Research Article: The Danger Signal Adenosine Induces Persistence of Chlamydial Infection through Stimulation of A2b Receptors

Date Published: December 14, 2009

Publisher: Public Library of Science

Author(s): Matthew A. Pettengill, Verissa W. Lam, David M. Ojcius, Jean Kanellopoulos.

Abstract: Infections with intracellular bacteria such as chlamydiae affect the majority of the world population. Infected tissue inflammation and granuloma formation help contain the short-term expansion of the invading pathogen, leading also to local tissue damage and hypoxia. However, the effects of key aspects of damaged inflamed tissues and hypoxia on continued infection with intracellular bacteria remain unknown. We find that development of Chlamydia trachomatis is reversibly retarded by prolonged exposure of infected cells to extracellular adenosine, a hallmark of hypoxia and advanced inflammation. In epithelial cells, this effect was mediated by the A2b adenosine receptor, unique in the adenosine receptor family for having a hypoxia-inducible factor (HIF1-α) binding site at its promoter region, and was dependent on an increase in the intracellular cAMP levels, but was independent of cAMP-dependent protein kinase (PKA). Further study of adenosine receptor signaling during intracellular bacterial infection could lead to breakthroughs in our understanding of persistent infections with these ubiquitous pathogens.

Partial Text: Chlamydia trachomatis species are the leading cause of bacterial sexually transmitted infection and preventable blindness [1]. Chlamydiae are obligate intracellular bacteria which mature and reproduce through a unique biphasic developmental cycle, infecting as metabolically inactive elementary bodies (EBs) and maturing into metabolically active but non-infectious reticulate bodies (RBs), which proliferate before condensing back into infectious EBs to complete the cycle [2]–[4]. Much of the pathology caused during Chlamydia infection is due to the inflammatory response it invokes from the host. The initial innate immune response recruits inflammatory cells and T cells necessary for resolution of infection, which depends heavily on production of IL-12 and IFN-γ [5]. Besides the dominant role of IFN-γ and a TH1 response for clearance of infection in vivo, IFN-γ has been implicated in the development of persistent Chlamydia infection in vitro [6], while other factors that could contribute to persistent pathogenic infection may be released from the infected tissue rather than uninfected immune cells.

To test whether adenosine exposure could affect the outcome of C. trachomatis infection in epithelial cells, we first measured the response to 5′-(N-ethylcarboxamido) adenosine (NECA), which stimulates Gs-coupled ARs. Cervical epithelial cells (HeLa 229) infected with C. trachomatis serovar LGV L2 were treated with NECA, which caused a 90% reduction in reinfectious chlamydiae within a few hours of addition. However, reinfectious bacteria recovered to levels of untreated host-cells by the end of the developmental cycle (Figure S2). This suggests that chlamydial development was substantially interrupted for short times after Gs-coupled AR stimulation, but that the effect was reversible, since chlamydial viability was not significantly affected.

Bacterial persistence has been studied in varied circumstances [15], [16], but may have unique characteristics for intracellular bacterial pathogens [14], [17]. Pathogens which are obligately intracellular typically have significantly reduced genome size and would be expected to have a lower capacity to withstand disruptions to their microenvironment, possibly developing alternate growth or subsistence mechanisms. Many alterations to the microenvironment during chlamydial infection lead to the initiation of a persistence program during which the chlamydiae experience severely diminished growth and modifications of both bacterial and inclusion development, although causative stimulants and the ultrastructural manifestations can vary [14].



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