Antiviral Mechanisms of Human Defensins

Abstract

Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, α- and β-defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data is known for α-defensins, molecular details for β-defensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis.

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

“…Importantly, most HD5 mutants that alter binding to AdV capsomers are also attenuated for HPV16 neutralization, indicating that HPV16 inhibition is likely dependent on a similar binding principle. Thus, future studies of HPV and other viral systems may reveal common principles that dictate ␣-defensin activity against nonenveloped viruses, defining a mechanism distinct from the more completely characterized activity of defensins against bacteria and enveloped viruses (6,49).…”

“…Although originally discovered due to their antibacterial activity, defensin antiviral activity against both enveloped and nonenveloped viruses has also been described. Neutralization of enveloped viruses, such as human immunodeficiency virus 1 (HIV-1), herpes simplex virus (HSV), and respiratory syncytial virus (RSV), is largely dependent on direct interactions of defensins with both viral attachment proteins and cellular receptors, as well as envelope damage, fusion inhibition, and modulation of host responses (6). Inhibition of these viruses may be due to multiple defensin actions rather than a single overriding inhibitory mechanism.…”

New Insights into Upper Airway Innate Immunity

“…They have far-reaching antimicrobial properties, which are capable of affecting membrane permeabilization in both bacteria and fungi, and of exhibiting a wide range of antiviral effects, including directly attacking viral envelopes, capsids, and glycoproteins, inhibiting viral entry, and preventing viral replication. 5,[50][51][52] Defensin expression is upregulated in the airway epithelium on pathogenic bacterial or viral exposure, 53,54 and elevated levels of ␤-defensins correlate with inflammation in patients with cystic fibrosis. 42 Cathelicidins are another major class of antimicrobial peptides, although LL-37 is the only cathelicidin member found in humans.…”

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation

“…9 Contrary to the suppressive effects on the immune system, vitamin D also has a protective effect against infections. This was first shown in tuberculosis, where the traditional treatments with sunlight and cod liver oil, rich in vitamin D, are viewed in a new light after the discovery of antimicrobial peptides induced by vitamin D. The two antimicrobial peptides under the influence of vitamin D are LL-37 (cathelicidin) and β-defensin 2, 10,11 which have activity against several bacteria, as well as viruses 12 and fungi. 13 We present here what we believe is currently the largest epidemiological study on adult HSCT patients examining clinical outcome with regards to vitamin D deficiency before HSCT, including both infectious and non-infectious complications.…”