Minimizing caging effects in murine lung microbiome studies Pantaleón García, Jezreel; Dickson, Robert P; Evans, Scott E
American journal of physiology. Lung cellular and molecular physiology,
08/2022, Letnik:
323, Številka:
2
Journal Article
Viral pneumonias remain global health threats, as exemplified in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, requiring novel treatment strategies both early and late in ...the disease process. We have reported that mice treated before or soon after infection with a combination of inhaled Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are broadly protected against microbial pathogens including respiratory viruses, but the mechanisms remain incompletely understood. The objective of this study was to validate strategies for immune modulation in a preclinical model of viral pneumonia and determine their mechanisms. Mice were challenged with the
in the presence or absence of Pam2-ODN treatment. Virus burden and host immune responses were assessed to elucidate Pam2-ODN mechanisms of action and to identify additional opportunities for therapeutic intervention. Enhanced survival of
pneumonia with Pam2-ODN treatment was associated with reductions in lung virus burden and with virus inactivation before internalization. We noted that mortality in sham-treated mice corresponded with CD8
T-cell lung inflammation on days 11-12 after virus challenge, after the viral burden had declined. Pam2-ODN blocked this injurious inflammation by minimizing virus burden. As an alternative intervention, depleting CD8
T cells 8 days after viral challenge also decreased mortality. Stimulation of local innate immunity within the lungs by TLR agonists early in disease or suppression of adaptive immunity by systemic CD8
T-cell depletion late in disease improves outcomes of viral pneumonia in mice. These data reveal opportunities for targeted immunomodulation to protect susceptible human subjects.
Garcia et al response to Yasuma and colleagues regarding their research letter on lung microbiota to changes of pulmonary innate immunity under healthy conditions. The authors inquire about their ...selection of time points and speculate that had they compared lung microbiota at an earlier time point after exposure, they might have observed an effect of innate immune modulation on lung communities. They agree with the authors that their findings do not exclude the possibility of a transient effect and stated as much in our original manuscript: Although they detected no appreciable effect of Pam2-ODN on lung bacterial communities 6 days after exposure, it is entirely possible that TLR agonism has a short-lived effect on lung microbiota that was resolved by the time of harvest due to the continuous exposure of the lungs to environmental microbiota.
Health professions education is one of the pillars of academic medicine; however, clinical educators often lack the appropriate resources to succeed in this field. Examples of these challenges ...include: lack of support for faculty development, mentorship, and high cost of resources, when available. In addition, challenges such as the Coronavirus disease (COVID-19) pandemic can affect healthcare personnel who are already struggling to provide adequate patient care while attempting to succeed in the role of educator and supervisor of trainees. Clinical educators face more challenges particularly in low-middle income countries as the limitations are more prominent and become key barriers to success. Similarly, due to COVID-19, these challenges can be far more evident in disadvantaged geographical, economic, and academic environments even in the United States. Herein, in this perspective paper, we define resource-limited settings in medical education, provide an overview of the most common barriers to career development as a clinical educator, and offer practical strategies to overcome some of these shortcomings.
There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin ...(H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.
Abstract
Bioactive molecule library screening may empirically identify effective combination therapies, but molecular mechanisms underlying favorable drug–drug interactions often remain unclear, ...precluding further rational design. In the absence of an accepted systems theory to interrogate synergistic responses, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in synergistic biological responses. OBIF performs full factorial analysis of feature expression data from single versus dual exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed transcriptomic and proteomic data of a dyad of immunostimulatory molecules that induces synergistic protection against influenza A and revealed unanticipated NF-κB/AP-1 cooperation that is required for antiviral protection. To demonstrate generalizability, OBIF analyzed data from a diverse array of Omics platforms and experimental conditions, successfully identifying the molecular clusters driving their synergistic responses. Hence, unlike existing synergy quantification and prediction methods, OBIF is a phenotype-driven systems model that supports multiplatform interrogation of synergy mechanisms.
Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs’ intrinsic host defenses by therapeutic delivery of ...certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (Δ
Ψm
), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
From the influenza pandemic of 1918–1919 to the most recent COVID-19 pandemic, respiratory infections remain a leading cause of mortality worldwide 1, 2. Concurrently, the development of ...high-throughput omics technologies has revolutionised research about host responses to known and emerging respiratory pathogens 3, accelerating our understanding of highly prevalent pulmonary diseases 4. Notably, omics technology-based characterisation of pathogens and host pathophysiology have critically supported diagnostic and therapeutic global health efforts during both the influenza A H1N1 and SARS-CoV-2 pandemics 5–7. Nonetheless, elucidation of key immune response mechanisms and development of host-targeted therapeutics remain important unrealised research and clinical priorities in the global fight against lower respiratory tract infections (LTRIs) 8, 9.
Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies
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