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Illuminating the hidden power of cell-autonomous immunity

Cell-Autonomous Immunity

In the evolutionary arms race with pathogens, humans have evolved various branches of natural defenses. The most ancient of these is the cell-autonomous immunity, which builds upon the intrinsic capacity of eukaryotic cells to detect invading mi­crobes and to react to the threat by inducing cellular responses that can limit pathogen replication and spread. Beside the induc­tion of micro­bicidal and microbial growth-restricting responses, this also includes the induction of host cell death pro­grams, by which the self-sacrifice of an individual in­fected cell can withdraw the patho­gen from its replicative niche. The significance of the protec­tion con­ferred by these re­sponses is highlighted by the observation that genetic defi­ciencies that compromise their execution can predispose animals to infections with usually non-path­o­genic environmental species. Moreover, many bacteria and viruses actively block cell-autono­mous immune responses, suggesting that the exist­ence of these defenses im­poses strong pres­sure on pathogens to evolve countermeas­ures. Indeed, it can be assumed that a microbe’s ability to suppress cell-autonomous immunity is a key determinant of its pathogenic poten­tial and likely also its host range, tis­sue tropism, and disease spec­trum.

 

Research Aims

The Sixt lab strives to apply state-of-the-art tools in mo­lecular genetics, microscopic imaging, high-throughput screening, and next generation sequencing technology to uncover the hid­den protective potential of pathogen-suppressed cellular defense path­ways, to identify the mo­lecular determinants of host de­fense and pathogenic countermeasures, and to find means to disturb their balance to the ben­efit of the host.

 

research aims

 

Experimental Model

Our main experimental model is the interaction of human cells with the obligate intracellular bacterial pathogen Chlamydia trachomatis. There are several reasons that make this species a particularly attractive sys­tem for studies on cell-autonomous immunity. First, C. trachomatis is a significant hu­man pathogen. It is one of the leading causes of preventable blindness and the most frequent bacterial agent of sexually transmitted disease with over 100 million annual new cases. Second, their obligate intra­cellular lifestyle and their developmental cycle, during which the bacteria alternate between the replicative reticulate body (RB) and the infec­tious elementary body (EB), make Chla­mydia spp. par­ticularly dependent on their host cell and thus a prominent target for cell-autonomous immunity. And third, in the light that molecu­lar genetic analyses in obligate intracellular bacteria are still chal­lenging and rarely applied, the recent “genetic revo­lu­tion” in the Chlamydia field, which for the first time enables us to generate and study mutant Chlamydia strains, offers unique possibili­ties to dis­cover so far unex­plored mechanisms of host-pathogen interac­tion.

Chlamydia infected cells cropped

Human epithelial cells infected with the intracellular bacterial pathogen Chlamydia trachomatis (bacteria (green), host cell nuclei (red), host cytoplasmic pathogen-associated molecular pattern sensor protein STING (white); confocal fluorescence microscopic image)

 

Significance

A better understanding of the protective significance and the molecular mechanisms of cell-autonomous immune responses will facilitate a better assessment of their suitability as drug targets and will thus pave the way for the development of innovative new treatment regi­mens that exploit our cell-intrinsic defenses to fight infectious disease.

 

 

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