Defensin-related cryptdin-17

The role of respiratory tract microbes and the relationship between respiratory tract and gut microbiomes in coronavirus disease 2019 (COVID-19) remain uncertain. Here, the metagenomes of sputum and fecal samples from 66 patients with COVID-19 at three stages of disease progression are sequenced. Respiratory tract, gut microbiome, and peripheral blood mononuclear cell (PBMC) samples are analyzed to compare the gut and respiratory tract microbiota of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between respiratory tract microbiome and immune response. In the respiratory tract, significantly fewer Streptococcus, Actinomyces, Atopobium, and Bacteroides are found in ICU than in nICU patients, while Enterococcus and Candida increase. In the gut, significantly fewer Bacteroides are found in ICU patients, while Enterococcus increases. Significant positive correlations exist between relative microbiota abundances in the respiratory tract and gut. Defensin-related pathways in PBMCs are enhanced, and respiratory tract Streptococcus is reduced in patients with COVID-19. A respiratory tract-gut microbiota model identifies respiratory tract Streptococcus and Atopobium as the most prominent biomarkers distinguishing between ICU and nICU patients. The findings provide insight into the respiratory tract and gut microbial dynamics during COVID-19 progression, considering disease severity, potentially contributing to diagnosis, and treatment strategies.

Cryptdin mRNA codes for the apparent precursor to a corticostatin/defensin-related peptide that accumulates to high levels in mouse intestinal crypt epithelium during postnatal development. The primary structure, intestinal cell distribution, and developmental appearance of cryptdin mRNA have been determined. Cryptdin mRNA is 450-480 nucleotides long. Translation of the partial cryptdin cDNA sequence reveals a 70-amino acid open reading frame that includes 32 carboxy-terminal residues that align with those in the consensus sequence, C.CR...C....ER..G.C....CCR, which is a common feature of leukocyte defensins and lung corticostatins (Selsted, M. E., D. M. Brown, R. J. DeLange, S. S. L. Harwig, and R. I. Lehrer. 1985. J. Biol. Chem. 260:4579-4584; Zhu, Q., J. Hu, S. Mulay, F. Esch, S. Shimasaki, and S. Solomon. 1988. Proc. Natl. Acad. Sci. USA. 85:592-596). In situ hybridization of cryptdin cDNA to paraformaldehyde-fixed, frozen sections of adult jejunum and ileum showed intense and specific labeling of epithelial cells in the base of all crypts. Analysis of sections from suckling mice showed that cryptdin mRNA is detectable in 10-20% of crypts in 10-d-old mice, in approximately 80% of crypts in 16-d-old mice, and in all crypts of mice 20 d and older. During the fourth week, the sequence accumulates in crypts to the maximal adult level. Cryptdin mRNA content in adult small intestine is independent both of T cell involvement and luminal bacteria. The role of cryptdin in small bowel physiology remains to be determined: cryptdin may inhibit bacterial translocation, modulate intestinal hormone synthesis, influence hormonal sensitivity of the intestinal epithelium, or exhibit a multiplicity of related activities.

β-Defensins are a group of vertebrate-specific antimicrobial peptides (AMPs) with microbicidal and immune regulatory functions. In spite of their conservation across the vertebrate lineage ranging from bony fish to human, the evolutionary origin of these molecules remains unsolved. We addressed this issue by comparing three-dimensional (3D) structure and genomic organization of β-defensins with those of big defensins, a family of invertebrate-derived β-defensin-related peptides with two distinct structural and functional domains. β-Defensins and the carboxyl-terminal domain of big defensins adopt a conserved β-sheet topology stabilized by three identical disulfide bridges. Genomic organization analysis revealed that the defensin domain of these two classes of molecules is encoded by a single exon with a positionally conserved phase-1 intron in its upstream. The genomic and 3D structural conservation provides convincing evidence for their evolutionary relationship, in which β-defensins emerged from an ancestral big defensin through exon shuffling or intronization of exonic sequences. The phylogenetic distribution of big defensins in Arthropoda, Mollusca and Cephalochordata suggests an early origin of the β-defensin domain, which can be traced to the common ancestor of bilateral metazoans.