Antimicrobial peptides: key components of the innate immune system

TLDR: An overview of cationic antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which are highly expressed and found in humans, as well as a brief discussion about widely abundant, well characterized AMPs in mammals.

Abstract: Life-threatening infectious diseases are on their way to cause a worldwide crisis, as treating them effectively is becoming increasingly difficult due to the emergence of antibiotic resistant strains. Antimicrobial peptides (AMPs) form an ancient type of innate immunity found universally in all living organisms, providing a principal first-line of defense against the invading pathogens. The unique diverse function and architecture of AMPs has attracted considerable attention by scientists, both in terms of understanding the basic biology of the innate immune system, and as a tool in the design of molecular templates for new anti-infective drugs. AMPs are gene-encoded short (<100 amino acids), amphipathic molecules with hydrophobic and cationic amino acids arranged spatially, which exhibit broad spectrum antimicrobial activity. AMPs have been the subject of natural evolution, as have the microbes, for hundreds of millions of years. Despite this long history of co-evolution, AMPs have not lost their ability to kill or inhibit the microbes totally, nor have the microbes learnt to avoid the lethal punch of AMPs. AMPs therefore have potential to provide an important breakthrough and form the basis for a new class of antibiotics. In this review, we would like to give an overview of cationic antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which are highly expressed and found in humans, as well as a brief discussion about widely abundant, well characterized AMPs in mammals, in addition to pharmaceutical aspects and the additional functions of AMPs.

Figures

Table 1: List of the major classes of AMPs produced in various organisms.

Figure 1: Schematic representation of α-defensins, β-defensins and cathelicidin (hCAP18). The conserved cysteines are highlighted in black box. The disulfide linkages for the α-defensins (1-6, 2-4, 3-5) and β-defensins (1-5, 2-4, 3-6) are

Figure 3: Different functions of AMPs in the host immune protection. AMPs can induce plethora of responses such as incitation of wound repair mechanism, genesis of vascular system, preventing obesity development, promote leukocyte

Figure 2: Models depicting the mode of action by membrane active AMPs. Peptides are

Table 2: List of peptides that went into clinical trials and their current status/outcome

Figure 4: AMPs activate innate immune system, which provides shorter, non-specific wide spectrum protection to the host without any memory. On the contrary, Vaccines activates adaptive immune system that provides long-term single pathogen protection with memory.

Full text

LUND UNIVERSITY
PO Box 117
221 00 Lund
+46 46-222 00 00
Antimicrobial peptides: key components of the innate immune system
Pasupuleti, M.; Schmidtchen, Artur; Malmsten, M.
Published in:
Critical Reviews in Biotechnology
DOI:
10.3109/07388551.2011.594423
2012
Link to publication
Citation for published version (APA):
Pasupuleti, M., Schmidtchen, A., & Malmsten, M. (2012). Antimicrobial peptides: key components of the innate
immune system.
Critical Reviews in Biotechnology
,
32
(2), 143-171.
https://doi.org/10.3109/07388551.2011.594423
Total number of authors:
3
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________________________________________________________________________
-1-
Antimicrobial peptides: key components of the innate immune system.
Mukesh Pasupuleti
1
*, Artur Schmidtchen
2
,
Martin Malmsten
3
.
1
Department of Microbiology and Immunology, Centre for Microbial Diseases and
Immunity Research, University of British Columbia, Vancouver, British Columbia,
Canada.
2
Division of Dermatology and Venereology, Department of Clinical Sciences,
Lund University, Biomedical Center, Lund, Sweden.
3
Department of Pharmacy, Uppsala
University, Biomedical Center, Uppsala, Sweden.
* Corresponding author
Mukesh Pasupuleti, Centre for Microbial Diseases and Immunity Research, Lower Mall
Research Station, University of British Columbia, Vancouver, V6T 1Z4, British
Columbia, Canada.
*mukesh@cmdr.ubc.ca
Key words: Antimicrobial peptides, innate immunity, immunomodulatory, liposome,
membrane active peptides, peptides, peptides mode of action.

________________________________________________________________________
-2-
Abstract
Life-threatening infectious diseases are on their way to cause a worldwide crisis, as
treating them effectively is becoming increasingly difficult due to the emergence of
antibiotic resistant strains. Antimicrobial peptides (AMPs) form an ancient type of innate
immunity found universally in all living organisms, providing a principal first-line of
defense against the invading pathogens. The unique diverse function and architecture of
AMPs has attracted considerable attention by scientists, both in terms of understanding
the basic biology of the innate immune system, and as a tool in the design of molecular
templates for new anti-infective drugs. AMPs are gene-encoded short (<100 amino
acids), amphipathic molecules with hydrophobic and cationic amino acids arranged
spatially, which exhibit broad spectrum antimicrobial activity. AMPs have been subject
of natural evolution, as have the microbes, for hundreds of millions of years. Despite this
long history of co-evolution, AMPs have not lost their ability to kill or inhibit the
microbes totally, nor have the microbes learnt to avoid the lethal punch of AMPs. AMPs
therefore have potential to provide an important break through and form the basis for a
new class of antibiotics. In this review, we would like to give an overview of cationic
antimicrobial peptides, origin, structure, functions, and mode of action of AMPs, which
are highly expressed and found in humans, as well as a brief discussion about widely
abundant, well characterized AMPs in mammals, in addition to pharmaceutical aspects
and additional functions of AMPs.

________________________________________________________________________
-3-
1. Introduction
Throughout evolution, the ability of an organism to protect itself from microbial or other
species invasion has been a key factor for survival. All species, from bacteria to humans,
resist the invasion of microorganisms through a simple mechanism, but complex in
functions, involving antimicrobial peptides (AMPs). AMPs are components of innate
immunity, forming the first-line of defense used by many organisms against the invading
pathogens (Jenssen et al., 2006). AMPs are gene-encoded short (<100 amino acids),
amphipathic molecules with broad-spectrum antimicrobial activity, displaying multiple
modes of action, including bacteriostatic, microbicidal, and cytolytic properties. Even
though AMPs are the first-line of defense against the invading microbes, ironically they
are a highly neglected aspect of immunology, and are normally only addressed passing in
general immunology textbooks. It is predicted that each species could contain a wide
variety of AMPs (Hancock and Rozek, 2002), hence describing all them is beyond the
scope of any review. Hence a complete inventory of antimicrobial peptides is neither
possible nor intended. Instead, illustrative examples are provided, demonstrating key
functional aspects of such peptides, as well as considerations and issues of importance for
their development to therapeutics.
2. History
A new area of research started in the 1960s, when Spitznagel and Zeya discovered that
basic proteins and peptides in polymorphonuclear (PMN) leukocytes display
antimicrobial properties (Zeya and Spitznagel, 1963; Zeya and Spitznagel, 1966), later
named “AMPs” (Ganz et al., 1985; Selsted et al., 1985). However, full fledged

________________________________________________________________________
-4-
investigations on AMPs started in 1972, when Boman observed that Drosophila
melanogaster, when injected with non-virulent strain of Aerobacter
cloacae followed by
a injection of virulent strain of the
same organism after few days, survived even after
subjection to high doses of these bacteria (Boman et al., 1972). In a following series
of
investigations in 1980, Boman and his group showed that a 35 amino acid molecule
(cecropin) is responsible for the strong antibacterial activity (Hultmark et al., 1980;
Steiner et al., 1981). Later, the significance of AMPs raised to higher level when Boman
and his colleagues demonstrated that AMPs are present in almost all invertebrates
investigated (Boman, 1981). A wide commercial interest in perusal of these molecules
started with the discovery of magainins in frog skin by Zasloff in 1987 (Zasloff, 1987).
This work for the first time showed that AMPs are not only molecules of lower
invertebrates, but also components of higher vertebrates. Since then, more than 1400
AMPs have been isolated from bacteria, insects and other invertebrates, amphibians,
birds, fishes, mammals, and plants (Wang and Wang, 2004; Wang et al., 2009a; Thomas
et al., 2010). During last few years, an increasing number of researchers world-wide have
contributed to the continued rapid expansion of the area.
3. Antimicrobial peptides
AMPs represent a universal feature of defense systems existing in all living forms, and
their presence in all along the evolutionary scale demonstrates their effectiveness and
significance in combating invading pathogens (Table 1). AMPs are promptly synthesized
and readily available shortly after an infection to rapidly neutralize a broad range of
microbes. The ability to produce AMPs is well preserved in almost all living organisms

Frequently asked questions

Q1. What are the contributions in this paper?

Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. You may not further distribute the material or use it for any profit-making activity or commercial gain • 

Q2. Why are AMPs promising therapeutic agents against infectious disease?

Due to their broad-spectrum antimicrobial activity and multiple functions, AMPs are promising therapeutic agents against infectious disease. 

Q3. What is the common cause of membrane rupture?

Depending on the composition of the membrane, also peptide-induced phase transitions or lipid segregation may cause membrane rupture (Lohner et al., 2008). 

Q4. What is the role of histidine in the phagocytosis of necr?

Histidine-rich glycoprotein specifically binds to necrotic cells via its amino-terminal domain and facilitates necrotic cell phagocytosis. 

Q5. How many parameters can influence the spectrum and activity of helical peptides?

-33-that at least seven parameters/descriptors (size, sequence, charge, amphipathicity, hydrophobicity, helical content, distance between the hydrophobic and hydrophilic faces of the helix) can influence the spectrum and activity range of helical peptides. 

Q6. What is the role of Attacin in the synthesis of outer membrane proteins?

an antibacterial protein from Hyalophora cecropia, inhibits synthesis of outer membrane proteins in Escherichia coli by interfering with omp gene transcription. 

Q7. What are the main reasons for AMPs antitumor activity?

Apart from the difference in cell membrane composition, fluidity, higher electro potential and glycosylation pattern of membrane-associated proteins have also been proposed as reasons for AMPs antitumor activity (Hoskin and Ramamoorthy, 2008). 

Q8. What is the peptide that inhibits the expression of TNF-alpha?

Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells. 

Q9. Why are AMPs synthesized by humans and other vertebrates amidated?

In addition, AMPs synthesized by humans and other vertebrates are amidated at the C-terminal, due to which these peptides are able to withstand bacterial enzymes for long times (Mueller and Driscoll, 2008; Stromstedt et al., 2009). 

Q10. How many defensins have been identified in humans?

In humans, more than 30 α-defensin geneshave been predicted using a bioinformatic approach (Schutte et al., 2002) , however at theprotein level only 6 α-defensins have been reported. 

Q11. What is the role of disulphide-bridged defensins in anti?

Defensins have been shown to have a broad-spectrum antimicrobial activity against bacteria, fungi, and enveloped viruses, although most defensins lose much of their antimicrobial activity at physiological concentration of Na+, Mg2+ or Ca2+ 

Q12. Why is it difficult for microbes to develop resistance to AMPs?

due to the presence of large numbers of AMPs in the host, it is difficult for microbes develop resistance to all AMPs at the same time. 

Q13. Why have many countries shifted their attention to AMPs?

Due to the drug regulations in many countries, much attention to the development of AMP therapeutics has been shifted to topically applied agents, as opposed to internal drug agents (Giuliani et al., 2007). 

Q14. What is the average hydrophobicity of a peptide?

Mean hydrophobicity of a peptide is defined as the proportion of hydrophobic residues within a peptide and is typically around 50% for most AMPs. 

Q15. Why do AMPs have a perfect amphipathic structure?

The reason being, when the peptide assumes helical structures all the hydrophobic and hydrophilic amino acids are on two different planes forming a perfect amphipathic structure. 

Q16. What is the role of CAP18 in the antimicrobial activity of a mouse?

Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model. 

Q17. What are the peptides that are derived from an interior sequence?

the N-terminal derived lactoferricins (Gifford et al., 2005) and the kaliocins derived from an interior sequence (Viejo-Diaz et al., 2005). 

Q18. What is the difference between electrostatic and hydrophobic interactions?

Since hydrophobic interactions are needed for antimicrobial activity at physiological electrolyte concentrations, a balance is therefore needed between electrostatic and hydrophobic interactions.