Human Rhinovirus Infection Induces Airway Epithelial Cell Production of Human β-Defensin 2 Both In Vitro and In Vivo

Abstract

We hypothesized that airway epithelial cells, the primary site of human rhinovirus (HRV) infection, provide a link between the innate and specific immune response to HRV via production of human β-defensin (HBD)-2, a potent in vitro attractant and activator of immature dendritic cells. Infection of primary cultures of human epithelial cells with several HRV serotypes induced expression of HBD-2 mRNA and protein, indicating that HBD-2 production was independent of viral receptor usage or mechanisms of viral RNA internalization. Induction of HBD-2 was dependent upon viral replication and could be mimicked by transfection of cells with synthetic dsRNA, but was not dependent upon epithelial production of IL-1. Studies with stable epithelial cell lines expressing HBD-2 promoter constructs, as well as inhibitor studies in primary cells, both demonstrated that induction of HBD-2 involves activation of the transcription factor, NF-κB. Other transcription factors must also be activated by HRV infection, however, as expression of HBD-3 mRNA was also induced and there is no putative NF-κB recognition sequence in the promoter of this gene. HBD-2 showed no direct antiviral activity against HRV. In vivo infection of normal human subjects with HRV-16 induced expression of mRNA for HBD-2 in nasal epithelial scrapings. Increases in mRNA correlated with viral titer and with increased levels of HBD-2 protein in nasal lavages. This represents the first demonstration that HRV infection induces epithelial expression of HBD-2 both in vitro and in vivo, and supports the concept that HBD-2 may play a role in host defense to HRV infection.

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.…”

The Relative Efficiency of Acquisition of MHC:Peptide Complexes and Cross-Presentation Depends on Dendritic Cell Type

“…In fact virally infected epithelial cells secrete many molecules that modulate the immune response, for example, upon viral infection by HIV, epithelial cells produce defensins (34,35). These are chemotactic factors that recruit T cells and monocytes (34).…”

Human Defensins in HIV Infection: Friends or Foes?

“…Stimulation of TLR3 has been shown to induce HBD1 and HBD2 expression in uterine epithelial cells (Schaefer et al, 2005). Induction of HBD2 and HBD3 but not HBD1 in bronchial epithelial cells in response to human rhinovirus infection is mediated by activation of nuclear factor-B (NF-B) but not of IL-1 (Proud et al, 2004). As TLR3 activation also induced HBD2 and HBD3, it is possible that intracellular double-stranded RNA generated during replication of rhinovirus may be involved in the regulation of HBDs (Duits et al, 2003;Proud et al, 2004).…”

“…HBDs are expressed by epithelial cells and hematopeotic cells (Duits et al, 2002;Ganz, 2003;Yang et al, 2004). While HBD1 is often constitutively expressed, expression of HBD2 and HBD3 can be induced by viruses, bacteria, microbial products and pro-inflammatory cytokines, such as tumor-necrosis factor (TNF) and interleukin-1 (IL-1) (Duits et al, 2003;Ganz, 2003;Proud et al, 2004;Sorensen et al, 2005;Yang et al, 2001). HBD1, HBD2 and HBD3 have been detected in various epithelial tissues (Fellermann and Stange, 2001;Garcia et al, 2001;Harder et al, 2001).…”

“…Induction of HBD2 and HBD3 but not HBD1 in bronchial epithelial cells in response to human rhinovirus infection is mediated by activation of nuclear factor-B (NF-B) but not of IL-1 (Proud et al, 2004). As TLR3 activation also induced HBD2 and HBD3, it is possible that intracellular double-stranded RNA generated during replication of rhinovirus may be involved in the regulation of HBDs (Duits et al, 2003;Proud et al, 2004). Similarly, HBD2 and HBD3 are induced in normal human oral epithelium cells, even in the absence of HIV-1 replication (Quinones-Mateu et al, 2003).…”