scholarly journals The Impact of Actotoxumab Treatment of Gnotobiotic Piglets Infected With Different Clostridium difficile Isogenic Mutants

2019 ◽  
Vol 221 (2) ◽  
pp. 276-284
Author(s):  
Hillary R Danz ◽  
Sangun Lee ◽  
Susan P Chapman-Bonofiglio ◽  
Melanie Ginese ◽  
Gillian Beamer ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Disease Severity ◽  
Mucosal Injury ◽  
Recurrent Infections ◽  
Wild Type ◽  
Antibiotic Resistant ◽  
Isogenic Mutants ◽  
The Impact ◽  
Unites States ◽  
Gnotobiotic Piglets

Abstract Nosocomial infections with Clostridium difficile are on the rise in the Unites States, attributed to emergence of antibiotic-resistant and hypervirulent strains associated with greater likelihood of recurrent infections. In addition to antibiotics, treatment with Merck anti-toxin B (TcdB) antibody bezlotoxumab is reported to reduce recurrent infections. However, treatment with anti-toxin A (TcdA) antibody actotoxumab was associated with dramatically increased disease severity and mortality rates in humans and gnotobiotic piglets. Using isogenic mutants of C. difficile strain NAPI/BI/027 deficient in TcdA (A−B+) or TcdB (A+B−), and the wild type, we investigated how and why treatment of infected animals with anti-TcdA dramatically increased disease severity. Contrary to the hypothesis, among piglets treated with anti-TcdA, those with A+B− infection were disease free, in contrast to the disease enhancement seen in those with wild-type or A−B+ infection. It seems that the lack of TcdA, through either deletion or neutralization with anti-TcdA, reduces a competitive pressure, allowing TcdB to freely exert its profound effect, leading to increased mucosal injury and disease severity.

scholarly journals Global Analysis of Cellular Factors and Responses Involved in Pseudomonas aeruginosa Resistance to Arsenite

2005 ◽  
Vol 187 (14) ◽  
pp. 4853-4864 ◽  
Author(s):  
Kislay Parvatiyar ◽  
Eyad M. Alsabbagh ◽  
Urs A. Ochsner ◽  
Michelle A. Stegemeyer ◽  
Alan G. Smulian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pseudomonas Aeruginosa ◽  
Glutathione Reductase ◽  
Type Strain ◽  
Wild Type Strain ◽  
Storage Proteins ◽  
Global Analysis ◽  
Wild Type ◽  
Isogenic Mutants ◽  
The Impact

ABSTRACT The impact of arsenite [As(III)] on several levels of cellular metabolism and gene regulation was examined in Pseudomonas aeruginosa. P. aeruginosa isogenic mutants devoid of antioxidant enzymes or defective in various metabolic pathways, DNA repair systems, metal storage proteins, global regulators, or quorum sensing circuitry were examined for their sensitivity to As(III). Mutants lacking the As(III) translocator (ArsB), superoxide dismutase (SOD), catabolite repression control protein (Crc), or glutathione reductase (Gor) were more sensitive to As(III) than wild-type bacteria. The MICs of As(III) under aerobic conditions were 0.2, 0.3, 0.8, and 1.9 mM for arsB, sodA sodB, crc, and gor mutants, respectively, and were 1.5- to 13-fold less than the MIC for the wild-type strain. A two-dimensional gel/matrix-assisted laser desorption ionization-time of flight analysis of As(III)-treated wild-type bacteria showed significantly (>40-fold) increased levels of a heat shock protein (IbpA) and a putative allo-threonine aldolase (GlyI). Smaller increases (up to 3.1-fold) in expression were observed for acetyl-coenzyme A acetyltransferase (AtoB), a probable aldehyde dehydrogenase (KauB), ribosomal protein L25 (RplY), and the probable DNA-binding stress protein (PA0962). In contrast, decreased levels of a heme oxygenase (HemO/PigA) were found upon As(III) treatment. Isogenic mutants were successfully constructed for six of the eight genes encoding the aforementioned proteins. When treated with sublethal concentrations of As(III), each mutant revealed a marginal to significant lag period prior to resumption of apparent normal growth compared to that observed in the wild-type strain. Our results suggest that As(III) exposure results in an oxidative stress-like response in P. aeruginosa, although activities of classic oxidative stress enzymes are not increased. Instead, relief from As(III)-based oxidative stress is accomplished from the collective activities of ArsB, glutathione reductase, and the global regulator Crc. SOD appears to be involved, but its function may be in the protection of superoxide-sensitive sulfhydryl groups.

scholarly journals A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection

2016 ◽  
Vol 23 (9) ◽  
pp. 774-784 ◽  
Author(s):  
Diane J. Schmidt ◽  
Gillian Beamer ◽  
Jacqueline M. Tremblay ◽  
Jennifer A. Steele ◽  
Hyeun Bum Kim ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Neutralizing Antibody ◽  
Antibiotic Resistant ◽  
Content Type ◽  
New Therapeutic Approaches ◽  
Cell Assays ◽  
Life Threatening ◽  
Hospital Stays ◽  
Serious Disease ◽  
Gnotobiotic Piglets

ABSTRACTClostridium difficileinfection (CDI), a leading cause of nosocomial infection, is a serious disease in North America, Europe, and Asia. CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors ofClostridium difficile, toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for bothC. difficiletoxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.

THE IMPACT OF OBESITY ON MORTALITY AND DISEASE SEVERITY IN PATIENTS WITH PULMONARY EMBOLISM IN UNITES STATES: A 13-YEAR NATIONAL ANALYSIS

CHEST Journal ◽  
2018 ◽  
Vol 154 (4) ◽  
pp. 1017A
Author(s):  
ZUBAIR KHAN ◽  
KHALED SROUR ◽  
MOHAMMAD SAUD KHAN ◽  
TAMER SAID AHMED ◽  
NAUMAN SIDDIQUI ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Disease Severity ◽  
National Analysis ◽  
The Impact ◽  
Unites States

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

Self-Administered Home Series Fecal “Minitransplants” for Recurrent Clostridium difficile Infection on a Rectal Remnant

2015 ◽  
Vol 24 (4) ◽  
pp. 531-533 ◽  
Author(s):  
Daniel Popa ◽  
Mihaela Laszlo ◽  
Lidia Ciobanu ◽  
Elena Ucenic ◽  
Manuela Mihalache ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Clostridium Difficile ◽  
Clostridium Difficile Infection ◽  
Toxic Megacolon ◽  
Fecal Microbiota ◽  
Recurrent Infections ◽  
Resonance Imaging ◽  
Vaginal Infection ◽  
Fecal Microbiota Transplant ◽  
Recurrent Clostridium Difficile Infection

A fecal microbiota transplant has proved to be an extremely effective method for patients with recurrent infections with Clostridium difficile. We present the case of a 65-year-old female patient with multiple Clostridium difficile infection (CDI) relapses on the rectal remnant, post-colectomy for a CDI-related toxic megacolon. The patient also evidenced associated symptomatic Clostridium difficile vaginal infection. She was successfully treated with serial fecal “minitransplants” (self-administered at home) and metronidazole ovules.Abbreviations: GI: gastrointestinal; MRI: magnetic resonance imaging; CDI: Clostridium difficile infection; FMT: fecal microbiota transplant.

Impact of influenza virus during pregnancy: from disease severity to vaccine efficacy

2020 ◽  
Vol 15 (7) ◽  
pp. 441-453
Author(s):  
Ana Vazquez-Pagan ◽  
Rebekah Honce ◽  
Stacey Schultz-Cherry
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Responses ◽  
Pregnant Women ◽  
Disease Severity ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Influenza Virus Infection ◽  
Severe Influenza ◽  
The Impact

Pregnant women are among the individuals at the highest risk for severe influenza virus infection. Infection of the mother during pregnancy increases the probability of adverse fetal outcomes such as small for gestational age, preterm birth and fetal death. Animal models of syngeneic and allogeneic mating can recapitulate the increased disease severity observed in pregnant women and are used to define the mechanism(s) of that increased severity. This review focuses on influenza A virus pathogenesis, the unique immunological landscape during pregnancy, the impact of maternal influenza virus infection on the fetus and the immune responses at the maternal–fetal interface. Finally, we summarize the importance of immunization and antiviral treatment in this population and highlight issues that warrant further investigation.

scholarly journals Allelic Exchange and Mutant Selection Demonstrate that Common Clinical embCAB Gene Mutations Only Modestly Increase Resistance to Ethambutol in Mycobacterium tuberculosis

2009 ◽  
Vol 54 (1) ◽  
pp. 103-108 ◽  
Author(s):  
Hassan Safi ◽  
Robert D. Fleischmann ◽  
Scott N. Peterson ◽  
Marcus B. Jones ◽  
Behnam Jarrahi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Vitro Selection ◽  
Gene Mutations ◽  
Wild Type ◽  
Mutant Selection ◽  
Preferential Growth ◽  
Allelic Exchange ◽  
High Level ◽  
Isogenic Mutants

ABSTRACT Mutations within codon 306 of the Mycobacterium tuberculosis embB gene modestly increase ethambutol (EMB) MICs. To identify other causes of EMB resistance and to identify causes of high-level resistance, we generated EMB-resistant M. tuberculosis isolates in vitro and performed allelic exchange studies of embB codon 406 (embB406) and embB497 mutations. In vitro selection produced mutations already identified clinically in embB306, embB397, embB497, embB1024, and embC13, which result in EMB MICs of 8 or 14 μg/ml, 5 μg/ml, 12 μg/ml, 3 μg/ml, and 4 μg/ml, respectively, and mutations at embB320, embB324, and embB445, which have not been identified in clinical M. tuberculosis isolates and which result in EMB MICs of 8 μg/ml, 8 μg/ml, and 2 to 8 μg/ml, respectively. To definitively identify the effect of the common clinical embB497 and embB406 mutations on EMB susceptibility, we created a series of isogenic mutants, exchanging the wild-type embB497 CAG codon in EMB-susceptible M. tuberculosis strain 210 for the embB497 CGG codon and the wild-type embB406 GGC codon for either the embB406 GCC, embB406 TGC, embB406 TCC, or embB406 GAC codon. These new mutants showed 6-fold and 3- to 3.5-fold increases in the EMB MICs, respectively. In contrast to the embB306 mutants, the isogenic embB497 and embB406 mutants did not have preferential growth in the presence of isoniazid or rifampin (rifampicin) at their MICs. These results demonstrate that individual embCAB mutations confer low to moderate increases in EMB MICs. Discrepancies between the EMB MICs of laboratory mutants and clinical M. tuberculosis strains with identical mutations suggest that clinical EMB resistance is multigenic and that high-level EMB resistance requires mutations in currently unknown loci.

scholarly journals Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 772
Author(s):  
Javier Conde ◽  
Marlene Schwarzfischer ◽  
Egle Katkeviciute ◽  
Janine Häfliger ◽  
Anna Niechcial ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Titanium Dioxide ◽  
Genetic Risk ◽  
Intestinal Inflammation ◽  
Sodium Sulphate ◽  
Food Additive ◽  
Wild Type ◽  
Dextran Sodium Sulphate ◽  
Risk Gene ◽  
The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

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