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


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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    • "Chlamydia pneumoniae CM-1 (ATCC, Manassas, VA) was propagated in HEp-2 cells as described [57]. HEp-2 cells and C. pneumoniae stocks were determined to be free of Mycoplasma contamination by PCR. "
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    ABSTRACT: Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5×10(5) CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis.
    PLoS ONE 10/2013; 8(10):e77447. DOI:10.1371/journal.pone.0077447 · 3.23 Impact Factor
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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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    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.
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    • "TLR2 was previously shown to stimulate the innate immune response during infection by Chlamydia muri - darum and C . pneumoniae , while TLR4 is thought to have no effect ( Prebeck et al . , 2001 ; Darville et al . , 2003 ; Naiki et al . , 2005 ; Cao et al . , 2007 ) . A role for TLR3 has been reported for infection of an oviduct cell line by the murine pathogen , C . muridarum ( Derbigny et al . , 2005 ; 2007 ; 2010 ) but never in animal studies . TLR3 effects on infec - tion by the human pathogens , C . trachomatis or C . pneu - moniae , have never been studied . Given our u"
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    ABSTRACT: Chlamydia pneumoniae is responsible for a high prevalence of respiratory infections worldwide and has been implicated in atherosclerosis. Inflammation is regulated by transcription factor (TF) networks. Yet, the core TF network triggered by chlamydiae remains largely unknown. Primary human coronary artery endothelial cells were mock-infected or infected with C. pneumoniae to generate human transcriptome data throughout the chlamydial developmental cycle. Using systems network analysis, the predominant TF network involved receptor, binding and adhesion, and immune response complexes. Cells transfected with interfering RNA against activator protein-1 (AP-1) members FOS, FOSB, JUN and JUNB had significantly decreased expression and protein levels of inflammatory mediators interleukin (IL)6, IL8, CD38 and tumor necrosis factor compared with controls. These mediators have been shown to be associated with C. pneumoniae disease. Expression of AP-1 components was regulated by MAPK3K8, a MAPK pathway component. Additionally, knockdown of JUN and FOS showed significantly decreased expression of Toll-like receptor (TLR)3 during infection, implicating JUN and FOS in TLR3 regulation. TLR3 stimulation led to elevated IL8. These findings suggest that C. pneumoniae initiates signaling via TLR3 and MAPK that activate AP-1, a known immune activator in other bacteria not previously shown for chlamydiae, triggering inflammation linked to C. pneumoniae disease.
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