scholarly journals A data-based mathematical modelling study to quantify the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica during treatment and relapse

2020 ◽  
Vol 17 (168) ◽  
pp. 20200299
Author(s):  
Myrto Vlazaki ◽  
Omar Rossi ◽  
David J. Price ◽  
Callum McLean ◽  
Andrew J. Grant ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Bacterial Infections ◽  
Post Treatment ◽  
Lymphoid Tissues ◽  
Detailed Knowledge ◽  
Antibiotic Administration ◽  
Mesenteric Lymph Nodes ◽  
Bacterial Populations ◽  
Spatio Temporal

Antibiotic therapy has drastically reduced the mortality and sequelae of bacterial infections. From naturally occurring to chemically synthesized, different classes of antibiotics have been successfully used without detailed knowledge of how they affect bacterial dynamics in vivo . However, a proportion of patients receiving antimicrobial therapy develop recrudescent infections post-treatment. Relapsing infections are attributable to incomplete clearance of bacterial populations following antibiotic administration; the metabolic profile of this antibiotic-recalcitrant bacterial subpopulation, the spatio-temporal context of its emergence and the variance of antibiotic–bacterial interactions in vivo remain unclear. Here, we develop and apply a mechanistic mathematical model to data from a study comparing the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica serovar Typhimurium in murine infections. Using the inferential capacity of our model, we show that the antibiotic-recalcitrant bacteria following ampicillin, but not ciprofloxacin, treatment belong to a non-replicating phenotype. Aligning with previous studies, we independently estimate that the lymphoid tissues and spleen are important reservoirs of non-replicating bacteria. Finally, we predict that post-treatment, the progenitors of the non-growing and growing bacterial populations replicate and die at different rates. Ultimately, the liver, spleen and mesenteric lymph nodes are all repopulated by progenitors of the previously non-growing phenotype in ampicillin-treated mice.

Immunomodulatory role of thyroid hormones: in vivo effect of thyroid hormones on the blastogenic response of lymphoid tissues

1983 ◽  
Vol 103 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Sadhana Chatterjee ◽  
Amar Singh Chandel
Keyword(s):  
Thyroid Hormones ◽  
Pokeweed Mitogen ◽  
Lymphoid Tissues ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph ◽  
Hormone Administration ◽  
Blastogenic Response ◽  
Significant Depression

Abstract. In an attempt to find out the mechanism of immunomodulation by thyroid hormones (T3 and T4), their in vivo effect on the blastogenic response of lymphocytes from various lymphoid tissues of hormonetreated and thyroidectomized rats were studied. The blastogenic response of lymphocytes from thymus, peripheral blood and mesenteric lymph nodes to pokeweed mitogen (PWM) was found to be increased significantly following T3 or T4 administration for 15 days or 30 days. However, the response to phytohaemagglutinin (PHA) increased only after 1 month of T3 or T4 administration. The blastogenic response of spleen cells to both PHA and PWM was, on the other hand, found to be depressed following 15 days of hormone administration. Thyroidectomy invariably induced significant depression in the blastogenic response to both PHA and PWM in lymphocytes of all the lymphoid tissues. Thyroid hormone (T3) administration was found to restore the blastogenic response of the lymphocytes of thyroidectomized animals.

scholarly journals Global vascular expression of murine CD34, a sialomucin-like endothelial ligand for L-selectin

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2554-2565 ◽  
Author(s):  
S Baumhueter ◽  
N Dybdal ◽  
C Kyle ◽  
LA Lasky
Keyword(s):  
Lymph Nodes ◽  
Immune Surveillance ◽  
Nod Mice ◽  
Lymphoid Tissues ◽  
Mesenteric Lymph Nodes ◽  
High Endothelial Venules ◽  
Endothelial Cell Surface ◽  
Vascular Expression

Abstract Extravasation of leukocytes into organized lymphoid tissues and into sites of inflammation is critical to immune surveillance. Leukocyte migration to peripheral lymph nodes (PLN), mesenteric lymph nodes (MLN) and Peyer's patches (PP) depends on L-selectin, which recognizes carbohydrate-bearing, sialomucin-like endothelial cell surface glycoproteins. Two of these ligands have been identified at the molecular level. One is the potentially soluble mucin, GlyCAM 1, which is almost exclusively produced by high endothelial venules (HEV) of PLN and MLN. The second HEV ligand for L-selectin is the membrane-bound sialomucin CD34. Historically, this molecule has been successfully used to purify human pluripotent bone marrow stem cells, and limited data suggest that human CD34 is present on the vascular endothelium of several organs. Here we describe a comprehensive analysis of the vascular expression of CD34 in murine tissues using a highly specific antimurine CD34 polyclonal antibody. CD34 was detected on vessels in all organs examined and was expressed during pancreatic and skin inflammatory episodes. A subset of HEV-like vessels in the inflamed pancreas of nonobese diabetic (NOD) mice are positive for both CD34 and GlyCAM 1, and bind to an L-selectin/immunoglobulin G (IgG) chimeric probe. Finally, we found that CD34 is present on vessels of deafferentiated PLN, despite the fact that these vessels are no longer able to interact with L-selectin or support lymphocyte binding in vitro or trafficking in vivo. Our data suggest that the regulation of posttranslational carbohydrate modifications of CD34 is critical in determining its capability to act as an L-selectin ligand. Based on its ubiquitous expression, we propose that an appropriately glycosylated form of vascular CD34 may act as a ligand for L-selectin-mediated leukocyte trafficking to both lymphoid and nonlymphoid sites.

scholarly journals Analysis of Salmonella enterica Serotype-Host Specificity in Calves: Avirulence of S. enterica Serotype Gallinarum Correlates with Bacterial Dissemination from Mesenteric Lymph Nodes and Persistence In Vivo

2002 ◽  
Vol 70 (12) ◽  
pp. 6788-6797 ◽  
Author(s):  
Susan M. Paulin ◽  
Patricia R. Watson ◽  
Annette R. Benmore ◽  
Mark P. Stevens ◽  
Philip W. Jones ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Host Specificity ◽  
Intestinal Mucosa ◽  
Salmonella Enterica ◽  
Systemic Disease ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph ◽  
Oral Inoculation ◽  
Pass Through

ABSTRACT Host and bacterial factors that determine whether Salmonella serotypes remain restricted to the gastrointestinal tract or penetrate beyond the mucosa and cause systemic disease remain largely undefined. Here, factors influencing Salmonella host specificity in calves were assessed by characterizing the pathogenesis of different serotypes. Salmonella enterica serotype Dublin was highly virulent intravenously, whereas S. enterica serotype Choleraesuis was moderately virulent. Both serotypes were virulent in calves infected orally. In contrast, S. enterica serotypes Gallinarum and Abortusovis were avirulent by either route. Serotypes Dublin, Gallinarum, and Abortusovis colonized the intestinal tract 24 h after oral inoculation, yet only serotype Dublin was consistently recovered from systemic tissues. Serotypes Dublin and Gallinarum invaded bovine intestines in greater numbers and induced greater enteropathogenic responses than serotypes Choleraesuis and Abortusovis. However, only serotype Dublin was able to persist within the intestinal mucosa, and use of a novel cannulation model demonstrated that serotype Dublin was able to pass through the mesenteric lymph nodes in greater numbers than serotype Gallinarum. Together, these results suggest that initial interactions with the intestinal mucosa do not correlate with host specificity, although persistence within tissues and translocation via efferent lymphatics appear to be crucial for the induction of bovine salmonellosis.

Immunity to Enteric Infection in Mice

1970 ◽  
Vol 1 (3) ◽  
pp. 243-250
Author(s):  
Frank M. Collins
Keyword(s):  
Salmonella Enteritidis ◽  
Virulent Strain ◽  
Sublethal Dose ◽  
Enteric Infection ◽  
Mesenteric Lymph Nodes ◽  
Bacterial Populations ◽  
Mesenteric Lymph ◽  
Specific Pathogen ◽  
Sublethal Doses

Specific pathogen-free CD-1 mice infected orally with sublethal doses (10 4 to 10 6 viable organisms) of Salmonella enteritidis rapidly developed extensive bacterial populations in the liver, spleen, and mesenteric lymph nodes. Although the pathogen did not multiply extensively in the gut, the infection persisted in the intestine at between 10 4 and 10 5 viable organisms throughout the experiment. S. gallinarum was less invasive than S. enteritidis when given by mouth; S. pullorum failed to survive in the intestine or to invade the tissues of orally infected mice. Vaccination with a sublethal dose of living S. enteritidis , either orally or intravenously, completely prevented the establishment of liver and spleen populations of a drug-resistant, virulent strain of S. enteritidis . Vaccination with an ethyl alcohol-killed vaccine given by various routes delayed the spread of the orally introduced challenge population to the liver and spleen by 1 to 2 days but was unable to prevent the subsequent growth of the pathogen in vivo, although the vaccinated mice survived the infection. The importance of these findings in relation to vaccination against typhoid fever in man is discussed.

scholarly journals Intracellular localization and properties of phosphate-dependent glutaminase in rat mesenteric lymph nodes

1984 ◽  
Vol 217 (1) ◽  
pp. 289-296 ◽  
Author(s):  
M S M Ardawi ◽  
E A Newsholme
Keyword(s):  
Bone Marrow ◽  
Lymph Nodes ◽  
Intracellular Localization ◽  
Lymphoid Tissues ◽  
Mesenteric Lymph Nodes ◽  
Ph Optimum ◽  
Mesenteric Lymph ◽  
Phosphorylated Compounds ◽  
Glutaminase Activity

Phosphate-dependent glutaminase was present at approximately similar activities in lymph nodes from mammals other than rat, and in thymus, spleen, Peyer's patches and bone marrow of the rat. This suggests that glutamine is important in all lymphoid tissues. Phosphate-dependent glutaminase activity was shown to be present primarily in the mitochondria of rat mesenteric lymph nodes, and most of the activity could be released by detergents. The properties of the enzyme in mitochondrial extracts were investigated. The pH optimum was 8.6 and the Km for glutamine was 2.0 mM. The enzyme was activated by phosphate, other phosphorylated compounds including phosphoenolpyruvate, and also leucine: 50% activation occurred at 5, 0.2 and 0.6 mM for phosphate, phosphoenolpyruvate and leucine respectively. The enzyme was inhibited by glutamate, 2-oxoglutarate, citrate and ammonia, and by N-ethylmaleimide and diazo-5-oxo-L-norleucine; 50% inhibition was observed at 0.7 and 0.1 mM for glutamate and 2-oxoglutarate respectively. Some of these properties may be important in the control of the enzyme activity in vivo.

scholarly journals The Inositol Phosphatase SHIP Controls Salmonella enterica Serovar Typhimurium Infection In Vivo

2008 ◽  
Vol 76 (7) ◽  
pp. 2913-2922 ◽  
Author(s):  
Jennifer L. Bishop ◽  
Laura M. Sly ◽  
Gerald Krystal ◽  
B. Brett Finlay
Keyword(s):  
Bone Marrow ◽  
Salmonella Enterica ◽  
Bacterial Infections ◽  
Sh2 Domain ◽  
M2 Macrophage ◽  
Cell Functions ◽  
Arginase 1 ◽  
Cytokine Analysis ◽  
Serovar Typhimurium

ABSTRACT The SH2 domain-containing inositol 5′-phosphatase, SHIP, negatively regulates various hematopoietic cell functions and is critical for maintaining immune homeostasis. However, whether SHIP plays a role in controlling bacterial infections in vivo remains unknown. Salmonella enterica causes human salmonellosis, a disease that ranges in severity from mild gastroenteritis to severe systemic illness, resulting in significant morbidity and mortality worldwide. The susceptibility of ship +/+and ship −/− mice and bone marrow-derived macrophages to S. enterica serovar Typhimurium infection was compared. ship −/− mice displayed an increased susceptibility to both oral and intraperitoneal serovar Typhimurium infection and had significantly higher bacterial loads in intestinal and systemic sites than ship +/+mice, indicating a role for SHIP in the gut-associated and systemic pathogenesis of serovar Typhimurium in vivo. Cytokine analysis of serum from orally infected mice showed that ship −/− mice produce lower levels of Th1 cytokines than do ship +/+ animals at 2 days postinfection, and in vitro analysis of supernatants taken from infected bone marrow-derived macrophages derived to mimic the in vivo ship−/− alternatively activated (M2) macrophage phenotype correlated with these data. M2 macrophages were the predominant population in vivo in both oral and intraperitoneal infections, since tissue macrophages within the small intestine and peritoneal macrophages from ship −/− mice showed elevated levels of the M2 macrophage markers Ym1 and Arginase 1 compared to ship +/+ cells. Based on these data, we propose that M2 macrophage skewing in ship −/− mice contributes to ineffective clearance of Salmonella in vivo.

scholarly journals Modeling the control of bacterial infections via antibiotic-induced proviruses

2019 ◽  
Author(s):  
Sara M. Clifton ◽  
Ted Kim ◽  
Jayadevi H. Chandrashekhar ◽  
George A. O’Toole ◽  
Zoi Rapti ◽  
...  
Keyword(s):  
Population Model ◽  
Bacterial Infections ◽  
Bacterial Population ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Antibiotic Administration ◽  
Bacterial Strains ◽  
Bacterial Populations ◽  
Latent Form ◽  
Over Time

Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacteria-phage relationship to examine the role that latent phage play on the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations.ImportanceAntibiotic-resistance is a growing concern for management of common bacterial infections. Here we show that antibiotics can be effective at sub-inhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.

scholarly journals Mesenteric Lymph Nodes Confine Dendritic Cell-Mediated Dissemination of Salmonella enterica Serovar Typhimurium and Limit Systemic Disease in Mice

2009 ◽  
Vol 77 (8) ◽  
pp. 3170-3180 ◽  
Author(s):  
Sabrina Voedisch ◽  
Christian Koenecke ◽  
Sascha David ◽  
Heike Herbrand ◽  
Reinhold Förster ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Lymph Nodes ◽  
Salmonella Enterica ◽  
Systemic Disease ◽  
Mouse Strains ◽  
Surgical Removal ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph ◽  
Serovar Typhimurium

ABSTRACT In humans with typhoid fever or in mouse strains susceptible to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, bacteria gain access to extraintestinal tissues, causing severe systemic disease. Here we show that in the gut-draining mesenteric lymph nodes (MLN), the majority of S. Typhimurium-carrying cells show dendritic-cell (DC) morphology and express the DC marker CD11c, indicating that S. Typhimurium bacteria are transported to the MLN by migratory DCs. In vivo FLT-3L-induced expansion of DCs, as well as stimulation of DC migration by Toll-like receptor agonists, results in increased numbers of S. Typhimurium bacteria reaching the MLN. Conversely, genetically impaired DC migration in chemokine receptor CCR7-deficient mice reduces the number of S. Typhimurium bacteria reaching the MLN. This indicates that transport of S. Typhimurium from the intestine into the MLN is limited by the number of migratory DCs carrying S. Typhimurium bacteria. In contrast, modulation of DC migration does not affect the number of S. Typhimurium bacteria reaching systemic tissues, indicating that DC-bound transport of S. Typhimurium does not substantially contribute to systemic S. Typhimurium infection. Surgical removal of the MLN results in increased numbers of S. Typhimurium bacteria reaching systemic sites early after infection, thereby rendering otherwise resistant mice susceptible to fatal systemic disease development. This suggests that the MLN provide a vital barrier shielding systemic compartments from DC-mediated dissemination of S. Typhimurium. Thus, confinement of S. Typhimurium in gut-associated lymphoid tissue and MLN delays massive extraintestinal dissemination and at the same time allows for the establishment of protective adaptive immune responses.

scholarly journals Absence of Platelet Endothelial Cell Adhesion Molecule 1, PECAM-1/CD31,In VivoIncreases Resistance to Salmonella enterica Serovar Typhimurium in Mice

2013 ◽  
Vol 81 (6) ◽  
pp. 1952-1963 ◽  
Author(s):  
Michael D. Lovelace ◽  
May Lin Yap ◽  
Jana Yip ◽  
William Muller ◽  
Odilia Wijburg ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Bacterial Load ◽  
Host Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Mesenteric Lymph Nodes ◽  
Serovar Typhimurium

ABSTRACTPECAM-1/CD31 is known to regulate inflammatory responses and exhibit pro- and anti-inflammatory functions. This study was designed to determine the functional role of PECAM-1 in susceptibility to murine primaryin vivoinfection withSalmonella entericaserovar Typhimurium and inin vitroinflammatory responses of peritoneal macrophages. Lectin profiling showed that cellular PECAM-1 and recombinant human PECAM-1-Ig chimera contain high levels of mannose sugars andN-acetylglucosamine. Consistent with this carbohydrate pattern, both recombinant human and murine PECAM-1-Ig chimeras were shown to bindS. Typhimurium in a dose-dependent mannerin vitro. Using oral and fecal-oral transmission models ofS. Typhimurium SL1344 infection, PECAM-1−/−mice were found to be more resistant toS. Typhimurium infection than wild-type (WT) C57BL/6 mice. While fecal shedding ofS. Typhimurium was comparable in wild-type and PECAM-1−/−mice, the PECAM-1-deficient mice had lower bacterial loads in systemic organs such as liver, spleen, and mesenteric lymph nodes than WT mice, suggesting that extraintestinal dissemination was reduced in the absence of PECAM-1. This reduced bacterial load correlated with reduced tumor necrosis factor (TNF), interleukin-6 (IL-6), and monocyte chemoattractant protein (MCP) levels in sera of PECAM-1−/−mice. Followingin vitrostimulation of macrophages with either wholeS. Typhimurium, lipopolysaccharide (LPS) (Toll-like receptor 4 [TLR4] ligand), or poly(I·C) (TLR3 ligand), production of TNF and IL-6 by PECAM-1−/−macrophages was reduced. Together, these results suggest that PECAM-1 may have multiple functions in resistance to infection withS. Typhimurium, including binding to host cells, extraintestinal spread to deeper tissues, and regulation of inflammatory cytokine production by infected macrophages.

scholarly journals Lying in Wait: Modeling the Control of Bacterial Infections via Antibiotic-Induced Proviruses

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Sara M. Clifton ◽  
Ted Kim ◽  
Jayadevi H. Chandrashekhar ◽  
George A. O’Toole ◽  
Zoi Rapti ◽  
...  
Keyword(s):  
Population Model ◽  
Bacterial Infections ◽  
Bacterial Population ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Antibiotic Administration ◽  
Bacterial Strains ◽  
Bacterial Populations ◽  
Latent Form ◽  
Over Time

ABSTRACT Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacterium-phage relationship to examine the role that latent phage play in the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations. IMPORTANCE Antibiotic resistance is a growing concern for management of common bacterial infections. Here, we show that antibiotics can be effective at subinhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.

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