Stimulation of toll-like receptor 2 by Coxiella burnetii is required for macrophage production of pro-inflammatory cytokines and resistance to infection
Authors: James E Samuel
Marco A Campos
Kati Kiss
Ricardo T Gazzinelli
Fanny N Lauw
Douglas T Golenbock
Craig R Roy
Dario S Zamboni
Ana C T Torrecilhas
Igor C Almeida
Journal: Journal of Biological Chemistry (2004)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: TLR2; TLR4; C. burnetii; immune response; cytokines
Affiliations: Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA. 

Abstract:  Innate and adaptive immune responses are initiated upon recognition of microbial molecules by Toll-like receptors (TLRs). We have investigated the importance of these receptors in the induction of pro-inflammatory cytokines and macrophage resistance to infection with Coxiella burnetii, an obligate intracellular bacterium and the etiological agent of Q fever. By using a Chinese hamster ovary/CD14 cell line expressing either functional TLR2 or TLR4, we determined that C. burnetii phase II activates TLR2 but not TLR4. Macrophages deficient for TLR2, but not TLR4, produced less tumor necrosis factor-alpha and interleukin-12 upon C. burnetii infection. Furthermore, it was found that TLR2 activation interfered with C. burnetii intracellular replication, as macrophages from TLR2-deficient mice were highly permissive for C. burnetii growth compared with macrophages from wild type mice or TLR4-deficient mice. Although LPS modifications distinguish virulent C. burnetii phase I bacteria from avirulent phase II organisms, electrospray ionization-mass spectrometry analysis showed that the lipid A moieties isolated from these two phase variants are identical. Purified lipid A derived from either phase I or phase II LPS failed to activate TLR2 and TLR4. Indeed, the lipid A molecules were able to interfere with TLR4 signaling in response to purified Escherichia coli LPS. These studies indicate that TLR2 is an important host determinant that mediates recognition of C. burnetii and a response that limits growth of this intracellular pathogen. 

Retracted: No

PubPeer comments:
 Theorem 1 in this paper is not correct. According to Definition 13, the addition limit requires not only the convergence of four sequences as claimed in Theorem 1 but also an essentially monotonic convergence. ![file] , 
 Theorem 1 seems ok with all numbers restricted in the  addition sequence , which guarantees the monotonicity condition. However, the rest of this paper is still questionable. Actually, this paper is a re-presentation of the following paper as an interval-valued version. Qian Lei, Zeshui Xu (2015) Derivative and Differential Operations of Intuitionistic Fuzzy Numbers. Int. J. Intell. Syst. 30, 468u2013498 See the comments in https: pubpeer.com publications 763257B958790969FC1AF53012DD5B , 
 Denote $$(a_1, b_1, c_1, d_1) = (.1, .4, .4, .4)$$ and $$(a_2, b_2, c_2, d_2) = (.1, .1, .4, .6)$$ Then $$frac{c_1}{c_2} =1 qquad frac{d_1}{d_2} = frac{.4}{.6} 1$$ Can the authors explain this issue? ![file] , 
 ![file] ![file] , 
 ![file] , 
 #4 Dear Hua Zhao, Thank you very much for your reply. Are you aware that when $$frac{c_1}{c_2} =1$$ the both terms $$frac{a_1 - a_2}{1 - a_2}$$ and $$frac{b_1 - b_2}{1-b_2}$$ should be **zero** in order to make the result of the subtraction operation $$tilde{a}_1 ominus tilde{alpha}_2$$ in Definition 4 meaningful as you claimed in the paper for an interval valued intuitionistic fuzzy number? , 
 #5 Dear Hua Zhao Thank you very much for your reply. Please see the details below in case you cannot figure out the calculation, Let $$tilde{alpha}_1 = (a_1, b_1, c_1, d_1) = (.1, .4, .4, .4)$$ and $$tilde{alpha}_2 = (a_2, b_2, c_2, d_2) = (.1, .1, .4, .6)$$ These two numbers meet the requirements in Definition 4 of your paper for subtraction, i.e., $$a_1 ge a_2, quad b_1 ge b_2, quad c_1 le c_2, quad d_1 le d_2$$ $$c_2 0,quad d_2 0$$ $$c_1(1-a_2) le c_2(1-a_1)$$ $$d_1(1-b_2) le d_2(1-b_1)$$ Hence, $$tilde{alpha}_1ominus tilde{alpha}_2 = left(frac{.1- .1}{ 1-.1},quad frac{.4 - .1}{1-.1},quad frac{.4}{.4},quad frac{.4}{.6}right)$$ Note that $$frac{.4 -.1}{1- .1}+ frac{.4}{.4} 1$$ This violates the conditions specified in Definition 1 of your paper. Hope that you can understand that no matter how many papers have been published on interval valued intuitionistic fuzzy numbers, it does not justify yours. Anyway, thank you again for your reply. ![file] ![file] , 
 ![file] ,