Linda Westermark

Umeå University, Umeå, Västerbotten, Sweden

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Publications (4)15.13 Total impact

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    ABSTRACT: Yersiniosis is a human disease caused by the bacteria Yersinia pseudotuberculosis or Y. enterocolitica. The infection is usually resolved, but can lead to post-infectious sequelae, including reactive arthritis and erythema nodosum. The commonly used Yersinia mouse infection model mimics acute infection in humans to some extent, but leads to systemic infection and eventual death. Here, we analyzed sublethal infection doses of Y. pseudotuberculosis in mice in real time using bioluminescent imaging, and found that infections using these lower doses result in extended periods of asymptomatic infections in a fraction of mice. In a search for the site for bacterial persistence, we found that the cecum was the primary colonization site, and was the site where the organism resided during a 115-day infection period. Persistent infection was accompanied by sustained fecal shedding of cultivable bacteria. Cecal patches were identified as the primary site for cecal colonization during persistence. Y. pseudotuberculosis were present in inflammatory lesions, in localized foci, or as single cells, and also in neutrophil exudates in the cecal lumen. The chronically colonized cecum may serve as a reservoir for dissemination of infection to extra-intestinal sites, and a chronic inflammatory state may trigger the onset of post-infectious sequelae. This novel mouse model for bacterial persistence in cecum has potential as an investigative tool to unveil a deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection.
    Infection and Immunity 06/2014; 82(8). DOI:10.1128/IAI.01793-14 · 4.16 Impact Factor
  • Linda Westermark, Anna Fahlgren, Maria Fällman
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    ABSTRACT: The human pathogenic species of the Gram negative Yersiniae genus preferentially target and inactivate cells of the innate immune defense, suggesting this to be a critical step for these bacteria to avoid elimination and cause disease. In this study, bacterial interactions with dendritic cells, macrophages, and polymorphonuclear neutrophils (PMNs) were analyzed in intestinal lymphoid tissues during early Y. pseudotuberculosis infection. Wild-type bacteria were shown to mainly interact with dendritic cells, but not with PMNs, day one post infection, while avirulent yopH and yopE mutants interrelated with PMNs in addition to dendritic cells. To unravel the role of PMNs during the early phase of infection, we depleted PMNs in mice using the α-Ly6G antibody, and could see a more efficient initial colonization by the wild-type strain as well as yopH, yopE, and yopK mutants day one post infection. Dissemination of yopH, yopE, and yopK mutants from the intestinal compartments to mesenteric lymph node was faster in PMN-depleted mice compared with undepleted mice, emphasizing the importance of effective targeting of PMNs by these Yops. In conclusion, escape of interaction with PMNs by the action of YopH, YopE, and YopK is a key feature of pathogenic Yersinia allowing colonization and effective dissemination.
    Infection and immunity 12/2013; DOI:10.1128/IAI.01634-13 · 4.16 Impact Factor
  • Linda Westermark, Anna Fahlgren, Maria Fällman
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    ABSTRACT: Dendritic cells play an important role in the immune response against pathogens, as they are responsible for the activation and control of both innate and adaptive immune responses. The CD11c-DTR(tg) model, which allows transient elimination of dendritic cells by diphtheria toxin-treatment (DTx), has been extensively used to study the importance of this immune cell during steady-state and infection conditions in mice. Infecting dendritic cell-depleted mice orally with Yersinia pseudotuberculosis results in a markedly reduced level of infection compared with infection of non-depleted mice. We show here that it is not the lack of dendritic cells per se that is responsible for the reduced infection efficiency, instead it is an immune response induced by the DTx-treatment that prevents the bacteria from establishing colonization in Peyer's patches. The DTx-induced depletion initiates an immune response, with elevated serum levels of keratinocyte-derived cytokine (KC) and recruitment of polymorphonuclear neutrophils to dendritic cell-containing organs, such as Peyer's patches. Since the window for having an animal depleted of dendritic cells is limited in time for this model, the DTx-mediated effect on the immune system complicates the use of this model in studies of early events during bacterial infections.
    Microbial Pathogenesis 07/2012; 53(3-4):154-61. DOI:10.1016/j.micpath.2012.06.004 · 2.00 Impact Factor
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    ABSTRACT: One important feature of Yersinia pseudotuberculosis that enables resistance against the host immune defence is delivery of the antiphagocytic effectors YopH and YopE into phagocytic cells. The tyrosine phosphatase YopH influences integrin signalling, and YopE impairs cytoskeletal dynamics by inactivating Rho GTPases. Here, we report the impact of these effectors on internalization by dendritic cells (DCs), which internalize antigens to orchestrate host immune responses. We found that this pathogen resists internalization by DCs via YopE. YopH that is important for blocking phagocytosis by macrophages and neutrophils and which is also present inside the DCs does not contribute to the resistance. However, the YopH targets Fyb and p130Cas show higher expression levels in macrophages than in DCs. Furthermore, live cell microscopy revealed that the cells internalize Y. pseudotuberculosis in different ways: the macrophages utilize a locally restricted receptor-mediated zipper mechanism, whereas DCs utilize macropinocytosis involving constitutive ruffling that randomly catches bacteria into membrane folds. We conclude that YopH impacts early phagocytic signalling from the integrin receptor to which the bacterium binds and that this tight receptor-mediated stimulation is absent in DC macropinocytosis. Inactivation of cytoskeletal dynamics by YopE affects ruffling activity and hence also internalization. The different modes of internalization can be coupled to the major functions of these respective cell types: elimination by phagocytosis and antigen sampling.
    Cellular Microbiology 09/2009; 11(12):1750-67. DOI:10.1111/j.1462-5822.2009.01365.x · 4.82 Impact Factor