Innate Immune Bypass of Translation Inhibition Upon Cellular Challenge by Legionella Pneumophila.
Asrat, Seblewongel.
2015
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Abstract: Many
pathogens, particularly those that require their host for survival, have devised
mechanisms to subvert the host immune response in order to survive and replicate
intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease,
promotes intracellular growth by translocating proteins into its host cytosol through
its type IV protein secretion machinery. At ... read moreleast 5 of the bacterial translocated
effectors interfere with the function of host cell elongation factors, blocking
translation and causing the induction of a unique host cell transcriptional profile. In
addition, L. pneumophila also interferes with translation initiation, by preventing
cap-dependent translation in host cells. We demonstrate here that protein translation
inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes
involved in the pathway are transcribed but fail to be translated due to the
bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory
cytokines, such as IL-1α and IL-1β, bypass this inhibition and get
synthesized in the presence of Legionella effectors. We show that the selective
synthesis of these genes requires MyD88 signaling and takes place in both infected cells
that harbor bacteria and neighboring bystander cells. We elucidate the global kinetics
of blockade and identify the spectrum of genes that host cells selectively synthesize
after Legionella significantly alters protein synthesis. Interestingly, one mechanism
that the innate immune system uses to overcome pathogen-induced translation inhibition
is transcript abundance, in which highly transcribed immunity-associated genes, such as
those encoding pro-inflammatory cytokines and chemokines, selectively get translated
under conditions of intoxication. We show that, for some genes, MyD88 plays a crucial
role under such conditions by enhancing the concentration of transcripts above a minimum
threshold necessary to support selective translation. Another mechanism used to overcome
translation inhibition depends on cis-acting mRNA elements, in which upstream open
reading frames (uORFs) within 5' untranslated regions (5'UTR) facilitate translation
reinitiating. Translation inhibition is a common virulence mechanism used by a number of
pathogens (e.g. Diphtheria Toxin, Shiga Toxin and Pseudomonas Exotoxin A). It has been a
mystery how host cells mount a pathogen-specific response and clear infection under
conditions in which protein synthesis is blocked by pathogens. Using Legionella
pneumophila as a model, a bacterium that efficiently blocks the host protein translation
machinery, we show that the innate immune system has devised various mechanisms to cope
with translation inhibition. Our findings elucidate some of these mechanisms and offer a
perspective of how host cells are able to cope with pathogen-encoded activities that
disrupt normal cellular processes and initiate a successful inflammatory
response.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Molecular Microbiology.
Advisor: Ralph Isberg.
Keyword: Microbiology.read less - ID:
- tm70n695v
- Component ID:
- tufts:20249
- To Cite:
- TARC Citation Guide EndNote
