration of
topically as a nose or throat spray would increase concentrations several-fold above the minimal inhibitory concentration (MIC) in the mucosa and might reduce virus load when administered soon after infection. Due to these promising tissue culture results, further preclinical and clinical studies are warranted to develop
as an additional treatment option for SARS-CoV-2 infection to complement vaccines, which is and will be the main pillar to combat the COVID-19 pandemic.
CD36 is a scavenger receptor that exhibits pleiotropic functions, including adhesion to thrombospondin, inhibition of angiogenesis, transport of long-chain fatty acids, and clearance of apoptotic ...cells. In addition, it has been implicated in the host immune response because it acts as a coreceptor for TLR2 and plays a role in Staphylococcus aureus infection. However, its role in other Gram-positive bacterial infections is unclear. In this study, using mice deficient in CD36, we sought to examine the role of CD36 in pneumococcal pneumonia, a major cause of morbidity and mortality worldwide. We show that CD36 is expressed on both alveolar macrophages and respiratory epithelial cells. Early in infection, CD36(-/-) mice have an exaggerated inflammatory response compared with wild-type littermate controls. In vitro studies using CD36(-/-) primary cells confirm the enhanced early inflammation in response to S. pneumoniae and its lipoteichoic acid, demonstrate that S. pneumoniae binds to cells via its phosphocholine residues, and suggest a role for CD36 in reducing inflammation induced by the phosphocholine residues of pneumococcal lipoteichoic acid. Later in infection, although CD36(-/-) mice exhibit impaired bacterial clearance, owing to a decreased capacity of CD36(-/-) macrophages to phagocytose S. pneumoniae, minor effects on mortality occur, in comparison with those in wild-type littermate control mice. These data show that CD36 contributes to the pulmonary host response during S. pneumoniae infection by virtue of its ability to act as a phagocytic receptor and as a modulator of the early innate immune response.
Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory ...functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Streptococcus pyogenes is a Gram-positive human pathogen that is recognized by yet unknown pattern recognition receptors (PRRs). Engagement of these receptor molecules during infection with S. ...pyogenes, a largely extracellular bacterium with limited capacity for intracellular survival, causes innate immune cells to produce inflammatory mediators such as TNF, but also type I interferon (IFN). Here we show that signaling elicited by type I IFNs is required for successful defense of mice against lethal subcutaneous cellulitis caused by S. pyogenes. Type I IFN signaling was accompanied with reduced neutrophil recruitment to the site of infection. Mechanistic analysis revealed that macrophages and conventional dendritic cells (cDCs) employ different signaling pathways leading to IFN-beta production. Macrophages required IRF3, STING, TBK1 and partially MyD88, whereas in cDCs the IFN-beta production was fully dependent on IRF5 and MyD88. Furthermore, IFN-beta production by macrophages was dependent on the endosomal delivery of streptococcal DNA, while in cDCs streptococcal RNA was identified as the IFN-beta inducer. Despite a role of MyD88 in both cell types, the known IFN-inducing TLRs were individually not required for generation of the IFN-beta response. These results demonstrate that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard arsenal of TLRs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The virome of lung transplant recipients (LTRs) under immunosuppressive therapy is dominated by non-pathogenic Anelloviridae and further includes several pathogenic viruses such as Herpesviruses or ...respiratory viruses. It is unclear whether the donor-derived virome in the transplanted lung influences recipient virome dynamics in other body compartments and if so, to which degree. Likewise, it is unknown whether dependencies exist among virus populations that mutually shape viral loads and kinetics.
To address these questions, we characterized viral communities in airways and plasma of 49 LTRs and analyzed their abundance patterns in a data modeling approach. We found distinct viral clusters that were specific for body compartments and displayed independent dynamics. These clusters robustly gathered specific viral species across the patient cohort. In the lung, viral cluster abundance associated with time after transplantation and we detected mutual exclusion of viral species within the same human host. In plasma, viral cluster dynamics were associated with the indication for transplantation lacking significant short-time changes. Interestingly, pathogenic viruses in the plasma co-occurred specifically with Alpha torque virus genogroup 4 and Gamma torque virus strains suggesting shared functional or ecological requirements.
In summary, the detailed analysis of virome dynamics after lung transplantation revealed host, body compartment, and time-specific dependency patterns among viruses. Furthermore, our results suggested genetic adaptation to the host microenvironment at the level of the virome and support the hypothesis of functional complementarity between Anellovirus groups and other persistent viruses. Video abstract.
T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, ...some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity. Both pathogenicity and plasticity are tightly linked to IL-23 signaling. Here, we show that the protein tyrosine kinase Tec is highly induced in Th17 cells. Th17 differentiation was enhanced at low interleukin-6 (IL-6) concentrations in absence of Tec, which correlates with increased STAT3 phosphorylation and higher
expression. Therefore, we uncovered a function for Tec in the IL-6 sensing
STAT3 by CD4
T cells, defining Tec as a fine-tuning negative regulator of Th17 differentiation. Subsequently, by using the IL-17A fate mapping mouse combined with
adoptive transfer models, we demonstrated that Tec not only restrained effector Th17 differentiation but also pathogenicity and plasticity in a T-cell intrinsic manner. Our data further suggest that Tec regulates inflammatory Th17-driven immune responses directly impacting disease severity in a T-cell-driven colitis model. Notably, consistent with the
findings, elevated levels of the IL-23 receptor (IL-23R) were observed on intestinal pre- and postconversion Th17 cells isolated from diseased
mice subjected to adoptive transfer colitis, highlighting a fundamental role of Tec in restraining IL-23R expression, likely
the IL-6-STAT3 signaling axis. Taken together, these findings identify Tec as a negative regulator of Th17 differentiation, pathogenicity, and plasticity, contributing to the mechanisms which help T cells to orchestrate optimal immune protection and to restrain immunopathology.
•Severe hemolytic disorders pose a serious risk for bacterial infections.•Hemolysis is associated with the release of its heme moiety.•Heme drives hemolysis-associated pathology due to its ...pro-oxidant, pro-inflammatory and immunomodulatory properties.•Excess labile heme inhibits bacterial phagocytosis and chemotaxis, ultimately impairing host defense against bacterial sepsis.
Heme is a vital, iron-containing prosthetic molecule present in a variety of proteins, of which hemoglobin is the most abundant. While the reactivity afforded by its central iron ion is essential for many cellular processes, it renders heme a potentially damaging molecule upon its release from hemeproteins, as it can catalyze the generation of reactive oxygen species. Severe intravascular hemolysis results in the leakage of vast amounts of hemoglobin, and subsequently, heme into the plasma. As such, heme is increasingly recognized as a major driving force for hemolysis-associated pathology including an increased risk for bacterial infections, due to its pro-oxidant, cytotoxic and immunomodulatory effects. Here, we provide a succinct review of recent, significant developments on how heme can influence innate immune functions, ranging from the maintenance of iron homeostasis by macrophages, the modulation of inflammatory responses, to its role in altering resistance mechanisms against bacterial infections.
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