Article

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.

0 Followers
 · 
120 Views
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aetiology of OAL is undefined, although much attention has been recently focused on determining whether OAL is caused by an autoimmune disorder, chronic antigenic stimulation or both. It is becoming evident that infectious agents underlying chronic eye infection, as Chlamydia, may play a role in ocular lymphomagenesis. The high prevalence of Chlamydophila psittaci in patients with OAL has suggested a potential oncogenic role for its tendency to cause chronic and persistent infections, although it has been documented an evident geographical variability and response to antibiotic treatment. For C. pneumoniae, the findings so far obtained are very limited not only for identification in OAL but also for the specific treatment with antibiotics. The recent molecular and cultural evidence of C. trachomatis in patients with OAL, seems to suggest that also this pathogen may contribute to pathogenesis of such lymphoma. The potential appli- cation of bacteria-eradicating therapy at local and systemic level may ultimately result in safer and more efficient therapeutic option for patients affected by these malignancies. Moreover, a close collaboration between experts in oph- thalmology, infectious diseases and hematology will help, in the future, to effectively manage this disease. This review attempts to weigh the currently available evidence regarding the role that Chlamydia play in development of OAL and focuses on patients with OAL observed at our Institution.
    Journal of Cancer Therapy 03/2013; 4(02):662-677. DOI:10.4236/jct.2013.42082
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Contradicting reports exist about the pathogenicity of Chlamydia pneumoniae and the severity of the respiratory disease they cause. This study aimed to clarify, in mice, our hypothesis that marked differences in virulence of well-defined C. pneumoniae strains might exist for lung infections. C57BL/6J mice were intranasally infected with equal amounts of five different, identically prepared laboratory strains of C. pneumoniae. Based on the clinical score, weight, histopathological score, the granulocyte marker-enzyme myeloperoxidase, and the amount of Chlamydiae in the lung tissue, the C. pneumoniae isolates exhibited clear differences in overall growth characteristics or clearance, and pathological potential. Thus, we could identify chlamydial strains (Kajaani-K6 and CWL-029), where mice became seriously ill, as well as a relatively low-virulent isolate (TWAR-183). Cytokine profiles also varied drastically between the five strains in extent and kinetic. Our results indicate that C. pneumoniae isolates differ markedly with regard to their interaction with the host and their pathological potential. This might also be true for the infection in humans. Because the genomic diversity of C. pneumoniae is rather small, more subtle genomic deviations account most likely for the apparent functional differences. Our results will be useful to identify additional virulence factors in the future.
    FEMS Immunology & Medical Microbiology 03/2009; 55(2):206-14. DOI:10.1111/j.1574-695X.2008.00503.x · 2.55 Impact Factor
  • Source
    • "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) "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chlamydial infections are prevalent worldwide. Immunological events related to both innate and adaptive immunity during chlamydial infection can aid in recovery from the disease, but they can also cause harmful effects (immunopathology). The host genetic factors (variation in innate immunity and adaptive response-related genes) can predispose individuals to infection and its sequelae as well as determine the effects of intervention. No effective vaccine is available for human use. Modern technologies and data obtained using different 'omics' techniques (genomics, proteomics, transcriptomics and immunomics) might help in designing novel, more efficient vaccines, hopefully also against chlamydial infections.
    FEMS Immunology & Medical Microbiology 02/2009; 55(2):167-77. DOI:10.1111/j.1574-695X.2008.00519.x · 2.55 Impact Factor
Show more