Dear RG members,
I would like to know how the body control the antimicrobial peptide (AMP) production during infection in a concentration dependent pathway. It is well known that, many of the AMPs have MIC ranges from 2-4 uM conc. They are also cytotoxic to host normal cells at 10-30 uM conc. So, how does the organism control the production of AMPs in a infection dependent pathway. Kindly help me in understanding the concept behind the regulatory mechanism of AMP biosynthesis and release during infection. In addition, I would like to know how these AMPs degrade after killing the parasites or bacteria. Does they really degrade or still present in the body circulation in an inactive form.
Thank you in advance
Best regards
Bikash
Dear Bikash,
Brief description on Infection Dependent Path way:
Production of antimicrobial peptides by the host has an important role in defense mechanism. In invertebrates and plants, organisms lack adaptive immunity, hence antimicrobial peptides constitute a major component of host defense. Both plants and invertebrates induce the synthesis of antimicrobial peptides in response to infection. The signaling pathways that mediate this response are similar to the acute response in animals most prominently the rel/NF-κB family.
Whereas in vertebrates, antimicrobial peptide synthesis is either constitutive or inducible by microbial macromolecules and/or cytokines. For eg: The epithelial β-defensin of the bovine trachea i.e the tracheal antimicrobial peptide (TAP), is synthesized in the airway epithelia when they are exposed to inhaled bacteria or lipopolysaccharide. This response is initiated by lipopolysaccharide receptors that ultimately signal transcriptional regulators including the NF-κB complex, acting on NF-κB binding motifs in the promoter of the TAP gene.
These vertebrates have also evolved with an adaptive immune system based on specific recognition of antigens. They possess highly diverse antigen recognition receptors generated by somatic gene rearrangements and somatic mutations in the genes that encode their antigen recognition sites. When its receptor binds an antigen, the immunocyte undergoes clonal expansion to generate an effector population, thus playing an important role in defense mechanism.
The main important feature of these antimicrobial peptides is the selectivity, which preferentially kills the bacteria than the host cell in initial mode of action. This is attributed by the cationic properties of peptides which has more affinity towards the negative charge on the bacterial membrane which helps in the selection of antigens for degradation. Even the mammalian cell has negatively charged gangliosides in its membrane which can form a weak hydrophobic interaction with AMPs. But since the binding is weaker AMPs tend to target only Bacterial cells.
For further details check the this link on mechanism of AMPs http://pharmrev.aspetjournals.org/content/55/1/27.full
Dear Dr. Hegde,
Thank you very much for your explanation. The attached article is very useful as per the mechanism of action is concern. As you mentioned, the AMP action is highly concentration dependent along with lipid heterogeneity. It has been seen that the same AMP can kill a bacterial cell at 2uM and can kill healthy RBC at 30 uM. Now during the infection, the host cell produce a higher concentration of AMP to invade all pathogens. My concern is after their parasitic or pathogenic activity, how they degrade in body. If they still present in body fluid at an optimal concentration they may kill host cells. I came to know about the macrophage mediated phagocytosis, but I am unable to understand the selectivity of such phagocytesis and its associated enzymatic mechanism.
Thank you for your nice and informative explanation.
Best regards
Bikash
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