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Innate and Adaptive Immune Dysfunction and Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Paula Osterhout, Christina S. Kim, Erika C. Claud
Paneth cells can directly phagocytose bacteria and contain granules that produce the antimicrobial proteins defensins and lysozyme (14–16). Defensins are molecules that have a hydrophobic portion that preferentially inserts into the cell membranes on bacteria, leading to fatal disruption of the bacteria membranes (17). Lysozyme also functions to disrupt the cell membranes of gastrointestinal invaders.
Secreted effectors of the innate mucosal barrier
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Michael A. McGuckin, Andre J. Ouellette, Gary D. Wu
Defensins comprise three families of cationic, cysteine-rich antimicrobial peptides, the α-, β-, and θ-defensins (Figure 4.6). The α-defensins are major granule constituents of mammalian phagocytic leukocytes and secretory granules of intestinal Paneth cells. α-Defensins are microbicidal against gram-positive and gram-negative bacteria, certain fungi, spirochetes, protozoa, and enveloped viruses in in vitro assays. Accounting for 5%–18% of total cellular protein in neutrophils, α-defensins are estimated to reach concentrations of ∼10 mg mL−1 as granules dissolve in phagolysosomes following ingestion of microorganisms; Paneth cells secrete α-defensins at concentrations of 25–100 mg mL−1 at the point of release. The biosynthesis of α-defensins requires posttranslational activation by lineage-specific proteinases. α-Defensins derive from inactive 10 kDa precursors that contain canonical signal sequences, electronegative proregions, and a 3.5–4 kDa mature α-defensin peptide in the C-terminal portion of the precursor, and α-defensin bactericidal activity is dependent on proteolytic conversion of inactive 8.4 kDa pro-α-defensins to active forms. The details of human and mouse Paneth cell α-defensin processing differ in that human Paneth cells store unprocessed pro-α-defensin precursors that are processed coincident with or after secretion by trypsin, whereas mouse pro-α-defensins are activated intracellularly by Mmp7.
Host Defense I: Non-specific Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The defensins are an important group of nonspecific antimicrobial peptides found in highest amount within the primary (azurophil) granules of neutrophils; they are also found in macrophages. Four such peptides have been described in humans. These are small cyclic polypeptides containing 29–35 residues. Defensins from various species have in vitro activity against bacteria, fungi, and some enveloped viruses. These molecules may also participate in cellular cytotoxicity mediated by neutrophils and macrophages. Defensins kill their targets by inserting into membranes and creating pores which permit passage of solutes, much as in complement-mediated lysis. By an unknown mechanism, defensins also lead to accumulation of single-stranded breaks in DNA.
FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota
Published in Gut Microbes, 2022
Xiaomin Su, Mengli Jin, Chen Xu, Yunhuan Gao, Yazheng Yang, Houbao Qi, Qianjing Zhang, Xiaorong Yang, Wang Ya, Yuan Zhang, Rongcun Yang
Defensins possess a broad spectrum of antimicrobial activity, maintain the homeostasis of gut microbiota, and modulate numerous cellular responses, which are crucial for gut defenses. We here found that FABP4 expressed in the Paneth cells of small intestine and colon can downregulate defensins expression through degrading PPARγ by K48 ubiquitination (Figure 8). HFD may modulate host defense peptides expression 27,69,70 and lead to a downregulation of host defensins and PPARγ. 19,27 But, little is known how HFD regulates the expression of host defensins. We demonstrate that the expression of FABP4 in gut Paneth cells can be promoted by HFD, especially PA, a main component in HFD. Lower Firmicutes/Bacteroidetes ratio, which is opposite to that (higher Firmicutes/Bacteroidetes ratio) in mice fed HFD 48–50 was found in FABP4fl/flpvillinCreT mice. Importantly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. Since alternation of the gut microbiota composition is related to multiple diseases such as metabolic symposium, our results imply that FABP4 might be a target for therapy against these diseases. These findings will also offer basic information for how to regulate infection and maintain gut homeostasis by Paneth cells.
Vitamin D in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects
Published in Journal of the American College of Nutrition, 2021
Navya Vyas, Shilia Jacob Kurian, Debasis Bagchi, Mohan K. Manu, Kavitha Saravu, Mazhuvancherry Kesavan Unnikrishnan, Chiranjay Mukhopadhyay, Mahadev Rao, Sonal Sekhar Miraj
Evidence is mounting on vitamin D’s mediatory role in the immune response to infection. The biologically active form of vitamin D modulates innate and adaptive immunity via genes regulated by the vitamin D receptor (VDR), a transcription factor (Figure 2). An in vitro study using human cell lines revealed around 15 genes operating as major mediators of vitamin D’s action in both innate and adaptive immunity (13). Therefore, vitamin D may be considered for combating viral infections in both clinical and preclinical studies (14). Vitamin D acts by binding to the VDR, a nuclear receptor, which dimerizes with an isoform of the retinoid X receptor (RXR), whereupon the VDR-RXR heterodimers bind to vitamin D response elements (VDRE) on the promoter regions of target genes (14). VDRE then promotes the transcription of antimicrobial peptides (AMPs) such as human cathelicidin (human cationic antimicrobial protein; hCAP18) and human β-defensin-2 (hBD-2). AMPs are endogenously synthesized molecules found on mucosal and epithelial layers of multicellular organisms that offer the first-line defense against infections (bacterial and viral). AMPs also possess immunomodulatory functions. Defensins and cathelicidins constitute the two major families of AMPs. Defensins consist of six α- and two β- subclasses. hCAP18/LL-37 is the only type of cathelicidins in humans (15). Additionally, VDR-RXR heterodimers can also displace the nuclear factors of activated T lymphocytes (T cells), thereby suppressing cytokine-related genes in humans (16).
Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2
Published in Expert Review of Anti-infective Therapy, 2021
Masoumeh Sadat Mousavi Maleki, Mosayeb Rostamian, Hamid Madanchi
Defensins modulate viral infection through several mechanisms that are performed by direct interaction with viral envelopes or through interactions with the virus potential target cells. They may also indirectly interfere with various stages of the viral life cycle [39] or modify the innate immune response to viral infections. Defensins involve in many activities include differentiation/maturation of T cell, macrophage, and dendritic cell, as well as recruiting of dendritic cells into infection sites, wound healing, regulation of cell death pathways, and induction of the production of pro-inflammatory cytokine by macrophages, mast cells and keratinocytes [40]. Also, defensins, more importantly, HNP-1, 2 and 4, possess antiviral activity against HIV [41]. The antiviral effects of HNP-4 against herpes simplex virus (HSV) [42], human papillomavirus (HPV) [43,44], respiratory syncytial virus (RSV) [45] have also been investigated. A study by Yongjie et al. found that HNP1-3 and their rabbit homolog, RNP1-5, could not evoke innate immune responses or have a direct effect on inhibiting SARS-CoV [46]. It has been reported that Rhesus θ-defensin (RTD1) could reduce pathological lung lesions in SARS-infected mice compared to the untreated group. The results of this study showed that RTD1 had no effect on the viral load, but it indirectly reduced pulmonary complications and the death of mice due to its anti-inflammatory effects [47].