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Infection and Immunity, January 2009, p. 21-22, Vol. 77, No. 1
0019-9567/09/$08.00+0 doi:10.1128/IAI.01403-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
| SPOTLIGHT |
Articles of Significant Interest Selected from This Issue by the Editors
New Innate Immune System Contributions to Colonization Resistance against Salmonella enterica Serovar TyphimuriumResistance of the mammalian gut to bacterial pathogens involves the innate immune system and a poorly understood role of the commensal microbiota in eliciting colonization resistance. Little is known about how these two protective mechanisms work separately or in concert with each other. Ashkar et al. (p. 214-222) used a multipronged approach involving interleukin-15 (IL-15) knockout mice, in vivo depletion of NK1.1+ cells from wild-type mice, and in vivo overexpression of IL-15 from a recombinant adenovirus to show that IL-15 and NK1.1+ cells are required to protect the murine gut from Salmonella enterica serovar Typhimurium, even in the presence of the commensal microbiota. This work suggests that the genetic background of the host influences innate colonization resistance.
Prolonged Activation of Prosurvival Kinases by Coxiella burnetii Promotes Survival of Macrophage Host Cells
Infection by the Q fever agent, Coxiella burnetii, confers a potent antiapoptotic effect on both macrophages and epithelial cells. Voth and Heinzen (p. 205-213) demonstrate both early and sustained activation (i.e., phosphorylation) of the prosurvival kinases Akt and Erk1/2 following C. burnetii infection of macrophages. Sustained activation is unusual as these kinases are normally quickly dephosphorylated following the transient activation associated with uptake of other pathogens. Treatment of infected cells with antagonists of Akt and Erk1/2 diminishes C. burnetii's antiapoptotic effect, suggesting that continual prosurvival signalling by these kinases is important for maintaining host cell viability for the duration of C. burnetii's lengthy infectious cycle.
Hypervirulence through Gene Quieting
Cryptococcus neoformans can undergo phenotypic switching to generate hypervirulent mucoid variants. Jain et al. (p. 128-140 ) report that such switching involves down regulation of several genes, including that encoding allergen 1 (ALL1). The biological relevance of this down regulation is supported by the fact that all1
strains mimic the hypervirulent mucoid phenotype. ALL1 has T-cell epitopes and is involved in capsule formation. Loss of ALL1 function affects virulence by altering the inflammatory response and virulence. This study provides new insights into the ability of this fungus to evade the human immune response and identifies down regulation of gene function by phenotypic switching as a virulence mechanism, which is reminiscent of antivirulence genes in other pathogens.
Chlamydia trachomatis Polymorphic Membrane Protein D Is an Oligomeric Type V Autotransporter
The type V secretion, or autotransporter (AT), pathway is a ubiquitous mechanism employed by gram-negative bacteria to deliver virulence factors important for pathogenesis. Swanson et al. (p. 508-516) show that Chlamydia trachomatis AT polymorphic protein D (PmpD) is a higher-order 23-nm flowerlike oligomer that appears as projections on the chlamydial surface. They also present novel findings showing that PmpD exists in infected cells as proteolytically derived soluble fragments that possess eukaryote-interacting motifs, implicating them in secondary functions important to chlamydial pathogenesis. These newly defined structures may represent novel targets for future vaccine or drug-based intervention.
Evidence for a Role of Monocytes in Dissemination and Brain Invasion by Cryptococcus neoformans
Brain invasion represents the key issue in the pathogenesis of cryptococcosis. Whether C. neoformans crosses the blood-brain barrier using a transcellular route through the endothelial cells or a paracellular route either as free yeasts or in monocytes (the "Trojan horse" hypothesis) remains controversial. Charlier et al. (p. 120-127) use different approaches, including infection of mice with bone marrow-derived monocytes loaded with yeasts in vitro or depletion of the phagocyte population of infected mice by clodronate injection, to demonstrate that monocytes participate in blood-brain barrier crossing and dissemination by C. neoformans. The monocyte subversion reported here appears to be another effective tool for C. neoformans to escape the host defenses. These results could impact future vaccine development since antibodies to capsular antigens could promote organ dissemination with these "Trojan horses."
T-Cell Responses to the Trypanosome Variant Surface Glycoprotein Are Not Limited to Hypervariable Subregions
Polarized Th1-cell responses directed against the variant surface glycoprotein (VSG) of African trypanosomes have been linked to host resistance. Dagenais et al. (p. 141-151) provide the first identification of T-cell reactive sites in a trypanosome VSG. The results show that variant-specific Th1-cell reactive sites are distributed throughout the N-terminal domain and are not clustered exclusively within hypervariable subregions of VSG, as suggested from early sequence and structural studies. Additionally, they show that T cells do not recognize residues within the relatively conserved C-terminal domain. Overall this study reveals the molecular basis of VSG specificity displayed by Th1 cells and provides an experimental basis for inducing cross-protective T-cell responses against conserved residues within the VSG C-terminal domain.
The Cytoplasmic Domain of an Anthrax Toxin Receptor Influences Toxin Binding
The interaction between the protective antigen component of anthrax toxin and its receptors exhibits similiarities to how integrins bind their ligands. Go et al. (p. 52-59) now show that, similarly to integrins, anthrax toxin receptor 1 can exist in different affinity states that are functionally linked to its cytoplasmic domain. This work suggests that cytoplasmic signals may alter the susceptibility of cells to intoxication.
Infection and Immunity, January 2009, p. 21-22, Vol. 77, No. 1
0019-9567/09/$08.00+0 doi:10.1128/IAI.01403-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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