No description available.

No description available.

No description available.

No description available.

Giardia lamblia undergoes antigenic variation of variant-specific surface proteins (VSPs) that are encoded by a family of ~150 vsp genes only one of which is expressed at a time. The vsp gene promoters have not been previously studied. A comparison of the upstream non-coding region of vsp genes shows that they lack the AT-rich regions found in other Giardia gene promoters. We have determined that the core promoters of vsp A6 and vsp C5 genes extend from -57 to + 6 and -50 to + 6 respectively. Through linker scanning analysis, we have also identified regions within the vsp A6 core promoter important for promoter activity that span -7-3, -12-8, -17-13 and -42-38.There is no sequence similarity in the upstream regions of the previously characterized vsp genes that were analyzed, with the exception of a seven nucleotide region that encompasses the translation initiation site: Py A A T G T T. We have demonstrated that the four nucleotides flanking the start codon are essential for promoter activity. This result suggests that it may be an Inr element, which by definition determines the site of transcription initiation. In addition, this element loosely resembles the metazoan Inr consensus: Py Py A A/T Py Py. Using 5′ RACE I have determined that for two vsp genes, the translation and transcription start sites are synonymous and reside within this conserved element. However, we were unable to identify protein factors that bind this region using electrophoretic mobility shift assays.A search for characteristic VSP motifs, such as CRGKA, amongst identified ORFs in the Giardia genome assembly in turn identified 180 ORFs which may be VSPs. Eighty one of these are found within contigs while 99 of these are found at contig and 80 ORFs have the Inr element identified in this study.This study supports the hypothesis that longer upstream non-coding regions of vsp genes play a role in regulating the expression of these genes and hence antigenic variation in G. lamblia.

Interest in the study of antiviral substances stems from the fact that classical chemotherapy as it is known in bacterial diseases has thus far not been successful in the field of viral diseases. However, any proven antiviral agent is a potential drug against virus infection. Although the ultimate goal of effective chemotherapy of virus infections may or may not be attained, information concerning such substances may provide clues to the nature of host-virus interactions and help to elucidate the patterns of the pathogenesis of virus diseases (Zimmermann and Schafer, 1960; Melnick and Rapp, 1965) and also to afford tools for the classification of viruses (Tamm and Eggers, 1962; Barry et al., 1962). [...]

The Citrobacter rodentium genome sequence contains a phoPQ operonhomologous (~79% identity) to that of S. typhimurium. We report that C. rodentiumPhoQ senses fluctuations in Mg2+ concentrations and acidic pH. Surprisingly, PhoQwas not activated by the presence of AMPs. However, activation by AMPs is observedwhen C. rodentium PhoP/PhoQ was expressed in as. typhimurium background. Weidentified an outer membrane protease of the omptin family that was responsible forinhibiting PhoQ activation by AMPs. In stark contrast to S. typhimurium, which relieson LPS modifications to resist AMPs, our results suggest that C. rodentium promotesresistance through a PhoP/PhoQ-dependent OM protease to inhibit disruption of theouter membrane by AMPs . / La séquence du génome de Citrobacter rodentium présente un opéron phoPQ(~79% identité) homologue à celui de S. typhimurium. Nous avons déterminé quePhoQ de C. rodentium perçoit les variations de pH et en Mg2+ du milieu environnant.De manière surprenante, les PAMs ne causent aucune augmentation d'activité dePhoQ. Néeanmoins, lorsque le système PhoP/PhoQ de C. rodentium est exprimé chezS. typhimurium les PAMs activent PhoQ. Nous avons identifié une protéine de lamembrane externe appartenant à la famille des omptin qui est responsable del'inactivité de PhoQ en présence des P AMs. Ces résultats suggèrent que le mécanismede résistance aux PAMs de C. rodentium serait régulé par le système PhoP/PhoQ et une protéase qui empêcherait la destruction de la membrane externe par les P AMs. Cemécanisme de défense est différent de celui du système PhoP/PhoQ de S. typhimuriumqui repose essentiellement sur des modification du LPS .

No description available.

<p> Flaviviruses are a diverse group of emerging arboviruses capable of infecting an extraordinarily broad range of vertebrate and invertebrate hosts. Nearly half of the viruses in this rapidly expanding genus have been reported to be pathogenic for humans, as well as other vertebrates. The spectrum of human disease includes asymptomatic and febrile illnesses, rash, arthralgia, encephalitis and hemorrhagic fever. The recent outbreak of Zika virus (ZIKV) has uncovered pathology in the form of microcephaly and Guillain-Barr&eacute; syndrome, cementing the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) antiviral responses in order to replicate and cause disease in vertebrates. The non-structural protein NS5 is a potent and specific antagonist of IFN signaling for human pathogenic flaviviruses such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis viruses (TBEVs). Intriguingly, each of these viruses exhibits different mechanisms of IFN antagonism, highlighting the complicated evolutionary nature of flaviviruses. This thesis work presents novel insights into the NS5-mediated antagonism of IFN signaling for several underexamined flaviviruses. Notably, all NS5 proteins examined were able to inhibit IFN-induced gene expression in a mammalian system, indicating a functional conservation of IFN antagonism for flavivirus NS5 proteins. However, mechanistically NS5 function was diverse. Of great interest, ZIKV NS5 bound to the human, but not mouse, IFN-regulated transcriptional activator STAT2 and targeted it for proteasomal degradation. This phenomenon may explain the requirement for IFN deficiency in order to observe ZIKV pathogenesis in mice. Furthermore, the mechanism of ZIKV NS5 resembles that of DENV NS5, but not that of its closer relative Spondweni virus (SPOV). However, unlike DENV NS5, ZIKV NS5 did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Consequently, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. The potent antagonism of human IFN responses by neglected flaviviruses such as SPOV and Usutu virus (USUV), coupled with similar ecologies to that of known human flavivirus pathogens, suggests their potential for broad emergence into the human population.</p><p>

<p> Bacterial strains from the <i>Mycobacterium tuberculosis</i> complex (MTBC) are functionally diverse and vary in both geographic distribution and potential to cause tuberculosis (TB) disease. <i>Mycobacterium africanum </i>&mdash;a lineage of the MTBC&mdash;is restricted to West Africa and causes slower progression to active tuberculosis (TB) after initial infection than other MTBC lineages. We hypothesized that this may be partly due to how bacterial strains from these lineages interact with the host immune response. Specifically, we predicted that <i>M. africanum</i> would induce less of the innate cytokine type I interferon because type I interferon has been shown to contribute to TB disease. Our studies focused on (1) whether diverse MTBC strains induce distinct levels of type I interferon in host cells, (2) the mechanism underlying differential type I interferon induction by diverse MTBC strains, and (3) the consequences of the type I interferon response during infection with diverse MTBC strains. We found that <i>M. africanum</i> induced less mitochondrial stress, less release of mitochondrial DNA and less cGAS- and STING-dependent type I interferon in macrophages than other <i> M. tuberculosis</i> strains. Furthermore, we found that <i> M. africanum</i> contained a polymorphism in the Esx-1 gene locus and was unable to secrete the virulence factor EspB through the Esx-1 secretion system, which may contribute to the reduced type I interferon induction by this strain. Finally, we found that type I interferon signaling was pathogenic during chronic <i>M. africanum</i> infection in mice, and thus that the ability to induce pathogenic levels of type I interferon is likely widespread in MTBC strains. Our data suggest that reduced mitochondrial stress and reduced type I interferon induction may contribute to the attenuation of <i> M. africanum</i>. Moreover, our data show that treatments that limit type I interferon induction could be effective in treating diverse mycobacterial infections. Therefore our studies provide insight into a mycobacterial virulence mechanism and highlight the importance of studying diverse clinical isolates of <i>M. tuberculosis</i>.</p><p>