HOW DOES THE BODY USE DNA AS AN ANTIMICROBIAL AGENT?


Tuesday, January 18, 2011 at 10:42AM Sarah Scoles / Brooke Napier | 2 Comments | Share Article Email Article

Generally when I think of antibiotics I imagine taking a pill that delivers tiny death packages to individual bacteria that have invaded my body. These micro-molecules float through my blood stream to be delivered to my organs, obliterating any foreign cells they can find, taking no prisoners.

In addition to these pilled, bottled and administered antibiotics, there are inherent antimicrobial activities your cells have evolved to combat pathogens & escape infection. One specific cell type has been shown to have potent antimicrobial activity for over 100 years, feared by all microbes large and small: the neutrophil (Metchnikoff, 1901).

Aside from being notorious for forming pus at the site of infected wounds, neutrophils are known for their immediate response to infection by migrating via the circulatory system to the site of inflammation (for an excellent review on neutrophils: Nature Immuno Reviews, Nathan, 2006). Once at the site of infection, neutrophils engage in full-contact battle by engulfing the pathogen in a membrane-bound vesicle called the phagosome. This phagosome will mature into the phagolysosome where microbes are exposed to antimicrobial peptides and reactive oxygen species. After maturation of the phagosome, most neutrophils undergo apoptosis, controlled and anti-inflammatory cell death. Recently scientists found that, in addition to apoptosis, neutrophils also have a very distinct and interesting cell death pathway that results in formation of neutrophil extracellular traps (NETs) (Brinkmann et al., 2004) (Fig 1).

What are NETs?

Brinkmann, et al. (2004) first described NETs as “extracellular fibers… composed of granule and nuclear constituents that disarm and kill bacteria extracellularly.” NETs get their fibrous structure from DNA, the major structural component. DNA is naturally negatively charged and binds to positively charged proteins and cationic antimicrobial peptides (CAMPs). Other enzymes such as neutrophil elastase (NE), an enzyme that degrades virulence factors of bacteria, also bind to NETs (Weinrauch, 2002). Bacteria secrete virulence factors to evade host antimicrobial mechanisms, & their degradation weakens the defense of the invading bacteria. In addition, like in the nucleus, DNA binds to histones (Fig 2), naturally bactericidal proteins (Hirsh, 1958).

But is the production of NETs an early pre-determined cellular fate, or is this pathway a late reaction to infection? Recently Papayannopoulos, et al. (2010), found that NE and myeloperoxidase (MPO) (Fig 2), two antimicrobial peptides that bind to DNA in NETs, regulate chromatin density during the formation of NETs. Chromatin decondensation is necessary for the relaxation and release of DNA, required for NET formation. This is excellent data, but we need to collect additional data to identify the beginning steps of NET formation in order to determine how and when neutrophil NET fate is determined.

Why I find this interesting?

I love the idea that our body has evolved countless mechanisms to fight bacteria – including a mechanism that involves cellular suicide and antimicrobial agents binding to a giant extracellular DNA net. Generally we think of DNA in the nucleus wound up around histones, occasionally being read by polymerases – but this new antimicrobial mechanism shows that there is versatility and that endless eukaryotic cellular components have dual functions. NETs showcase how beautifully we have evolved.

References:
Hirsch JG, J Exp Med 108(6), 925 (1958)
Weinrach Y, et al. Nature 417, 91 (2002)
Metchnikoff E, Limmunité Dans Les Maladies Infectieuses (1901)
Papayannopoulos V, J Cell Bio, 191(3), 677 (2010)

Brinkmann, V. (2004). Neutrophil Extracellular Traps Kill Bacteria Science, 303 (5663), 1532-1535 DOI: 10.1126/science.1092385

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