This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shasby, D. M. Articles by McCray, P. Search for Related Content PubMed PubMed Citation Articles by Shasby, D. M. Articles by McCray, P.

Sepsis and Innate Immunity

University of Iowa College of Medicine Iowa City, Iowa

Cecal ligation and puncture has been a useful model for studying sepsis. Over the last decade, this and similar models have identified receptors, cytokines, and signaling pathways that participate in the host's defense against life-threatening infection. Despite a number of apparently paradoxical and deleterious effects of some of these receptors, cytokines, and signaling on acute physiology, they have survived evolution and in all likelihood contribute to the survival of the host.

The same bacteria that cause sepsis in the model of cecal ligation and puncture normally reside within the lumen of the intestine. Within the intact intestinal lumen the bacteria do not cause infection, in part, because elements of innate immunity limit their multiplication and penetration of the intestinal epithelium (1, 2). Among these elements of innate immunity are cationic antimicrobial peptides secreted by myeloid and epithelial cells (3). Invasive Shigella inhibit the production of these antimicrobial peptides by intestinal epithelium to facilitate their infection of the epithelial cells (1). Mammals make more than 500 antimicrobial peptides, and their ancestry dates back some 300 million years (4). There are two major families of antimicrobial peptides: defensins and cathelicidins. Both families are cationic and amphipathic proteins, facilitating binding to and penetration of negatively charged microbial membranes. The defensins have a common ß sheet structural core stabilized by three disulfide bonds (3). The cathelicidins have a more diverse structure, but all members of the family share a 100-amino acid N-terminal prosequence, the cathelin domain. The antimicrobial activity of most of the cathelicidins is dependent on proteolytic cleavage of the cathelin prosequence from the cationic antimicrobial peptide sequence (4). Both defensins and cathelicidins are microbicidal in low micromolar concentrations and avidly bind lipopolysaccharide.

In this issue of the Journal (pp. 187–194), Giacometti and colleagues report that intravenous administration of SMAP-29, a sheep cathelicidin, rescued rats from otherwise inevitable death after cecal ligation and puncture (5). SMAP-29 was effective when given immediately after the cecal ligation and puncture procedure and also if given 6 hours later (a sequence with more inference for clinical sepsis). In an earlier report using a less rigorous model of sepsis, the human cathelicidin, LL-37, also protected mice against endotoxemia (6). In terms of death, SMAP-29 was not more efficacious than imipenem. SMAP-29 and polymyxin B, both of which avidly bind endotoxin, were, however, more effective in limiting plasma levels of endotoxin and tumor necrosis factor- than was imipenem.

If the efficacy of this intervention is similar to imipenem why all the fuss? Cathelicidins are microbicidal against a broad spectrum of organisms, including aerobic and anaerobic gram-positive and gram-negative bacteria, fungi, and viruses (4). Resistance to the microbicidal activity is rare (7). They avidly bind endotoxin and they also bind CD-14, and thereby block endotoxin production of tumor necrosis factor- (8). Recent mouse models have provided compelling evidence of the important in vivo host defense roles of mammalian antimicrobial peptides. Mice deficient in the mouse cathelicidin, CRAMP, have a normal phenotype in a sterile environment, but are more susceptible to infection when exposed to bacteria and infected wounds heal poorly because of inadequate angiogenesis (9, 10). Moreover, mice expressing the human enteric defensin HD-5 in the crypts of the small intestine demonstrate remarkable resistance to infection and septicemia from Salmonella (11). Cathelicidins are decreased in burn wounds and in atopic dermatitis, both of which are associated with increased infection (7). In contrast, the human cathelicidin, LL-37, is increased in psoriatic skin lesions and these are resistant to infection. Systemic inflammatory response syndrome is the initial response to sepsis, and the production of cathelicidins is increased by ligation of TLR receptors. Compensatory antiinflammatory response syndrome follows the systemic inflammatory response syndrome and is characterized by immunosuppression. If cathelicidins are decreased in burn wounds, could they be decreased in compensatory antiinflammatory response syndrome? If they are decreased in atopic dermatitis skin, how about asthmatic airways or the airways of patients with acute respiratory distress syndrome?

In addition to their antimicrobial activities, cathelicidins also modify inflammatory responses. References to tumor necrosis factor- production and to angiogenesis were made above. In addition, cathelicidins are chemotactic for neutrophils and the cathelin domain acts as an anti-protease (7). The human cathelicidin, LL-37, stimulates expression of messenger RNA for several chemokines and their receptors, independent of tumor necrosis factor- (6). These complex effects make it more difficult to predict the efficacy of these peptides in a more complex setting of sepsis than what exists in a rat subjected to cecal ligation and puncture. While Giacometti and coworkers did not detect major changes in the physiology of the rats exposed to SMAP-29, more subtle effects on endothelial and epithelial barriers and on activation of inflammation by antimicrobial peptides may be significant in more complex settings of longer duration.

Most of the cationic-amphipathic antimicrobial peptides are also toxic for cells in concentrations similar to or only a log greater than those that are microbicidal. Protein engineering can reduce these toxic properties of the peptides with very small effects on their microbicidal activity (12). The effect of these amino acid substitutions, however, on the more complex pro- and antiinflammatory and wound healing effects of the antimicrobial peptides are not known.

The observations of Giacometti and colleagues are encouraging and suggest that supplemental antimicrobial peptides might be useful in the clinical setting of sepsis. A potential added benefit of such a strategy is the ability of natural antimicrobials to act synergistically with other host defense peptides and proteins (13). It will also be interesting to know if their production in airway epithelium is compromised in the setting of compensatory antiinflammatory response syndrome. A more detailed investigation of their safety and their net effects in the broader context of inflammation will be important before we begin to think of use in humans.

FOOTNOTES

Conflict of Interest Statement: D.M.S. and P.M. have no declared conflict of interest.

REFERENCES

1. Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G. Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 2001;7:180–185.[CrossRef][Medline]
2. Gomez HF, Ochoa TJ, Herrera-Insua I, Carlin LG, Cleary TG. Lactoferrin protects rabbits from Shigella flexneri–induced inflammatory enteritis. Infect Immun 2002;70:7050–7053.[Abstract/Free Full Text]
3. Zasloff M. Antimicrobial peptides in health and disease. N Engl J Med 2002;347:1199–1200.[Free Full Text]
4. Zanetti M. Cathelicidins, multifuntional peptides of the innate immunity. J Leukoc Biol 2004;75:1–10.[Free Full Text]
5. Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, D'Amato G, Circo R, Orlando F, Skerlavaj B, Silvestri C, Saba V, et al. Cathelicidin peptide sheep myeloid antimicrobial peptide-29 Prevents Endotoxin-induced Mortality in Rat Models of Septic Shock. Am J Respir Crit Care Med 2004;169:187–194.[Abstract/Free Full Text]
6. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol 2002;169:3883–3891.[Abstract/Free Full Text]
7. Gallo RL, Murakami M, Ohtake T, Zaiou M. Biology and clinical relevance of naturally occurring antimicrobial peptides. J Allergy Clin Immunol 2002;110:823–831.[CrossRef][Medline]
8. Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, Heumann D. Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. J Immunol 2001;167:3329–3338.[Abstract/Free Full Text]
9. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, Pestonjamasp V, Piraino J, Huttner K, Gallo RL. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001;414:454–457.[CrossRef][Medline]
10. Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe T, Issbrucker K, Unterberger P, Zaiou M, Lebherz C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest 2003;111:1665–1672.[CrossRef][Medline]
11. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003;422:522–526.[CrossRef][Medline]
12. Sawai MV, Waring AJ, Kearney WR, McCray PB Jr, Forsyth WR, Lehrer RI, Tack BF. Impact of single-residue mutations on the structure and function of ovispirin/novispirin antimicrobial peptides. Protein Eng 2002;15:225–232.[Abstract/Free Full Text]
13. Yan H, Hancock RE. Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob Agents Chemother 2001;45:1558–1560.[Abstract/Free Full Text]

This article has been cited by other articles:

				F. Dal-Pizzol, L. P. Di Leone, C. Ritter, M. R. Martins, A. Reinke, D. Pens Gelain, A. Zanotto-Filho, L. F. de Souza, M. Andrades, D. F. Barbeiro, et al. Gastrin-releasing Peptide Receptor Antagonist Effects on an Animal Model of Sepsis Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 84 - 90. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shasby, D. M. Articles by McCray, P. Search for Related Content PubMed PubMed Citation Articles by Shasby, D. M. Articles by McCray, P.