MyD88 is pivotal for the early inflammatory response and subsequent bacterial clearance and survival in a mouse model of Chlamydia pneumoniae pneumonia

Division of Pediatrics Infectious Diseases and Immunology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90048, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2005; 280(32):29242-9. DOI: 10.1074/jbc.M503225200
Source: PubMed

ABSTRACT Chlamydia pneumoniae is the causative agent of respiratory tract infections and a number of chronic diseases. Here we investigated the involvement of the common TLR adaptor molecule MyD88 in host responses to C. pneumoniae-induced pneumonia in mice. MyD88-deficient mice were severely impaired in their ability to mount an acute early inflammatory response toward C. pneumoniae. Although the bacterial burden in the lungs was comparable 5 days after infection, MyD88-deficient mice exhibited only minor signs of pneumonia and reduced expression of inflammatory mediators. MyD88-deficient mice were unable to up-regulate proinflammatory cytokines and chemokines, demonstrated delayed recruitment of CD8+ and CD4+ T cells to the lungs, and were unable to clear the pathogen from their lungs at day 14. At day 14 the MyD88-deficent mice developed a severe, chronic lung inflammation with elevated IL-1beta and IFN-gamma leading to increased mortality, whereas wild-type mice as well as TLR2- or TLR4-deficient mice recovered from acute pneumonia and did not show delayed bacterial clearance. Thus, MyD88 is essential to recognize C. pneumoniae infection and initiate a prompt and effective immune host response against this organism leading to clearance of bacteria from infected lungs.

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    • "These host receptors selectively recognize a broad spectrum of microbial components and endogenous molecules released by injured tissue [45]. In particular, TLR4 and TLR2 have been reported to be essential mediators of C. pneumoniae related host cell activation and defense and MyD88, the central TLR signaling adaptor molecule during Chlamydial infections, is crucial for the initiation of effective host defenses induced by recognition of C. pneumoniae by TLRs [46]. "
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    • "Experimental parameters such as the applied doses or the type of anaesthesia differed in these investigations. Quite a few studies have investigated the different susceptibility of mouse strains (Buzoni-Gatel et al., 1994; Qiu et al., 2004; Min-Oo et al., 2007; Miyairi et al., 2007), or the susceptibility of knock-out mice to one specific chlamydial isolate in order to reveal the role of hostcell genes (Mueller et al., 2004; Naiki et al., 2005; Rodriguez et al., 2006; Rothfuchs et al., 2006; Miyairi et al., 2007; Penttila et al., 2008; Yang et al., 2008). Additionally, only recently a study comparing pathogenic diversity among Chlamydia trachomatis ocular strains in nonhuman primates using microarray-based comparative genome sequencing has been published. "
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    • "Bacterial clearance and survival in mice Naiki et al. (2005) C. pneumoniae IFN-g production in mouse bone marrow macrophages Rothfuchs et al. (2004) Sonicated C. pneumoniae IFN-g synthesis (through IL-18 release) in PBMC Netea et al. (2004) C. trachomatis Colocalizes with the inclusion O'Connell et al. (2006) C. trachomatis Induction of IFN-g-inducible protein 10 in mice Nagarajan et al. (2005) TRIF C. muridarum IFN-b production in oviduct epithelial cells Derbigny et al. (2007) Nod1 Proteoglycan motif of C. trachomatis and C. muridarum NF-kB activation, secretion of proinflammatory cytokines in human epithelial endocervical cell line Welther-Stahl et al. (2006) C. pneumoniae Activation of human endothelial cells Opitz et al. (2005) "
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