scholarly journals The rovA Mutant of Yersinia enterocolitica Displays Differential Degrees of Virulence Depending on the Route of Infection

2003 ◽  
Vol 71 (6) ◽  
pp. 3512-3520 ◽  
Author(s):  
Peter H. Dube ◽  
Scott A. Handley ◽  
Paula A. Revell ◽  
Virginia L. Miller
Keyword(s):  
Yersinia Enterocolitica ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Systemic Disease ◽  
Lethal Dose ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Wild Type ◽  
Global Regulator ◽  
Kinetics Of

ABSTRACT Yersinia enterocolitica is an invasive enteric pathogen that causes significant inflammatory disease. Recently, we identified and characterized a global regulator of virulence (rovA). When mice are infected orally with the rovA mutant they are attenuated by 50% lethal dose (LD50) analysis and have altered kinetics of infection. Most significantly, mice orally infected with the rovA mutant have greatly reduced inflammation in the Peyer's patches compared to those infected with wild-type Y. enterocolitica. However, we present data here indicating that when the rovA mutant bacteria are delivered intraperitoneally (i.p.), they are significantly more virulent than when delivered orally. The i.p. LD50 for the rovA mutant is only 10-fold higher than that of the wild-type Y. enterocolitica, and there are significant inflammatory responses to the rovA mutant that are evident in the liver and spleen. Altogether, these data suggest that the RovA regulon may be required for the early events of the infection that occur in the Peyer's patches. Furthermore, these data suggest that the RovA regulon may be dispensable for Y. enterocolitica systemic disease and inflammatory responses if the Peyer's patches are bypassed.

scholarly journals Salmonella Exploits Caspase-1 to Colonize Peyer's Patches in a Murine Typhoid Model

2000 ◽  
Vol 192 (2) ◽  
pp. 249-258 ◽  
Author(s):  
Denise M. Monack ◽  
David Hersh ◽  
Nafisa Ghori ◽  
Donna Bouley ◽  
Arturo Zychlinsky ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mammalian Cells ◽  
Yersinia Pseudotuberculosis ◽  
Lethal Dose ◽  
Cysteine Proteases ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Wild Type ◽  
M Cell ◽  
Caspase 1

Salmonella typhimurium invades host macrophages and induces apoptosis and the release of mature proinflammatory cytokines. SipB, a protein translocated by Salmonella into the cytoplasm of macrophages, is required for activation of Caspase-1 (Casp-1, an interleukin [IL]-1β–converting enzyme), which is a member of a family of cysteine proteases that induce apoptosis in mammalian cells. Casp-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines IL-1β and IL-18 to produce bioactive cytokines. We show here that mice lacking Casp-1 (casp-1−/− mice) had an oral S. typhimurium 50% lethal dose (LD50) that was 1,000-fold higher than that of wild-type mice. Salmonella breached the M cell barrier of casp-1−/− mice efficiently; however, there was a decrease in the number of apoptotic cells, intracellular bacteria, and the recruitment of polymorphonuclear lymphocytes in the Peyer's patches (PP) as compared with wild-type mice. Furthermore, Salmonella did not disseminate systemically in the majority of casp-1−/− mice, as demonstrated by significantly less colonization in the PP, mesenteric lymph nodes, and spleens of casp-1−/− mice after an oral dose of S. typhimurium that was 100-fold higher than the LD50. The increased resistance in casp-1−/− animals appears specific for Salmonella infection since these mice were susceptible to colonization by another enteric pathogen, Yersinia pseudotuberculosis, which normally invades the PP. These results show that Casp-1, which is both proapoptotic and proinflammatory, is essential for S. typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice.

scholarly journals The Proinflammatory Response Induced by Wild-Type Yersinia pseudotuberculosis Infection Inhibits Survival of yop Mutants in the Gastrointestinal Tract and Peyer's Patches

2006 ◽  
Vol 74 (3) ◽  
pp. 1516-1527 ◽  
Author(s):  
Lauren K. Logsdon ◽  
Joan Mecsas
Keyword(s):  
Yersinia Pseudotuberculosis ◽  
Intestinal Inflammation ◽  
Peyer's Patches ◽  
Host Responses ◽  
Infection Model ◽  
Peyer’S Patches ◽  
Wild Type ◽  
Single Strain ◽  
Infection Models ◽  
Ifn Γ

ABSTRACT Single-strain infections and coinfections are frequently used to assess roles of virulence factors in infected tissues. After oral inoculation of mice, Yersinia pseudotuberculosis yopE and yopH mutants colonize the intestines and Peyer's patches in single-strain infections but fail to persist in competition with wild-type Y. pseudotuberculosis, indicating that these two infection models provide different insights into the roles of Yops. To determine how wild-type Y. pseudotuberculosis hinders yop mutant survival, yop mutant colonization and host responses were investigated in several different infection models that isolated specific features of wild-type Y. pseudotuberculosis infection. Infection with wild-type Y. pseudotuberculosis caused significantly more inflammation than yop mutants. Results from coinfections of gamma interferon (IFN-γ)−/− mice revealed that IFN-γ-regulated defenses target these mutants, suggesting that YopE and YopH protect Y. pseudotuberculosis from these defenses in BALB/c mice. We developed an oral-intraperitoneal infection model to evaluate the effects of spleen and liver colonization by Y. pseudotuberculosis on yop mutants in the intestines. Spleen and liver infection increased inflammation and decreased yop mutant survival in the intestines, indicating that infection of these organs has consequences in intestinal tissues. Finally, competition infections with Y. pseudotuberculosis mutants with various abilities to induce inflammation demonstrated that survival of the yopE, but not the yopH, mutant was consistently decreased in inflamed tissues. In summary, infection with Y. pseudotuberculosis in intestinal and systemic sites induces intestinal inflammation, which decreases yop mutant survival. Thus, competition studies with wild-type yersiniae reveal critical roles of Yops in combating host responses to a normal virulent infection.

scholarly journals Listeria monocytogenes Phospholipase C-Dependent Calcium Signaling Modulates Bacterial Entry into J774 Macrophage-Like Cells

1999 ◽  
Vol 67 (4) ◽  
pp. 1770-1778 ◽  
Author(s):  
Sandra J. Wadsworth ◽  
Howard Goldfine
Keyword(s):  
Listeria Monocytogenes ◽  
Calcium Signaling ◽  
Phospholipase C ◽  
Virulence Factors ◽  
Intracellular Signaling ◽  
Lethal Dose ◽  
Listeriolysin O ◽  
Wild Type ◽  
J774 Macrophage ◽  
Kinetics Of

ABSTRACT Listeria monocytogenes secretes several proteins that have been shown to contribute to virulence. Among these is listeriolysin O (LLO), a pore-forming hemolysin that is absolutely required for virulence. Two other virulence factors are phospholipases: a phosphatidylinositol-specific phospholipase C (PI-PLC [plcA]) and a broad-range PLC (plcB). Although mutations in plcA or plcB resulted in small increases in mouse 50% lethal dose (LD50), deletions in both genes resulted in a 500-fold increase in LD50. We have examined the role of these secreted proteins in host intracellular signaling in the J774 macrophage-like cell line. Measurements of cytosolic free calcium ([Ca2+]i) have revealed a rapid spike upon exposure of these cells to wild-typeL. monocytogenes. This is followed by a second peak at 5 min and a third prolonged peak with a maximal [Ca2+]i of 800 to 1,000 nM. The pattern of calcium changes was greatly altered by deletion of any of the three virulence factors. An LLO mutant produced none of these elevations in [Ca2+]i; however, a transient elevation was observed whenever these bacteria entered the cell. A PI-PLC mutant produced a diminished single elevation in [Ca2+]i at 15 to 30 min. A broad-range PLC mutant produced only the first calcium spike. Studies with inhibitors suggested that the first elevation arises from influx of calcium from the extracellular medium through plasma membrane channels and that the second and third elevations come from release of Ca2+ from intracellular stores. We observed that internalization of wild-type bacteria and the broad-range PLC mutant was delayed for 5 to 10 min, but the LLO and PI-PLC mutants were internalized rapidly upon infection. Inhibitors that affected calcium signaling changed the kinetics of association of wild-type bacteria with J774 cells, the kinetics of entry, and the efficiency of escape from the primary phagosome.

scholarly journals Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches

2002 ◽  
Vol 196 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Takaharu Okada ◽  
Vu N. Ngo ◽  
Eric H. Ekland ◽  
Reinhold Förster ◽  
Martin Lipp ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Chemokine Receptor ◽  
Cell Entry ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Wild Type ◽  
High Endothelial Venules ◽  
Cell Homing ◽  
T Cell Homing

B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4−/− B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We also find that CXCR4 can contribute to T cell homing. Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized. In Peyer's patches, B cell entry is dependent on CXCR5 in addition to CCR7/CXCR4. CXCL12 (SDF1) is displayed broadly on HEVs, whereas CXCL13 (BLC) is found selectively on Peyer's patch follicular HEVs. These findings establish the principal chemokine and chemokine receptor requirements for B cell entry to lymph nodes and Peyer's patches.

scholarly journals Protective Role of Interleukin-6 during Yersinia enterocolitica Infection Is Mediated through the Modulation of Inflammatory Cytokines

2004 ◽  
Vol 72 (6) ◽  
pp. 3561-3570 ◽  
Author(s):  
Peter H. Dube ◽  
Scott A. Handley ◽  
James Lewis ◽  
Virginia L. Miller
Keyword(s):  
Yersinia Enterocolitica ◽  
Inflammatory Cytokines ◽  
Bacterial Infections ◽  
Transforming Growth Factor ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Lethal Dose ◽  
T Cell Response ◽  
Cytokine Signaling

ABSTRACT Yersinia enterocolitica is a gram-negative enteric pathogen responsible for a number of gastrointestinal disorders. A striking feature of the pathology of a Y. enterocolitica infection is inflammation. Recently, we demonstrated a role for interleukin-1α (IL-1α) in the establishment of intestinal inflammation in response to a Y. enterocolitica infection. A cytokine directly affected by IL-1 levels is IL-6. A previous report suggested that IL-6 plays an anti-inflammatory role during Y. enterocolitica infection, and in other systems IL-6 has been shown to be proinflammatory. Therefore, a closer examination of the roles of IL-6 and inflammatory cytokines in the control of Y. enterocolitica infection in IL-6−/− mice was undertaken. Y. enterocolitica organisms were more virulent in the IL-6−/− mice (60-fold decreased 50% lethal dose) and colonized systemic tissues more rapidly and to a higher level than in the wild-type mice. One role of IL-6 during a Y. enterocolitica infection may be the downmodulation of the inflammatory response. The IL-6−/− mice have a more robust TH1 T-cell response, as well as hyperinflammatory pathologies. These phenotypes appear to be due to the misregulation of tumor necrosis factor alpha, monocyte chemotactic protein 1, IL-10, transforming growth factor β1, and gamma interferon in the IL-6−/− mouse. These data provide further insight into the intricate cytokine signaling pathways involved in the regulation of inflammatory responses and the control of bacterial infections.

scholarly journals Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells

2015 ◽  
Vol 90 (3) ◽  
pp. 1499-1506 ◽  
Author(s):  
Abimbola O. Kolawole ◽  
Mariam B. Gonzalez-Hernandez ◽  
Holly Turula ◽  
Chenchen Yu ◽  
Michael D. Elftman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Peyer's Patches ◽  
Epithelial Barrier ◽  
Target Cells ◽  
Lymphoid Tissues ◽  
Peyer’S Patches ◽  
M Cells ◽  
Intestinal Epithelial ◽  
Wild Type ◽  
Intestinal Epithelial Barrier

ABSTRACTA critical early step in murine norovirus (MNV) pathogenesis is crossing the intestinal epithelial barrier to reach the target cells for replication, i.e., macrophages, dendritic cells, and B cells. Our previous work showed that MNV replication decreases in the intestines of mice conditionally depleted of microfold (M) cells. To define the importance of Peyer's patch (PP) M cells during MNV pathogenesis, we used a model of BALB/c mice deficient in recombination-activating gene 2 (Rag2) and the common gamma chain (γc) (Rag-γc−/−), which lack gut-associated lymphoid tissues (GALT), such as Peyer's patches, and mature GP2+M cells. Rag-γc−/−mice were infected intraperitoneally or perorally with MNV-1 or CR3 for 24 or 72 h. Although the intestinal laminae propriae of Rag-γc−/−mice have a higher frequency of certain MNV target cells (dendritic cells and macrophages) than those of wild-type mice and lack others (B cells), Rag-γc−/−and wild-type BALB/c mice showed relatively similar viral loads in the intestine following infection by the intraperitoneal route, which provides direct access to target cells. However, Rag-γc−/−mice were not productively infected with MNV by the oral route, in which virions must cross the intestinal epithelial barrier. These data are consistent with a model whereby PP M cells are the primary route by which MNV crosses the intestinal epithelia of BALB/c mice.IMPORTANCENoroviruses (NoVs) are prevalent pathogens that infect their hosts via the intestine. Identifying key factors during the initial stages of virus infection in the host may provide novel points of intervention. Microfold (M) cells, antigen-sampling cells in the intestine, were previously shown to provide a gateway for murine NoV (MNV) into the host, but the relative importance of this uptake pathway remained unknown. Here we show that the absence of gut-associated lymphoid tissues (GALT), such as Peyer's patches, which contain high numbers of mature M cells, renders BALB/c mice refractory to oral infection with MNV. These findings are consistent with the model that M cells represent the primary route by which MNV crosses the intestinal epithelial barrier and infects underlying immune cells during a productive infection.

scholarly journals Superantigen YPMa Exacerbates the Virulence ofYersinia pseudotuberculosis in Mice

2000 ◽  
Vol 68 (5) ◽  
pp. 2553-2559 ◽  
Author(s):  
Christophe Carnoy ◽  
Chantal Mullet ◽  
Heide Müller-Alouf ◽  
Emmanuelle Leteurtre ◽  
Michel Simonet
Keyword(s):  
Yersinia Pseudotuberculosis ◽  
Systemic Infection ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Wild Type ◽  
Bacterial Inoculation ◽  
Mesenteric Lymph Nodes ◽  
Strain Determination ◽  
Mouse Model Of Infection

ABSTRACT Yersinia pseudotuberculosis, a gram-negative bacterium responsible for enteric and systemic infection in humans, produces a superantigenic toxin designated YPMa (Y. pseudotuberculosis-derived mitogen). To assess the role of YPMa in the pathogenesis of Y. pseudotuberculosis, we constructed a superantigen-deficient mutant and compared its virulence in a mouse model of infection to the virulence of the wild-type strain. Determination of the survival rate after intravenous (i.v.) bacterial inoculation of OF1 mice clearly showed that inactivation ofypmA, encoding YPMa, reduced the virulence of Y. pseudotuberculosis. Mice infected i.v. with 104 and 105 wild-type bacteria died within 9 days, whereas mice infected with the ypmA mutant survived 12 and 3 days longer, respectively. This decreased virulence of the ypmAmutant strain was not due to an impaired colonization of the spleen, liver, or lungs. In contrast to i.v. challenge, bacterial inoculation by the intragastric (i.g.) route did not reveal any difference in virulence between wild-type Y. pseudotuberculosis and theypmA mutant since the 50% lethal doses were identical for both strains. Moreover, inactivation of ypmA gene did not affect the bacterial growth of Y. pseudotuberculosis in Peyer's patches, mesenteric lymph nodes (MLNs), and spleen after oral infection. Histological studies of spleen, liver, lungs, heart, Peyer's patches, and MLNs after i.v. or i.g. challenge with the wild type or the ypmA mutant did not reveal any feature that can be specifically related to YPMa. Our data show that the superantigenic toxin YPMa contributes to the virulence of Y. pseudotuberculosis in systemic infection in mice.

scholarly journals Yersinia enterocolitica YopH-Deficient Strain Activates Neutrophil Recruitment to Peyer's Patches and Promotes Clearance of the Virulent Strain

2016 ◽  
Vol 84 (11) ◽  
pp. 3172-3181 ◽  
Author(s):  
Mabel N. Dave ◽  
Juan E. Silva ◽  
Ricardo J. Eliçabe ◽  
María B. Jeréz ◽  
Verónica P. Filippa ◽  
...  
Keyword(s):  
Mutant Strain ◽  
Yersinia Enterocolitica ◽  
Oral Vaccine ◽  
Bacterial Load ◽  
Neutrophil Recruitment ◽  
Peyer's Patches ◽  
Host Cells ◽  
Peyer’S Patches ◽  
Content Type ◽  
Blood Neutrophils

Yersinia enterocoliticaevades the immune response by injectingYersiniaouter proteins (Yops) into the cytosol of host cells. YopH is a tyrosine phosphatase critical forYersiniavirulence. However, the mucosal immune mechanisms subverted by YopH duringin vivoorogastric infection withY. enterocoliticaremain elusive. The results of this study revealed neutrophil recruitment to Peyer's patches (PP) after infection with a YopH-deficient mutant strain (Y. enterocoliticaΔyopH). While theY. enterocoliticawild-type (WT) strain in PP induced the major neutrophil chemoattractant CXCL1 mRNA and protein levels, infection with theY. enterocoliticaΔyopHmutant strain exhibited a higher expression of the CXCL1 receptor, CXCR2, in blood neutrophils, leading to efficient neutrophil recruitment to the PP. In contrast, migration of neutrophils into PP was impaired upon infection withY. enterocoliticaWT strain.In vitroinfection of blood neutrophils revealed the involvement of YopH in CXCR2 expression. Depletion of neutrophils duringY. enterocoliticaΔyopHinfection raised the bacterial load in PP. Moreover, the clearance of WTY. enterocoliticawas improved when an equal mixture ofY. enterocoliticaWT andY. enterocoliticaΔyopHstrains was used in infecting the mice. This study indicates thatY. enterocoliticaprevents early neutrophil recruitment in the intestine and that the effector protein YopH plays an important role in the immune evasion mechanism. The findings highlight the potential use of theY. enterocoliticaYopH-deficient strain as an oral vaccine carrier.

scholarly journals Comparison of Tissue-Selective Proinflammatory Gene Induction in Mice Infected with Wild-Type, DNA Adenine Methylase-Deficient, and Flagellin-Deficient Salmonella enterica

2007 ◽  
Vol 75 (12) ◽  
pp. 5627-5639 ◽  
Author(s):  
Raphael Simon ◽  
Douglas M. Heithoff ◽  
Michael J. Mahan ◽  
Charles E. Samuel
Keyword(s):  
Immune Response ◽  
Bacterial Load ◽  
Gene Induction ◽  
Peyer's Patches ◽  
Host Gene ◽  
Peyer’S Patches ◽  
Wild Type ◽  
Dna Adenine Methylase ◽  
Proinflammatory Gene ◽  
Interferon System

ABSTRACT Mutants of Salmonella enterica serovar Typhimurium deficient in DNA adenine methylase (Dam) are attenuated for virulence in mice and confer heightened immunity in vaccinated animals. In contrast, infection of mice with wild-type (WT) strains or flagellin-deficient mutants of Salmonella causes typhoid fever. Here we examined the bacterial load and spatiotemporal kinetics of expression of several classes of host genes in Peyer's patches, the liver, and the spleen following oral infection of mice with WT, dam mutant, or flagellin-deficient (flhC) Salmonella. The genes evaluated included inflammatory (interleukin-1β [IL-1β], tumor necrosis factor alpha), chemokine (macrophage inflammatory protein 2), Th1/Th2 indicator (IL-12p40, IL-4), and interferon system (beta interferon [IFN-β], IFN-γ, protein Mx1 GTPase, RNA-dependent protein kinase, inducible nitric oxide synthase, suppressor of cytokine signaling 1) beacons. We showed that maximal interferon system and proinflammatory gene induction occurred by 5 days after infection and that the levels were comparable for the WT and flhC strains but were significantly lower for the dam mutant. Additionally, host gene expression in systemic tissues of individual animals was dependent on the bacterial load in the Peyer's patches for mice infected with WT, dam mutant, or flhC mutant Salmonella as early as 8 h after infection. Moreover, a bacterial load threshold in the Peyer's patches was necessary to stimulate the host gene induction in the liver and spleen. Taken together, these results suggest that bacterial load and the accompanying strain-specific cytokine signature are important determinants of the host innate immune response and associated disease manifestations observed in dam mutant Salmonella-infected animals compared to the immune response and disease manifestations observed in WT and flhC mutant Salmonella-infected animals.

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