The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected.

Faculty of Military Health Sciences University of Defense Hradec Kralove Czech Republic

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Anthony LSD, Burke RD, Nano FE. Growth of Francisella spp. in rodent macrophages. Infect Immun. 1991;59:3291–3296. PubMed PMC

Bandouchova H, Sedlackova J, Pohanka M, Novotny L, Hubalek M, Treml F, Vitula F, Pikula J. Tularemia induces different biochemical responses in BALB/c mice and common voles. BMC Infect Dis. 2009a;9:101. PubMed PMC

Bandouchova H, Sedlackova J, Hubalek M, Pohanka M, Peckova L, Treml F, Vitula F, Pikula J. Susceptibility of selected murine and microtine species to infection by a wild strain of Francisella tularensis subsp. holarctica. Vet Med (Czech) 2009b;54:64–74.

Bell BL, Mohapatra NP, Gunn JS. Regulation of virulence gene transcripts by the Francisella novicida orphan response regulator PmrA: role of phosphorylation and evidence of MGlA/SspA interaction. Infect Immun. 2010;78:2189–2198. PubMed PMC

Bergsbaken T, Cookson BT. Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation. J Leukoc Biol. 2009;86:1153–1158. PubMed PMC

Bosio CM. The subversion of the immune system by Francisella tularensis. Frontiers in Microbiology. 2011. www.frontiersin.org, volume 2, article 9, PubMed DOI PMC

Elkins KL, Colombini SM, Krieg AM, De Pascalis R. NK cells activated in vivo by bacterial DNA control the intracellular growth of Francisella tularensis LVS. Microbes Infect. 2009;11:49–56. PubMed

Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, Eisenlohr L, Landel CP, Alnemri ES. The AIM2 inflammmasome is critical for innate immunity to Francisella tularensis. Nat Immunol. 2010;11:385–393. PubMed PMC

Fortier AH, Green SJ, Polsinelli T, Jones TR, Crawford RM, Leiby DA, Elkins KL, Meltzer MS, Nacy CA. Life and death of an intracellular pathogen: Francisella tularensis and the macrophage. Immunol Ser. 1994;60:349–361. PubMed

Fujii T, Mori Y, Tominaka T, Hayasaka I, Kawashima K. Maintenance of constant blood acetylcholine content bofore and after feeding in young chimpanzees. Neurosci Lett. 1997;227:21–24. PubMed

Fulop M, Mastoeni P, Green M, Titball RW. Role of antibody to lipopolysacharide in protection against low – and high – virulence strains of F. tularensis. Vaccine. 2001;19:4465–4472. PubMed

Jae SY, Heffernan KS, Yoon ES, Lee MK, Fernhall B, Park WH. The inverse assoctiation between cardiorespiratory fitness and C-reative protein is mediated by autonomic function: a possible role of the cholinergic antiinflammatory pathway. Mol Med. 2009;15:291–296. PubMed PMC

Kaufer D, Friedman A, Seldman S, Soreq H. Acute stress facilitates long–lasting changes in cholinergic gene expression. Nature. 2003;393:373–377. PubMed

Kepp O, Galluzzi L, Zitvogel L, Kroemer G. Pyroptosis – a cell death modality of its kind. Eur J Immunol. 2010;40:627–630. PubMed

Kopman AF, Eikermann M. Antagonism of non-depolarising neuromuscular block: current practice. Anaesthesia. 2009;64:22–30. PubMed

Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel-Moreno J, Guglani L, Alcorn JF, Strawbridge H, Park SM, Onishi R, Nyugen N, Walter MJ, Pociask D, Randall TD, Gaffen SL, Iwakura Y, Kolls JK, Khader SA. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31:799–810. PubMed PMC

Lykkesfeldt J. Malondialdehyde as biomarker of oxidative damage to lipids caused by smoking. Clin Chim Acta. 2007;380:50–58. PubMed

Pohanka M, Pavlis O, Skladal P. Diagnosis of tularemia using piezoelectric biosensor technology. Talanta. 2007;71:981–985. PubMed

Pohanka M, Bandouchova H, Novotny L, Pavlis O, Treml F, Sedlackova J, Pikula J. Assessment of low-molecular-weight antioxidants in Francisella tularenis infected hosts: comparison of two rodents with different susceptibility to tularemia. Neuro Endocrinol Lett. 2009;30(suppl. 1):186–191. PubMed

Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdes-Ferrer SI, Patel NB, Chavan S, Al-Abed Y, Yang H, Tracey KJ. The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med. 2009;15:195–202. PubMed PMC

Sotnikova R, Ponist S, Navarova J, Mihalova D, Tomekova V, Strosova M, Bauerova K. Effects of sesame oil in the model of adjuvant arthritis. Neuro Endocrinol Lett. 2009;30(suppl 1):22–24. PubMed

Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–859. PubMed

Tracey KJ. Reflex control of immunity. Natur Rev Immunol. 2009;9:418–428. PubMed PMC

Tyagi E, Agrawal R, Nath C, Shukla R. Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation. Neurochem Int. 2010;56:135–142. PubMed

Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susaria S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–388. PubMed

Yamamoto K, Sawada Y, Iga T. Comparative pharmacokinetics of four cholinesterase inhibitors in rats. Biol Pharm Bull. 1995;18:1292–1295. PubMed

Yee D, Rhinebbart-Jones TR, Elkins L. Loss of either CD4+ or DC8+ T cells does not affect the magnitude of protective immunity to an intracellular pathogen Francisella tularensis strain LVS. J Immunol. 1996;157:5042–5048. PubMed