Surviving Innate Immunity

News & Comment TRENDS in Microbiology 1

Letter

local or toxin-mediated disease effects, number of individuals colonized Surviving innate invading deep tissues only in groups with asymptomatically greatly exceeds the immunity broader defects in innate or acquired low incidence of invasive infection. Is it immunity (e.g. neonates, the elderly or possible that in rare events a quantum In a complex environment, higher chemotherapy patients). ‘switch’ to higher CAMP resistance allows organisms face the constant threat of As discussed by Dr Peschel, the genetic invasion? Alternatively, do some patients microbial infection. To defend against this approach of generating and screening have congenital or acquired defects onslaught of potential pathogens, all bacterial mutants for alterations in CAMP in their specific ability to mount an known members of the plant and animal sensitivity has been fruitful in elucidating appropriate CAMP response to minor kingdoms use an innate immune system. a feature common to several resistant injury? When considering the A key component of innate immunity species – and supports an unattractive pathogenesis of infections through is the production of small, cationic (sic) hypothesis: bacteria that can epithelial barriers, the ability of the antimicrobial peptides (CAMPs). In successfully modify the normal anionic microorganism to avoid or resist CAMP- mammals, recent discoveries from gene constituents of their cell walls with mediated defenses must be considered. therapy and gene-knockout studies have cationic substitutions repulse rather The defining quality of some important confirmed that CAMPs play a crucial role than attract positively charged natural human pathogens thus could be an ‘innate in defense against invasive bacterial antibiotics. These charge alterations have immunity to innate immunity’. Such a disease [1,2]. As is increasingly the case been achieved in diverse fashions such strategy will require mechanisms to with pharmaceutical antibiotics, bacteria as modifications of lipoteichoic acid circumvent multiple immune defense exposed to human CAMPs appear to polymers with D-alanine (S. aureus), events, both soluble and cellular, that have evolved under selective pressure phosphotidylglycerol with L-lysine have evolved at the epithelial interface to develop mechanisms of resistance. (S. aureus), or lipopolysaccharide lipid A with our environment. Increased Although these selective pressures with aminoarabinose (Salmonella enterica appreciation of the molecular and existed before the dawn of modern and Legionella pneumophila). Alternative genetic basis of CAMP resistance medicine, and indeed have existed resistance mechanisms include proteolytic offers fundamental new insights into throughout evolution, CAMPs still exhibit digestion of the antimicrobial peptide pathogen–host interactions and could a broad spectrum of activity against (S. enterica) or proton-motive-force- reveal several promising new targets for diverse Gram-positive and Gram- dependent efflux pumps (Neisseria antibiotic therapy. negative bacterial species. The ability to gonorrhoeae). Confirming the importance resist killing by CAMPs, as discussed of CAMP in host defense, isogenic Victor Nizet by Andreas Peschel in a recent issue of bacterial mutants with decreased CAMP Dept of Pediatrics, Trends in Microbiology [3], is likely to resistance are less virulent than their Richard L. Gallo* be a discriminating feature of several wild-type parent strains in animal models Depts of Pediatrics and Medicine, bacterial pathogens. of invasive bacterial infection [6–8]. University of California, In humans, CAMPs are elaborated by A puzzling consideration is how some San Diego School of Medicine, skin keratinocytes and mucosal epithelial bacterial species that are sensitive to La Jolla, CA 92093, USA. cells at low levels under baseline killing by human CAMPs in vitro *e-mail: [email protected] conditions, but can be induced specifically sometimes produce invasive infections References in response to injury or infectious stimuli in healthy individuals. The intestinal 1 Bals, R. et al. (1999) Augmentation of innate host [4,5]. CAMPs are also concentrated in pathogen Shigella spp. and the skin and defense by expression of a cathelicidin the granules of circulating bone-marrow- respiratory tract pathogen group A antimicrobial peptide. Infect. Immun. 67, 6084–6089 derived cells and are recruited to the sites Streptococcus (GAS) are examples. For 2 Nizet, V. et al. (2001) Innate antimicrobial peptide of epithelial inflammation. Bacteria such Shigella, the solution could lie in the protects the skin from invasive bacterial infection. as Staphylococcus aureus and Salmonella ability of the organism to suppress the Nature 414, 454–457 spp. that generally exhibit intrinsic production of CAMPs by intestinal 3 Peschel, A. (2002) How do bacteria resist human CAMP resistance should possess a epithelial cells [9]. Resistant GAS antimicrobial peptides? Trends Microbiol. 10, 179–186 survival advantage on damaged mutants can be identified in the 4 Diamond, G. et al. (1996) Inducible expression of epithelium, in deeper body tissues and laboratory upon serial exposure to an antibiotic peptide gene in lipopolysaccharide- in the phagocytic vacuoles of leukocytes. increasing concentrations of CAMPs, and challenged tracheal epithelial cells. Proc. Natl. This is supported by the observations that these mutants are hypervirulent upon Acad. Sci. U. S. A. 93, 5156–5160 S. aureus is the most common cause of challenge of animals [2]. It is interesting 5 Dorschner, R.A. et al. (2001) Cutaneous injury induces the release of cathelicidin anti-microbial human wound infections and deep-tissue to speculate that a mutation conferring peptides active against group A Streptococcus. abscesses and Salmonella spp. are CAMP resistance might not prove J. Invest. Dermatol. 117, 91–97 leading agents of chronic systemic advantageous to the organism in 6 Gunn, J.S. et al. (2000) Genetic and functional infections, including enteric fever. epithelial colonization or host–host analysis of a PmrA–PmrB-regulated locus necessary for lipopolysaccharide modification, Bacterial species generally more sensitive transmission where even greater antimicrobial peptide resistance, and oral to CAMPs, such as Escherichia coli, can evolutionary selective pressures exist. For virulence of Salmonella enterica serovar occupy a niche on mucosal surfaces with many human bacterial pathogens, the Typhimurium. Infect. Immun. 68, 6139–6146

7 Robey, M. et al. (2001) Identification of Legionella 8 Peschel, A. et al. (2001) Staphylococcus aureus 9 Islam, D. et al. (2001) Downregulation of pneumophila rcp,apagP-like gene that confers resistance to human defensins and evasion of bactericidal peptides in enteric infections: a novel resistance to cationic antimicrobial peptides and neutrophil killing via the novel virulence factor immune escape mechanism with bacterial DNA promotes intracellular infection. Infect. Immun. MprF is based on modification of membrane lipids as a potential regulator. Nat. Med. 7, 180–185 69, 4276–4286 with L-lysine. J. Exp. Med. 193, 1067–1076 DOI: 10.1016/S0966-842X(02)02406-X