Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Apr;117(4):836-41.
doi: 10.1016/j.jaci.2005.12.1345. Epub 2006 Feb 14.

Cathelicidin deficiency predisposes to eczema herpeticum

Michael D Howell  1 , Andreas Wollenberg, Richard L Gallo, Michael Flaig, Joanne E Streib, Cathy Wong, Tatjana Pavicic, Mark Boguniewicz, Donald Y M Leung
Affiliations

Cathelicidin deficiency predisposes to eczema herpeticum

Michael D Howell et al. J Allergy Clin Immunol. 2006 Apr.

Abstract

Background: The cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV).

Objective: This study investigated the potential role of cathelicidins in host susceptibility to HSV infection.

Methods: Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10).

Results: The cathelicidin peptide LL-37 (human cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing (P < .001) within the physiologic range. The importance of cathelicidins in antiviral skin host defense was confirmed by the observation of higher levels of HSV-2 replication in cathelicidin-deficient (Cnlp-/-) mouse skin (2.6 +/- 0.5 pg HSV/pg GAPDH, P < .05) compared with that seen in skin from their wild-type counterparts (0.9 +/- 0.3). Skin from patients with ADEH exhibited significantly (P < .05) lower levels of cathelicidin protein expression than skin from patients with AD. We also found a significant inverse correlation between cathelicidin expression and serum IgE levels (r2 = 0.46, P < .05) in patients with AD and patients with ADEH.

Conclusion: This study demonstrates that the cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH.

Clinical implications: A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.

PubMed Disclaimer

Figures

Figure 1
Figure 1
LL-37 exhibits anti-viral activity against HSV. Physiologic concentrations of LL-37 were pre-incubated with HSV-2 for 24 hours and then added to BS-C-1 for an additional 24 hours to evaluate HSV-2 gene expression by real-time RT-PCR (A) or 48 hours to investigate functionally active virus using a standard plaque assay (B). *** indicates a significant difference of p<0.001 as compared to 0 μM.
Figure 1
Figure 1
LL-37 exhibits anti-viral activity against HSV. Physiologic concentrations of LL-37 were pre-incubated with HSV-2 for 24 hours and then added to BS-C-1 for an additional 24 hours to evaluate HSV-2 gene expression by real-time RT-PCR (A) or 48 hours to investigate functionally active virus using a standard plaque assay (B). *** indicates a significant difference of p<0.001 as compared to 0 μM.
Figure 2
Figure 2
Exogenous LL-37 rescues HSV infected keratinocytes. Human keratinocytes were infected with 0.05 pfu/cell HSV-2 for six hours and then treated with physiologic concentrations of LL-37 for an additional 18 hours. RNA was isolated from the cells and the levels of HSV-2 gene expression evaluated by real-time RT-PCR. **indicates a significant difference of p<0.01 as compared to HSV alone.
Figure 3
Figure 3
Essential role of cathelicidins in controlling HSV replication in the skin. Skin biopsies from BALB/c (n=5) and Cnlp KO (n=5) mice were stimulated with HSV-2 for 24 hours and evaluated for HSV-2 gene expression. RNA was collected from the tissue and the levels of HSV-2 evaluated by real-time RT-PCR. *indicates a significant difference of p<0.05.
Figure 4
Figure 4
Expression of cathelicidin elevated in AD as compared to ADEH skin. A. Paraffin embedded skin explants from AD (n=10) and ADEH (n=10) patients were cut into 5 μm sections and stained for human cathelicidin. B. The intensity of the immunostaining was visually scored on a scale from 0 to 5, with 0 indicating no staining and 5 the most intense staining. *indicates statistical significance of p<0.05.
Figure 4
Figure 4
Expression of cathelicidin elevated in AD as compared to ADEH skin. A. Paraffin embedded skin explants from AD (n=10) and ADEH (n=10) patients were cut into 5 μm sections and stained for human cathelicidin. B. The intensity of the immunostaining was visually scored on a scale from 0 to 5, with 0 indicating no staining and 5 the most intense staining. *indicates statistical significance of p<0.05.
Figure 5
Figure 5
Correlation between serum IgE levels and cathelicidin expression in AD and ADEH patients. Serum IgE levels were determined from AD (n=9) and ADEH (n=9) patients. Regression analysis was performed on log transformed serum IgE values and LL-37 protein expression.
See this image and copyright information in PMC

References

    1. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003;361:151–60. - PubMed
    1. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004;113:651–7. - PMC - PubMed
    1. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60. - PubMed
    1. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9. - PubMed
    1. Wollenberg A, Wetzel S, Burgdorf WHC, Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;112:667–74. - PubMed

Publication types

MeSH terms