You can find a couple of key human pathogens in the family of Chlamydiaceae. Distinct serovars of Chlamydia trachomatis result in sexually-transmitted disease and eye infections whereas C. pneumoniae (TWAR) is a typical reason behind community-acquired respiratory infection. Chlamydia species are obligate, intracellular bacteria sharing a specialized developing cycle which happens inside a guarded vacuole known as an inclusion. These organisms could be recognized by 2 different types: the infectious, metabolically inert elementary body (EB) and the reproducing non-infectious type, known as the reticulate body (RB). The cycle is finished when re-differentiation of RBs back to infectious EBs occurs. Chlamydia contains a type III secretion system (T3SS) required for delivery of effector proteins in to the host for host-cell interactions. This virulence system appears to have been carefully recognized in a number of mammalian pathogens. On account of deficiency of a tractable genetic system for Chlamydia species, we have to utilize chemical genetics as a technique to examine molecular facets of the T3SS. We have discovered that the T3S-inhibitors INP0010 and INP0400 prevent the developmental period and hinder secretion of T3S effector proteins in C. pneumoniae and C. trachomatis, with virtually no cytotoxic influence. The system controlling the signal(s) for primary in addition to terminal differentiation of RBs is actually not described in Chlamydia. The outcomes indicate the likelihood that C. pneumoniae gets iron through the intracellular trafficking pathway of endocytosed transferrin.
Contents
Additional papers not included in thesis
INTRODUCTION
Chlamydiaceae
Historical view of Chlamydia
TWAR – an orienteer-related disease?
Taxonomy
Structure of Chlamydia in general and C. pneumoniae in particular
Morphology
LPS
Peptidoglycan
Polymorphic membrane proteins
Major outer membrane protein
Heat shock proteins
The developmental cycle
The key players of Chlamydia
Attachment
Internalization
Internalization: Endocytosis – mediated via activation of the actin cytoskeleton
The inclusion – a chlamydial protected site
Inclusion membrane proteins
Primary differentiation and proliferation
Re-differentiation
Exit from the host cell
Bacteria and iron
Chlamydia and iron
Chlamydial persistence
Clinical manifestations
Acute infection
Chronic infection
C. pneumoniae and atherosclerosis
Atherosclerosis
Atherosclerosis and animal models
Lipoprotein (a) as a mouse model for atherosclerosis
C. pneumoniae in atherosclerosis
Antimicrobial trials have questioned the C. pneumoniae infection theory
C. pneumoniae and inflammation of the vascular system
Pro-inflammatory cytokines
C. pneumoniae and pro-inflammatory cytokines
Bacterial infection of bone demonstrates similar cytokine induction as in atherosclerosis
The type three secretion system (T3SS)
Historical observations of a possible T3SS
First evidence of a chlamydial T3SS
Composition of the chlamydial T3S injectisome
Basal apparatus
The Chlamydia translocon
Chaperones of the T3SS
Transcriptional regulation of T3SS chaperones
The needle complex
Gating of T3S machinery
Effector proteins
Other secreted proteins
Extracellular T3SS
Intracellular T3SS
Temporal transcription of T3SS genes
Stress of the T3SS
Antibiotics
Antimicrobial resistance is a global problem
Antibiotic treatment of C. pneumoniae infection
Small molecules
Chemical genetics and small chemical molecules
Small molecules as inhibitors of virulence
Small Molecules and inhibition of T3SS
OBJECTIVES OF THIS THESIS
RESULTS AND DISCUSSION
Paper I
Screening of T3SS inhibitors using Y. pseudotuberculosis T3SS
INP0010 inhibits C. pneumoniae intraceullar propagation…….
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Source: Umea University