scholarly journals Course of Infection with the Emergent Pathogen Brucella microti in Immunocompromised Mice

2011 ◽  
Vol 79 (10) ◽  
pp. 3934-3939 ◽  
Author(s):  
María P. Jiménez de Bagüés ◽  
Alba de Martino ◽  
Juan F. Quintana ◽  
Ana Alcaraz ◽  
Julián Pardo
Keyword(s):  
Nk Cell ◽  
Bacterial Load ◽  
Cell Activity ◽  
Specific Model ◽  
Wild Rodents ◽  
Content Type ◽  
Immunodeficient Mice ◽  
Emergent Pathogen ◽  
Immunocompromised Mice ◽  
Species Specific

ABSTRACTA newBrucellaspecies,Brucella microti, has been isolated from wild rodents and found to be pathogenic in mice. The biological relevance of this new mouse pathogen is clear, as it allows us to studyBrucellainfection in a species-specific model. The course of infection in wild-type (wt) and immunodeficient mice that lack B (Jh), T and B (SCID), or T, B, and NK (SCID.Beige) cells was analyzed over 3 weeks. wt mice completely cleared bacteria from the liver and spleen after that time. However, SCID mice showed a much higher bacterial load in the spleen and liver than wt and Jh mice after 1 week and maintained the same level during the next 2 weeks. All mice tested survived for the 3 weeks. In contrast, the bacterial levels in mice that lacked NK cell activity progressively increased and these mice succumbed to infection after 16 to 18 days. Histopathology analysis of infected mice showed extensive areas of necrotic tissue and thrombosis in liver after 1 week in all infected SCID.Beige mice but were not seen in either SCID or wt animals. These processes were dramatically increased after 21 days, corresponding with the death of SCID.Beige animals. Our results indicate that T and/or B cells are required for the control of infection with the mouse pathogenBrucella microtiin liver and spleen but that NK cells are crucial for survival in the absence of B and T cells. In addition, they suggest that controlled granuloma formation is critical to clear this type of infection in wt mice.

scholarly journals Monitoring Tuberculosis Drug Activity in Live Animals by Using Near-Infrared Fluorescence Imaging

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Raphael Sommer ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Near Infrared ◽  
Imaging System ◽  
Limit Of Detection ◽  
Bacterial Load ◽  
Genetically Engineered ◽  
Fluorescent Imaging ◽  
Effective Vaccine ◽  
Content Type ◽  
Immunodeficient Mice

ABSTRACT Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis. In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and fastidious procedure that delays the progression of drugs down the pipeline and towards the clinic. In this investigation, we report the construction, optimization, and characterization of genetically engineered near-infrared (NIR) fluorescent reporter strains of the pathogens Mycobacterium marinum and Mycobacterium tuberculosis that enable the direct visualization of bacteria in infected zebrafish and mice, respectively. Fluorescence could be measured precisely in infected immunodeficient mice, while its intensity appeared to be below the limit of detection in immunocompetent mice, probably because of the lower bacterial load obtained in these animals. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by CFU enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals in real time. The NIR fluorescent imaging system disclosed here is a valuable resource for TB research and can serve to accelerate drug development.

Host specificity and in vivo infectivities of the mouse coccidian parasites Eimeria krijgsmanni

2014 ◽  
Vol 59 (2) ◽  
Author(s):  
Kazuki Hashimoto ◽  
Tetsuya Tanaka ◽  
Makoto Matsubayashi ◽  
Kyoko Endo ◽  
Rika Umemiya-Shirafuji ◽  
...  
Keyword(s):  
Host Specificity ◽  
Primary Infection ◽  
Nk Cell ◽  
Cell Activity ◽  
Mouse Strains ◽  
Minor Role ◽  
Immunodeficient Mice ◽  
Significant Difference ◽  
Immunocompetent Mice ◽  
Infection Experiments

AbstractIn the present study, infection experiments of E. krijgsmanni using various hosts were conducted to elucidate the host specificity among some animals and the infectivity to mouse strains. According to the results, the infection was not found in most animals, except for rats, in which some oocyst shedding was detected, and there was no significant difference in infectivity among mouse strains. Additionally, oocyst shedding was hardly detectable in a secondary infection to immunocompetent mice, although it was found in immunodeficient mice. These results indicated that only immunocompetent mice could develop adaptive immunity against reinfection by stimuli of the primary infection. Furthermore, the infection experiments were performed with splenic macrophage (Mφ)-depleted mice with a reagent and Beige (Bg) mice known to be a strain of mice with low NK cell activity. No significant effect was found in primary or secondary infections in the Mφ-depleted mice, whereas the mortality rate was clearly increased in Bg mice inoculated with a large number of oocysts. Their oocyst shedding was similar to that of immunocompetent hosts. Taken together, these results suggested that Mφ has only a minor role in the immune response, but the NK cell has an important function in resistance to primary infection of E. krijgsmanni.

scholarly journals Preventive Effect of the Herbal Preparation, HemoHIM, on Cisplatin-Induced Immune Suppression

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Seul-Ki Kim ◽  
Da-Ae Kwon ◽  
Hak Sung Lee ◽  
Hyun Kyu Kim ◽  
Won-Ki Kim
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Interleukin 4 ◽  
Control Group ◽  
Herbal Preparation ◽  
Necrosis Factor Alpha ◽  
Immunocompromised Mice

We determined the functional effect of the herbal preparation, HemoHIM, on the immune system, by examining the immunomodulatory activities of HemoHIM using immunocompromised mice. In this study, to examine the effect on the restoration of immune cells and balance in the immune system, we utilized a cisplatin-induced immunosuppression mouse model. Mice were injected intraperitoneally with cisplatin, an immunosuppressive anticancer, and then received oral doses of 100, 250, and 500 mg/kg of HemoHIM for 14 days. The HemoHIM prevented the cisplatin-induced loss of body and organ weight. In terms of innate immunity, natural killer (NK) cell activity and phagocytosis increased in the HemoHIM group compared to the cisplatin control group. The HemoHIM group also showed a significantly higher expression of Th1-mediated cytokines (interferon gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α)) and inhibited the production of Th2-mediated cytokine interleukin-4 (IL-4) compared to cisplatin control group. These findings indicate that HemoHIM enhances immune activity by modulating immune cell activity and cytokine secretion in immune-suppressed mice.

Establishment of a Metastasizing Human Cell Line Based Multiple Myeloma Model in Immunodeficient Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4784-4784
Author(s):  
Julia B. Schueler ◽  
Dagmar Wider ◽  
Martin Wagner ◽  
Heiner Fiebig ◽  
Monika Engelhardt
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
Nk Cell ◽  
Cell Activity ◽  
Infiltration Rate ◽  
Nk Cell Activity ◽  
Immunodeficient Mice ◽  
Knock Down ◽  
Pre Treatment

Abstract Multiple myeloma (MM) accounts for 10% of all hematological malignancies, leads to devastating bone destruction, bone pain, renal failure, and hematopoietic insufficiency. In order to allow a better understanding of MM, the establishment of functional and reproducible in vivo models is pursued worldwide. Of available models, xenograft models in immunodeficient mice (IDM) reproduce the clinical situation best. Using the different MM cell lines (MMCLs) L363 and RPMI8226, we tested their ability to engraft in IDM under different conditions. As the supportive effect of bone marrow (BM) stroma has been suggested to be vital, we injected L363 or RPMI8226 into a freshly prepared mouse tibia which was implanted subcutaneously (sc) into IDM. In a second approach, we injected MMCLs directly into the tibia of the recipient mouse. Furthermore, the influence of IL-6, matrigel, pre-treatment with an anti-mouse CD122-antibody (Ab) and/or the use of NOD/SCID-IL2-receptor-gamma-chain−/− (IL2−/−) mice, instead of conventional NOD/SCID mice, was evaluated. Tumor growth was monitored by a) multiparameter flow-cytometry (FACS; detection of human HLA-DR, HLA-A,B,C, CD45 and CD138), b) immunohistological detection of human CD138+ cells in tumor implants, BM and spleen and c) a fluorescence-based in vivo imaging system. L363 and RPMI8226 engrafted reliably at the injection site and in distant organs, independent of the experimental conditions (using IL-6, matrigel and/or pre-treatment with anti-CD122-Ab). L363 cells showed higher take- and metastases-rates compared to RPMI8226. The knock-down of NK cell activity, either by Ab-treatment or by genetic engineering, enhanced the tumor take rate with both MMCLs in 8/8 mice. With RPMI8226, the BM infiltration rate was 1.5–1.8% in all examined murine models. In contrast, BM-infiltration rates of L363 cells negatively correlated with the NK cell activity of the host: L363 cells metastasized particularly well to the BM when injected into anti-CD122-pretreated mice or intratibialy into IL-2−/− mice. Engraftment of circulating cells into the peripheral blood and spleen was found with both MMCLs irrespective of the mouse strain, pretreatment or implantation site. Matrigel or IL-6 showed no relevant engraftment effect, neither sc, nor with the intratibial approach. We conclude that the establishment of a metastasizing cell line-based human MM in vivo model was successfully pursued. We observed that the knock-down of NK cell activity was essential for both MMCLs, whereas the influence of matrigel or IL-6 treatment could be neglected. Furthermore, the intratibial approach optimized especially the L363 model in terms of infiltration rate to clinically relevant sites. With this optimized transplant approach, we aim to determine whether this allows MM engraftment using primary patient specimens, which should also enable us to test novel anti-myeloma agents.

scholarly journals Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Dereje A. Negatu ◽  
Joe J. J. Liu ◽  
Matthew Zimmerman ◽  
Firat Kaya ◽  
Véronique Dartois ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Molecular Mass ◽  
Propionic Acid ◽  
Bacterial Load ◽  
Cell Activity ◽  
Antitubercular Activity ◽  
Whole Cell ◽  
Content Type ◽  
Dependent Growth

ABSTRACT Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis . Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1 H -indol-3-yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo . The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates.

scholarly journals Antibacterial Role for Natural Killer Cells in Host Defense to Bacillus anthracis

2011 ◽  
Vol 80 (1) ◽  
pp. 234-242 ◽  
Author(s):  
Christine M. Gonzales ◽  
Courtney B. Williams ◽  
Veronica E. Calderon ◽  
Matthew B. Huante ◽  
Scott T. Moen ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bacillus Anthracis ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Bacterial Load ◽  
Intervention Strategy ◽  
Content Type

ABSTRACTNatural killer (NK) cells have innate antibacterial activity that could be targeted for clinical interventions for infectious disease caused by naturally occurring or weaponized bacterial pathogens. To determine a potential role for NK cells in immunity toBacillus anthracis, we utilized primary human and murine NK cells,in vitroassays, andin vivoNK cell depletion in a murine model of inhalational anthrax. Our results demonstrate potent antibacterial activity by human NK cells againstB. anthracisbacilli within infected autologous monocytes. Surprisingly, NK cells also mediate moderate antibacterial effects on extracellular vegetative bacilli but do not have activity against extracellular or intracellular spores. The immunosuppressive anthrax lethal toxin impairs NK gamma interferon (IFN-γ) expression, but neither lethal nor edema toxin significantly alters the viability or cytotoxic effector function of NK cells. Compared to human NK cells, murine NK cells have a similar, though less potent, activity against intracellular and extracellularB. anthracis. Thein vivodepletion of murine NK cells does not alter animal survival following intranasal infection withB. anthracisspores in our studies but significantly increases the bacterial load in the blood of infected animals. Our studies demonstrate that NK cells participate in the innate immune response againstB. anthracisand suggest that immune modulation to augment NK cell function in early stages of anthrax should be further explored in animal models as a clinical intervention strategy.

scholarly journals Toll-Like Receptor 2 (TLR2) and TLR9 Play Opposing Roles in Host Innate Immunity against Salmonella enterica Serovar Typhimurium Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1641-1649 ◽  
Author(s):  
Renhui Zhan ◽  
Qiuju Han ◽  
Cai Zhang ◽  
Zhigang Tian ◽  
Jian Zhang
Keyword(s):  
Innate Immunity ◽  
Host Defense ◽  
Salmonella Enterica ◽  
Nk Cell ◽  
Bacterial Load ◽  
Content Type ◽  
Serovar Typhimurium ◽  
High Bacterial Load

Toll-like receptors (TLRs) are evolutionarily conserved host proteins that are essential for effective host defense against pathogens. However, recent studies suggest that some TLRs can negatively regulate immune responses. We observed here that TLR2 and TLR9 played opposite roles in regulating innate immunity against oral infection ofSalmonella entericaserovar Typhimurium in mice. WhileTLR9−/−mice exhibited shortened survival, an increased cytokine storm, and more severeSalmonellahepatitis than wild-type (WT) mice,TLR2−/−mice exhibited the opposite phenomenon. Further studies demonstrated that TLR2 deficiency and TLR9 deficiency in macrophages both disrupted NK cell cytotoxicity againstS. Typhimurium-infected macrophages by downregulating NK cell degranulation and gamma interferon (IFN-γ) production through decreased macrophage expression of the RAE-1 NKG2D ligand. But more importantly, we found thatS. Typhimurium-infectedTLR2−/−macrophages upregulated inducible nitric oxide synthase (iNOS) expression, resulting in a lower bacterial load than that in WT macrophagesin vitroand liversin vivoas well as low proinflammatory cytokine levels. In contrast,TLR9−/−macrophages showed decreased reactive oxygen species (ROS) expression concomitant with a high bacterial load in the macrophages and in livers ofTLR9−/−mice.TLR9−/−macrophages were also more susceptible than WT macrophages toS. Typhimurium-induced necroptosisin vitro, likely contributing to bacterial spread and transmissionin vivo. Collectively, these findings indicate that TLR2 negatively regulates anti-S. Typhimurium immunity, whereas TLR9 is vital to host defense and survival againstS. Typhimurium invasion. TLR2 antagonists or TLR9 agonists may thus serve as potential anti-S. Typhimurium therapeutic agents.

scholarly journals Varicella-Zoster Virus and Herpes Simplex Virus 1 Differentially Modulate NKG2D Ligand Expression during Productive Infection

2015 ◽  
Vol 89 (15) ◽  
pp. 7932-7943 ◽  
Author(s):  
Tessa M. Campbell ◽  
Brian P. McSharry ◽  
Megan Steain ◽  
Barry Slobedman ◽  
Allison Abendroth
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Nkg2d Ligand ◽  
Nk Cell Activity ◽  
Herpes Simplex Virus 1 ◽  
Varicella Zoster ◽  
Ligand Expression ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTNatural killer (NK) cell-deficient patients are particularly susceptible to severe infection with herpesviruses, especially varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). The critical role that NK cells play in controlling these infections denotes an intricate struggle for dominance between virus and NK cell antiviral immunity; however, research in this area has remained surprisingly limited. Our study addressed this absence of knowledge and found that infection with VZV was not associated with enhanced NK cell activation, suggesting that the virus uses specific mechanisms to limit NK cell activity. Analysis of viral regulation of ligands for NKG2D, a potent activating receptor ubiquitously expressed on NK cells, revealed that VZV differentially modulates expression of the NKG2D ligands MICA, ULBP2, and ULBP3 by upregulating MICA expression while reducing ULBP2 and ULBP3 expression on the surface of infected cells. Despite being closely related to VZV, infection with HSV-1 produced a remarkably different effect on NKG2D ligand expression. A significant decrease in MICA, ULBP2, and ULBP3 was observed with HSV-1 infection at a total cellular protein level, as well as on the cell surface. We also demonstrate that HSV-1 differentially regulates expression of an additional NKG2D ligand, ULBP1, by reducing cell surface expression while total protein levels are unchanged. Our findings illustrate both a striking point of difference between two closely related alphaherpesviruses, as well as suggest a powerful capacity for VZV and HSV-1 to evade antiviral NK cell activity through novel modulation of NKG2D ligand expression.IMPORTANCEPatients with deficiencies in NK cell function experience an extreme susceptibility to infection with herpesviruses, in particular, VZV and HSV-1. Despite this striking correlation, research into understanding how these two alphaherpesviruses interact with NK cells is surprisingly limited. Through examination of viral regulation of ligands to the activating NK cell receptor NKG2D, we reveal patterns of modulation by VZV, which were unexpectedly varied in response to regulation by HSV-1 infection. Our study begins to unravel the undoubtedly complex interactions that occur between NK cells and alphaherpesvirus infection by providing novel insights into how VZV and HSV-1 manipulate NKG2D ligand expression to modulate NK cell activity, while also illuminating a distinct variation between two closely related alphaherpesviruses.

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