Attenuation

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Under attenuation (of lat. Attenuare "become thin, weaken, diminish") or Virulenzminderung , attenuation , is meant in the microbiology targeted reduction of pathogenic properties of a pathogen ( virulence ), remains but to give its viability at the same or only slightly is reduced. A similar concept is antivirulence with the difference that the pathogen is not defused in the laboratory, but directly in the body using appropriate drugs. In attenuation, the aim is to preserve the surface properties of the pathogen ( epitopes ) that are essential for the immune defense and thus to maintain its immunogenicity . Hence, attenuation is one way of producing live vaccines for active immunization.

principle

Attenuation takes advantage of the pathogen's natural property of being able to reproduce slightly in a host that is unfavorable for it at the beginning, but often not causing any disease. In the case of viruses , for example, this is explained by the fact that those receptors on the virus surface that allow uptake in a specific target cell are not adapted to the cells of the new host. Furthermore, the genes for immune evasion and some virulence factors are unnecessary in cell cultures and are therefore often deleted , e.g. B. Modified Vaccinia Ankara Virus .

After multiple passages (either in a cell culture , a chicken embryo or a living animal), those mutants of the pathogen are selected that can still reproduce and that are replicated in fewer numbers or with fewer symptoms when transferred to the original host (e.g. humans). Cultivation of the pathogen at less favorable, low temperatures (approx. 25 ° C) is also used for attenuation. B. the influenza vaccine strain Ann Arbor . When bacteria are attenuated , stable strains are usually grown that have either purposefully or accidentally lost their disease-causing genes ( islands of pathogenicity ).

The attenuation is used for the following pathogens for vaccine production: Influenza virus ( Influenza Vaccine ), measles virus ( measles vaccine ), mumps virus ( Mumps vaccine ), rubella virus ( Rubellaimpfstoff or combined in the MMR vaccine ), yellow fever virus ( Yellow Fever vaccine ), poliovirus ( polio vaccine ), varicella-zoster Virus ( varicella vaccine ), respiratory syncytial virus , human rotavirus ( rotavirus vaccine ), smallpox virus ( smallpox vaccine ), Mycobacterium tuberculosis (as Bacillus Calmette-Guérin ) and Salmonella typhi ( typhoid vaccine ).

Antivirulence

Antivirulant substances reduce the virulence of the pathogen during infection. This can happen , for example, by blocking the toxin function , toxin transport , cell adhesion or the regulation of virulence genes. It is crucial that there are no effects impairing the fitness of the pathogen, as this would immediately lead to selection pressure and the development of resistance to the active substance.

In a study on Pseudomonas aeruginosa , Mellbye and Schuster confirmed the assumption that no resistance is developed to active substances that inhibit quorum sensing in bacterial cultures.

history

The attenuation was accidentally discovered in Louis Pasteur's laboratory in 1879 . A staff member should infect chickens with a fresh culture of Pasteurella multocida before their vacation to test their resistance . However, infection did not occur until after a month with an aged culture, after which the chickens showed less pronounced symptoms and survived. These chickens were immune to a later infection with a fresh culture , which Pasteur wrongly attributed to the bacterial culture's longer exposure to oxygen.

literature

  • C. Mims, HM Dockrell et al .: Medical microbiology / infectiology . Munich (Elsevier) 2006 p. 551f, ISBN 3-437-41272-8
  • A. Bauernfeind and M. Shah: Lexicon of Microbiology and Infectiology , 2nd Edition, Stuttgart 1995
  • L. Pasteur, Chamberland and Roux: De l'attenuation des virus et de leur retour à la virulence. In: Comptes rendus 92 (1881), 492
  • M. Theiler, HH Smith: The effect of prolonged cultivation in vitro upon the pathogenicity of Yellow Fever Virus. In: J Exp Med. (1937), Vol. 65, No. 6, pp. 767-786. PMID 19870633 ; PMC 2133530 (free full text).

Individual evidence

  1. ^ R. Frechette: 22. New Developments in Antibacterial Drug R&D . In: JE Macor (Ed.): Annual Reports in Medicinal Chemistry , Volume 42, p. 360. Academic Press, 2007. ISBN 0-12-373912-8
  2. ^ AE Clatworthy, E. Pierson, DT Hung: Targeting virulence: a new paradigm for antimicrobial therapy. In: Nature chemical biology . Volume 3, Number 9, September 2007, pp. 541-548, doi: 10.1038 / nchembio.2007.24 . PMID 17710100 . (Review).
  3. ↑ DA Rasko, V. Sperandio: Anti-virulence strategies to combat bacteria-mediated disease. In: Nature reviews. Drug discovery. Volume 9, Number 2, February 2010, pp. 117-128, doi: 10.1038 / nrd3013 . PMID 20081869 . (Review).
  4. ↑ B. Mellbye, M. Schuster: The sociomicrobiology of antivirulence drug resistance: a proof of concept. In: mBio. Volume 2, number 5, 2011, p., Doi: 10.1128 / mBio.00131-11 . PMID 21990612 . PMC 3190357 (free full text).
  5. ^ Historyofvaccines.org: 1879 First Laboratory Vaccine