19 research outputs found
Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity
Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD
Quantum Chemical Studies of the Structure and Stability of N‑Methylated DNA Nucleobase Dimers: Insights into the Mutagenic Base Pairing of Damaged DNA
DNA
is constantly under attack from exogenous and endogenous sources
that modify the chemical structure of the nucleobases. A common type
of nucleobase damage is N-methylation, which can result in mutagenesis.
Nevertheless, these lesions are often repaired by the DNA repair enzyme
AlkB, albeit at varying rates. Herein we use density functional theory
(B3LYP-D3(BJ)/6-311++G(2df,2p)//B3LYP/6-31G(d,p)) to comprehensively
examine the structural and energetic properties of base pairs between
seven nucleobase lesions resulting from N-methylation on the Watson–Crick
(WC) binding face and each canonical nucleobase. By characterizing
105 stable nucleobase dimers, we provide fundamental details regarding
the preferred lesion base pairings. Specifically, we reveal that the
flexibility of the methylamino group resulting from methylation of
an exocyclic amino substituent allows the 2MeG, 4MeC, and 6MeA lesions
to maintain a preference for canonical WC base pairing, which correlates
with the experimentally reported lack of mutagenicity for these damage
products. In contrast, calculated distortions in key structural parameters
and altered binding energies for base pairs involving adducts formed
upon methylation of a ring nitrogen (namely, 1MeG, 3MeT, 1MeA, and
3MeC) help rationalize the associated mutagenicity and repair efficiencies.
Most importantly, our work provides molecular-level information about
the interactions between N-methylated and canonical nucleobases that
is critical for future large-scale modeling of damaged DNA and enzyme–DNA
complexes that strive to further uncover the mutagenicity and repair
propensities of these detrimental lesions
Dynamic Pneumococcal Genetic Adaptations Support Bacterial Growth and Inflammation during Coinfection with Influenza
Streptococcus pneumoniae (pneumococcus) is one of the primary bacterial pathogens that complicates influenza virus infections. These bacterial coinfections increase influenza-associated morbidity and mortality through a number of immunological and viral-mediated mechanisms, but the specific bacterial genes that contribute to postinfluenza pathogenicity are not known. Here, we used genome-wide transposon mutagenesis (Tn-Seq) to reveal bacterial genes that confer improved fitness in influenza virus-infected hosts. The majority of the 32 genes identified are involved in bacterial metabolism, including nucleotide biosynthesis, amino acid biosynthesis, protein translation, and membrane transport. We generated mutants with single-gene deletions (SGD) of five of the genes identified, SPD1414, SPD2047 (cbiO1), SPD0058 (purD), SPD1098, and SPD0822 (proB), to investigate their effects on in vivo fitness, disease severity, and host immune responses. The growth of the SGD mutants was slightly attenuated in vitro and in vivo, but each still grew to high titers in the lungs of mock- and influenza virus-infected hosts. Despite high bacterial loads, mortality was significantly reduced or delayed with all SGD mutants. Time-dependent reductions in pulmonary neutrophils, inflammatory macrophages, and select proinflammatory cytokines and chemokines were also observed. Immunohistochemical staining further revealed altered neutrophil distribution with reduced degeneration in the lungs of influenza virus-SGD mutant-coinfected animals. These studies demonstrate a critical role for specific bacterial genes and for bacterial metabolism in driving virulence and modulating immune function during influenza-associated bacterial pneumonia.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]