Spectrum of Trained Innate Immunity Induced by Low-VirulenceCandidaSpecies against Lethal Polymicrobial Intra-abdominal Infection

ABSTRACTPolymicrobial intra-abdominal infections (IAI) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of polymicrobial IAI and demonstrated that coinfection withCandida albicansandStaphylococcus aureus(C. albicans/S. aureus) results in 80 to 90% mortality in 48 to 72 h due to robust local and systemic inflammation. Surprisingly, inoculation withCandida dubliniensisandS. aureusresulted in minimal mortality, and rechallenge of mice with lethalC. albicans/S. aureusconferred >90% protection up to 60 days postinoculation. Protection was mediated by Gr-1+polymorphonuclear leukocytes, indicating a novel form of trained innate immunity (TII). The purpose of this study was to determine the microbial requirements and spectrum of innate-mediated protection. In addition toCandida dubliniensis, several other low-virulenceCandidaspecies (C. glabrata,C. auris, andC. albicansefg1Δ/Δcph1Δ/Δ) andSaccharomyces cerevisiaeconferred significant protection with or withoutS. aureus. ForC. dubliniensis-mediated protection, hyphal formation was not required, with protection conferred as early as 7 days after primary challenge but not at 120 days, and also following multiple lethalC. albicans/S. aureusrechallenges. This protection also extended to a lethal intravenous (i.v.)C. albicanschallenge but had no effect in theC. albicansvaginitis model. Finally, studies revealed the ability of the low-virulenceCandidaspecies that conferred protection to invade the bone marrow by 24 h post-primary challenge, with a positive correlation between femoral bone marrow fungal infiltration at 48 h and protection upon rechallenge. These results support and further extend the characterization of this novel TII in protection against lethal fungal-bacterial IAI and sepsis.

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Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus

Infection and Immunity ◽

10.1128/iai.01059-15 ◽

2015 ◽

Vol 84 (1) ◽

pp. 90-98 ◽

Cited By ~ 27

Author(s):

Evelyn E. Nash ◽

Brian M. Peters ◽

Paul L. Fidel ◽

Mairi C. Noverr

Keyword(s):

Staphylococcus Aureus ◽

Transcription Factor ◽

Inflammatory Factors ◽

Prostaglandin E ◽

Strongly Correlated ◽

Content Type ◽

Experimental Mouse Model ◽

Experimental Mouse ◽

Intra Abdominal Infection ◽

Abdominal Infections

Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model ofCandida albicans-Staphylococcus aureusintra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement forC. albicansmorphogenesis. However, the contribution of virulence factors coregulated during the yeast-to-hypha transition is unknown. This also raised the question of whether otherCandidaspecies that are unable to form hyphae are as virulent asC. albicansduring polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida(NAC) species with various morphologies andC. albicanstranscription factor mutants (efg1/efg1andcph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed thatS. aureuscoinoculated withC. kruseiorC. tropicaliswas highly lethal, similar toC. albicans, whileS. aureus-C. dubliniensis,S. aureus-C. parapsilosis, andS. aureus-C. glabratacoinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E2(PGE2) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation withC. albicansstrains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that selectCandidaspecies, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE2acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability ofC. albicansto induce mortality from an intra-abdominal polymicrobial infection.

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β-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01173-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1328-1335 ◽

Cited By ~ 18

Author(s):

Rodrigo E. Mendes ◽

Mariana Castanheira ◽

Leanne Gasink ◽

Gregory G. Stone ◽

Wright W. Nichols ◽

...

Keyword(s):

Complicated Urinary Tract Infection ◽

Resistance Mechanisms ◽

Phase 2 ◽

Screening Criteria ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Baseline Visit ◽

Intra Abdominal Infection

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials.Enterobacteriaceaedisplaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content.Enterobacteriaceae(one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTIE. colihad the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producingE. coli, except for oneE. cloacaeisolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBLEnterobacteriaceaeisolate was recovered at the baseline visit. When an ESBLEnterobacteriaceaeisolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-likeE. coliisolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.

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Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice

Infection and Immunity ◽

10.1128/iai.01268-15 ◽

2016 ◽

Vol 84 (3) ◽

pp. 782-789 ◽

Cited By ~ 18

Author(s):

Mingquan Zheng ◽

William Horne ◽

Jeremy P. McAleer ◽

Derek Pociask ◽

Taylor Eddens ◽

...

Keyword(s):

Antimicrobial Activity ◽

Klebsiella Pneumoniae ◽

Lipocalin 2 ◽

T Helper 17 ◽

Content Type ◽

Interleukin 22 ◽

Intra Abdominal Infection ◽

Abdominal Infections

Interleukin 22 (IL-22) is an IL-10-related cytokine produced by T helper 17 (Th17) cells and other immune cells that signals via IL-22 receptor alpha 1 (IL-22Ra1), which is expressed on epithelial tissues, as well as hepatocytes. IL-22 has been shown to have hepatoprotective effects that are mediated by signal transducer and activator of transcription 3 (STAT3) signaling. However, it is unclear whether IL-22 can directly regulate antimicrobial programs in the liver. To test this hypothesis, hepatocyte-specific IL-22Ra1 knockout (Il22Ra1Hep−/−) and Stat3 knockout (Stat3Hep−/−) mice were generated and subjected to intra-abdominal infection withKlebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepaticIl22Ra1andStat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity againstK. pneumoniae, which was dependent on lipocalin 2 (LCN2). However,in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniaebactericidal activityin vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.

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Faculty Opinions recommendation of Pivotal advance: characterization of mouse liver phagocytic B cells in innate immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14267361.15779573 ◽

2012 ◽

Author(s):

Michael Cancro

Keyword(s):

Innate Immunity ◽

B Cells ◽

Mouse Liver

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Faculty Opinions recommendation of Mobilization of hematopoietic stem cells as a result of innate immunity-mediated sterile inflammation in the bone marrow microenvironment-the involvement of extracellular nucleotides and purinergic signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732792335.793568507 ◽

2019 ◽

Author(s):

John F DiPersio

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Innate Immunity ◽

Hematopoietic Stem Cells ◽

Purinergic Signaling ◽

Bone Marrow Microenvironment ◽

Sterile Inflammation ◽

Extracellular Nucleotides ◽

Hematopoietic Stem

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Characterization of mouse bone marrow-derived macrophages differentiated in L929 cell conditioned medium and colony stimulating factor-1 in Listeria monocytogenes in-fection

Can Tho University Journal of Science ◽

10.22144/ctu.jen.2019.037 ◽

2019 ◽

Vol Vol.11(3) ◽

pp. 42

Author(s):

Thao, T.T.

Keyword(s):

Bone Marrow ◽

Listeria Monocytogenes ◽

Conditioned Medium ◽

L929 Cell ◽

Mouse Bone Marrow ◽

Colony Stimulating Factor ◽

Stimulating Factor ◽

Cell Conditioned Medium

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Isolation and characterization of bone marrow-derived mesenchymal progenitor cells with myogenic and neuronal properties

Experimental Cell Research ◽

10.1016/j.yexcr.2006.12.017 ◽

2007 ◽

Vol 313 (5) ◽

pp. 1008-1023 ◽

Cited By ~ 59

Author(s):

Mitsutaka Shiota ◽

Toshio Heike ◽

Munetada Haruyama ◽

Shiro Baba ◽

Atsunori Tsuchiya ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Mesenchymal Progenitor Cells ◽

Isolation And Characterization

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Acetabular and femoral bone marrow in patients with hip osteoarthrosis: Cellular landscape of immune and stromal compartments

Bone Reports ◽

10.1016/j.bonr.2021.100844 ◽

2021 ◽

Vol 14 ◽

pp. 100844

Author(s):

Drenka Trivanovic ◽

Janek Hader ◽

Maximilian Leucht ◽

Theresa Kreuzahler ◽

Bianca Schlierf ◽

...

Keyword(s):

Bone Marrow ◽

Femoral Bone ◽

Femoral Bone Marrow

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The Role of [18F]Fluciclovine PET/CT in the Characterization of High-Risk Primary Prostate Cancer: Comparison with [11C]Choline PET/CT and Histopathological Analysis

Cancers ◽

10.3390/cancers13071575 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1575

Author(s):

Lucia Zanoni ◽

Riccardo Mei ◽

Lorenzo Bianchi ◽

Francesca Giunchi ◽

Lorenzo Maltoni ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Malignant Lesion ◽

Lesion Detection ◽

Histopathological Analysis ◽

Choline Pet ◽

Primary Prostate Cancer ◽

Pet Ct

The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax; target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the “blinded” prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively; whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.

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