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

2015 ◽  
Vol 84 (1) ◽  
pp. 90-98 ◽  
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.

scholarly journals Prostaglandin E2Receptor Antagonist with Antimicrobial Activity against Methicillin-ResistantStaphylococcus aureus

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Mélanie A. C. Ikeh ◽  
Paul L. Fidel ◽  
Mairi C. Noverr
Keyword(s):  
Antimicrobial Activity ◽  
Receptor Antagonist ◽  
Enzyme Inhibitors ◽  
Lethal Dose ◽  
Prostaglandin E ◽  
Protective Effects ◽  
Physiological Concentration ◽  
Content Type ◽  
Abdominal Infections

ABSTRACTPolymicrobial intra-abdominal infections (IAI) involvingCandida albicansandStaphylococcus aureusare associated with severe morbidity and mortality (∼80%). Our laboratory discovered that the immunomodulatory eicosanoid prostaglandin E2(PGE2) plays a key role in the lethal inflammatory response during polymicrobial IAI using a mouse model of infection. In studies designed to uncover key PGE2biosynthesis/signaling components involved in the response, selective eicosanoid enzyme inhibitors and receptor antagonists were selected and prescreened for antimicrobial activity againstC. albicansorS. aureus. Unexpectedly, we found that the EP4receptor antagonist L-161,982 had direct growth-inhibitory effects onS. aureusin vitroat the physiological concentration required to block the PGE2interaction with EP4. This antimicrobial activity was observed with methicillin-sensitiveS. aureusand methicillin-resistantS. aureus(MRSA) strains, with the MIC and minimum bactericidal concentration values for planktonic cells being 50 μg/ml and 100 μg/ml, respectively. In addition, L-161,982 inhibitedS. aureusbiofilm formation and had activity against preformed mature biofilms. More importantly, treatment of mice with L-161,982 following intraperitoneal inoculation with a lethal dose of MRSA significantly reduced the bioburden and enhanced survival. Furthermore, L-161,982 protected mice against the synergistic lethality induced by coinfection withC. albicansandS. aureus. The antimicrobial activity of L-161,982 is independent of EP4receptor inhibitory activity; an alternative EP4receptor antagonist exerted no antimicrobial or protective effects. Taken together, these findings demonstrate that L-161,982 has potent antimicrobial activity against MRSA and may represent a significant therapeutic alternative in improving the prognosis of mono- or polymicrobial infections involving MRSA.

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

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Elizabeth A. Lilly ◽  
Junko Yano ◽  
Shannon K. Esher ◽  
Emily Hardie ◽  
Paul L. Fidel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
Polymorphonuclear Leukocytes ◽  
Candida Dubliniensis ◽  
Content Type ◽  
Hyphal Formation ◽  
Intra Abdominal Infection ◽  
Abdominal Infections ◽  
Femoral Bone Marrow

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.

scholarly journals A Membrane-Bound Transcription Factor is Proteolytically Regulated by the AAA+ Protease FtsH in Staphylococcus aureus

2020 ◽  
Vol 202 (9) ◽  
Author(s):  
Won-Sik Yeo ◽  
Chiamara Anokwute ◽  
Philip Marcadis ◽  
Marcus Levitan ◽  
Mahmoud Ahmed ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Dna Binding ◽  
Cytoplasmic Membrane ◽  
Agar Plate ◽  
Repeat Sequence ◽  
Chromosomal Dna ◽  
Content Type ◽  
Membrane Bound

ABSTRACT In bacteria, chromosomal DNA resides in the cytoplasm, and most transcription factors are also found in the cytoplasm. However, some transcription factors, called membrane-bound transcription factors (MTFs), reside in the cytoplasmic membrane. Here, we report the identification of a new MTF in the Gram-positive pathogen Staphylococcus aureus and its regulation by the protease FtsH. The MTF, named MbtS (membrane-bound transcription factor of Staphylococcus aureus), is encoded by SAUSA300_2640 and predicted to have an N-terminal DNA binding domain and three transmembrane helices. The MbtS protein was degraded by membrane vesicles containing FtsH or by the purified FtsH. MbtS bound to an inverted repeat sequence in its promoter region, and the DNA binding was essential for its transcription. Transcriptional comparison between the ftsH deletion mutant and the ftsH mbtS double mutant showed that MbtS could alter the transcription of over 200 genes. Although the MbtS protein was not detected in wild-type (WT) cells grown in a liquid medium, the protein was detected in some isolated colonies on an agar plate. In a murine model of a skin infection, the disruption of mbtS increased the lesion size. Based on these results, we concluded that MbtS is a new S. aureus MTF whose activity is proteolytically regulated by FtsH. IMPORTANCE Staphylococcus aureus is an important pathogenic bacterium causing various diseases in humans. In the bacterium, transcription is typically regulated by the transcription factors located in the cytoplasm. In this study, we report an atypical transcription factor identified in S. aureus. Unlike most other transcription factors, the newly identified transcription factor is located in the cytoplasmic membrane, and its activity is proteolytically controlled by the membrane-bound AAA+ protease FtsH. The newly identified MTF, named MbtS, has the potential to regulate the transcription of over 200 genes. This study provides a molecular mechanism by which a protease affects bacterial transcription and illustrates the diversity of the bacterial transcriptional regulation.

scholarly journals Candida albicans-Staphylococcus aureus Polymicrobial Peritonitis Modulates Host Innate Immunity

2013 ◽  
Vol 81 (6) ◽  
pp. 2178-2189 ◽  
Author(s):  
Brian M. Peters ◽  
Mairi C. Noverr
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Inflammatory Infiltrate ◽  
Antimicrobial Treatment ◽  
Device Fabrication ◽  
Enzyme Linked Immunosorbent Assay ◽  
Prostaglandin E ◽  
Content Type ◽  
Cox Inhibitor ◽  
Monomicrobial Infection

ABSTRACTDespite advances in medical device fabrication and antimicrobial treatment therapies, fungal-bacterial polymicrobial peritonitis remains a serious complication for surgery patients, those on peritoneal dialysis, and the critically ill. Using a murine model of peritonitis, we have demonstrated that monomicrobial infection withCandida albicansorStaphylococcus aureusis nonlethal. However, coinfection with these same doses leads to a 40% mortality rate and increased microbial burden in the spleen and kidney by day 1 postinfection. Using a multiplex enzyme-linked immunosorbent assay, we have also identified a unique subset of innate proinflammatory cytokines (interleukin-6, granulocyte colony-stimulating factor, keratinocyte chemoattractant, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α) that are significantly increased during polymicrobial versus monomicrobial peritonitis, leading to increased inflammatory infiltrate into the peritoneum and target organs. Treatment of coinfected mice with the cyclooxygenase (COX) inhibitor indomethacin reduces the infectious burden, proinflammatory cytokine production, and inflammatory infiltrate while simultaneously preventing any mortality. Further experiments demonstrated that the immunomodulatory eicosanoid prostaglandin E2(PGE2) is synergistically increased during coinfection compared to monomicrobial infection; indomethacin treatment also decreased elevated PGE2levels. Furthermore, addition of exogenous PGE2into the peritoneal cavity during infection overrode the protection provided by indomethacin and restored the increased mortality and microbial burden. Importantly, these studies highlight the ability of fungal-bacterial coinfection to modulate innate inflammatory events with devastating consequences to the host.

scholarly journals Morphogenesis Is Not Required for Candida albicans-Staphylococcus aureus Intra-Abdominal Infection-Mediated Dissemination and Lethal Sepsis

2014 ◽  
Vol 82 (8) ◽  
pp. 3426-3435 ◽  
Author(s):  
Evelyn E. Nash ◽  
Brian M. Peters ◽  
Glen E. Palmer ◽  
Paul L. Fidel ◽  
Mairi C. Noverr
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Inflammatory Responses ◽  
Early Time ◽  
Neutrophil Infiltration ◽  
Physical Interaction ◽  
Content Type ◽  
Abdominal Infection ◽  
Lethal Sepsis ◽  
Intra Abdominal Infection

ABSTRACTIntra-abdominal polymicrobial infections cause significant morbidity and mortality. An established experimental mouse model ofStaphylococcus aureus-Candida albicansintra-abdominal infection results in ∼60% mortality within 48 h postinoculation, concomitant with amplified local inflammatory responses, while monomicrobial infections are avirulent. The purpose of this study was to characterize early local and systemic innate responses during coinfection and determine the role ofC. albicansmorphogenesis in lethality, a trait involved in virulence and physical interaction withS. aureus. Local and systemic proinflammatory cytokines were significantly elevated during coinfection at early time points (4 to 12 h) compared to those in monoinfection. In contrast, microbial burdens in the organs and peritoneal lavage fluid were similar between mono- and coinfected animals through 24 h, as was peritoneal neutrophil infiltration. After optimizing the model for 100% mortality within 48 h, using 3.5 × 107C. albicans(5× increase), coinfection withC. albicansyeast-locked or hypha-locked mutants showed similar mortality, dissemination, and local and systemic inflammation to the isogenic control. However, coinfection with the yeast-lockedC. albicansmutant given intravenously (i.v.) andS. aureusgiven intraperitoneally (i.p.) failed to induce mortality. These results suggest a unique intra-abdominal interaction between the host andC. albicans-S. aureusthat results in strong inflammatory responses, dissemination, and lethal sepsis, independent ofC. albicansmorphogenesis.

scholarly journals Identification of Specific Components of the Eicosanoid Biosynthetic and Signaling Pathway Involved in Pathological Inflammation during Intra-abdominal Infection withCandida albicansandStaphylococcus aureus

2018 ◽  
Vol 86 (7) ◽  
Author(s):  
Mélanie A. C. Ikeh ◽  
Paul L. Fidel ◽  
Mairi C. Noverr
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Fungal Pathogens ◽  
Interleukin 10 ◽  
Cellular Damage ◽  
Prostaglandin E ◽  
Content Type ◽  
Monomicrobial Infection ◽  
Intra Abdominal Infection ◽  
Cox 1

ABSTRACTPolymicrobial intra-abdominal infections (IAIs) are a significant cause of morbidity and mortality, particularly when fungal pathogens are involved. Our experimental murine model of IAI involving intraperitoneal inoculation ofCandida albicansandStaphylococcus aureusresults in synergistic lethality (∼80%) due to exacerbated inflammation. Monomicrobial infection results in no mortality, despite a microbial burden and dissemination similar to those in a coinfection. In the coinfection model, the immunomodulatory eicosanoid prostaglandin E2(PGE2) was determined to be necessary and sufficient to induce mortality, implicating PGE2as the central mediator of the amplified inflammatory response. The aim of this study was to identify key components of the PGE2biosynthetic and signaling pathway involved in the inflammatory response and explore whether these can be targeted to prevent or reduce mortality. Using selective pharmacological inhibitors of cyclooxygenases (COX) or PGE2receptor antagonists in theC. albicans-S. aureusIAI mouse model, we found that inhibition of COX and/or blocking of PGE2receptor 1 (EP1) or PGE2receptor 3 (EP3) signaling reduced proinflammatory cytokine production, promoted interleukin-10 production, reduced cellular damage in the peritoneal cavity, and, most importantly, significantly improved survival. The greatest effect on survival was obtained by the simultaneous inhibition of COX-1 activity and EP1 and EP3 receptor signaling. Importantly, early inhibition of PGE2pathways dramatically improved the survival of fluconazole-treated mice compared with that achieved with fluconazole treatment alone. These findings indicate that COX-1 and the EP1 and EP3 receptors mediate the downstream pathological effects of PGE2during polymicrobial IAI and may serve as effective therapeutic targets.

scholarly journals Thermal and Nutritional Regulation of Ribosome Hibernation inStaphylococcus aureus

2018 ◽  
Vol 200 (24) ◽  
Author(s):  
Arnab Basu ◽  
Kathryn E. Shields ◽  
Christopher S. Eickhoff ◽  
Daniel F. Hoft ◽  
Mee-Ngan F. Yap
Keyword(s):  
Staphylococcus Aureus ◽  
Transcription Factor ◽  
Stress Response ◽  
Nutrient Sensing ◽  
Dependent Manner ◽  
Nutritional Regulation ◽  
Content Type ◽  
General Stress Response ◽  
Regulatory Pathways ◽  
General Stress

ABSTRACTThe translationally silent 100S ribosome is a poorly understood form of the dimeric 70S complex that is ubiquitously found in all bacterial phyla. The elimination of the hibernating 100S ribosome leads to translational derepression, ribosome instability, antibiotic sensitivity, and biofilm defects in some bacteria. InFirmicutes, such as the opportunistic pathogenStaphylococcus aureus, a 190-amino acid protein calledhibernating-promotingfactor (HPF) dimerizes and conjoins two 70S ribosomes through a direct interaction between the HPF homodimer, with each HPF monomer tethered on an individual 70S complex. While the formation of the 100S ribosome in gammaproteobacteria and cyanobacteria is exclusively induced during postexponential growth phase and darkness, respectively, the 100S ribosomes inFirmicutesare constitutively produced from the lag-logarithmic phase through the post-stationary phase. Very little is known about the regulatory pathways that controlhpfexpression and 100S ribosome abundance. Here, we show that a general stress response (GSR) sigma factor (SigB) and a GTP-sensing transcription factor (CodY) integrate nutrient and thermal signals to regulatehpfsynthesis inS. aureus, resulting in an enhanced virulence of the pathogen in a mouse model of septicemic infection. CodY-dependent regulation ofhpfis strain specific. An epistasis analysis further demonstrated that CodY functions upstream of the GSR pathway in a condition-dependent manner. The results reveal an important link betweenS. aureusstress physiology, ribosome metabolism, and infection biology.IMPORTANCEThe dimerization of 70S ribosomes (100S complex) plays an important role in translational regulation and infectivity of the major human pathogenStaphylococcus aureus. Although the dimerizing factor HPF has been characterized biochemically, the pathways that regulate 100S ribosome abundance remain elusive. We identified a metabolite- and nutrient-sensing transcription factor, CodY, that serves both as an activator and a repressor ofhpfexpression in nutrient- and temperature-dependent manners. Furthermore, CodY-mediated activation ofhpfmasks a secondaryhpftranscript derived from a general stress response SigB promoter. CodY and SigB regulate a repertoire of virulence genes. The unexpected link between ribosome homeostasis and the two master virulence regulators provides new opportunities for alternative druggable sites.

scholarly journals Identification of Effectors of Synergistic Lethality in Candida albicans-Staphylococcus aureus Polymicrobial Intra-abdominal Infection

2021 ◽  
Author(s):  
◽  
Olivia Todd ◽  
Keyword(s):  
Staphylococcus Aureus ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Candida Species ◽  
Toxin Production ◽  
Extracellular Ph ◽  
Abdominal Infection ◽  
Intra Abdominal Infection

Candida albicans, an opportunistic fungal pathogen, and Staphylococcus aureus, a ubiquitous pathogenic bacterium, are among the most prevalent causes of nosocomial infections and cause severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so how microbial “cross-talk” shapes human health and disease. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with C. albicans and S. aureus leads to synergistic lethality whereas monomicrobial infection is nonlethal. Therefore, we aimed to identify staphylococcal virulence determinants that drive lethal synergism in polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that co-infection with C. albicans led to a striking 80-100% mortality rate within 20 h p.i while monomicrobial infections were non-lethal. Use of a GFP-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by qPCR, Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted α- and δ-toxins. C. albicans-mediated elevated toxin production and hemolytic activity was determined to be agrA-dependent and genetic knockout and complementation of hla identified ⍺-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infection 8 h p.i. demonstrated equivalent bacterial burden in the peritoneal cavity, but significantly elevated levels of α-toxin (3-fold) and the eicosanoid PGE2 (4-fold) during co-infection. Importantly, prophylactic passive vaccination using the monoclonal anti-⍺-toxin antibody MEDI4893* led to significantly improved survival rates as compared to treatment with isotype control antibody. Collectively, these results define α-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo. We next sought to unravel the mechanism by which C. albicans drives enhanced staphylococcal ⍺-toxin production. Using a combination of functional and genetic approaches, we determined that an intact agr quorum sensing regulon is necessary for enhanced ⍺-toxin production during coculture and that a secreted candidal factor likely is not implicated in elevating agr activation. As the agr system is pH sensitive, we observed that C. albicans raises the pH during polymicrobial growth and that this correlates with increased agr activity and ⍺-toxin production. By using a C. albicans mutant deficient in alkalinization (stp2Δ/Δ), we confirmed that modulation of the extracellular pH by C. albicans can drive agr expression and toxin production. Additionally, the use of various Candida species (C. glabrata, C. dubliniensis, C. tropicalis, C. parapsilosis, and C. krusei) demonstrated that those capable of raising the extracellular pH correlated with elevated agr activity and ⍺-toxin production during coculture. Overall, we demonstrated that alkalinization of the extracellular pH by the Candida species leads to sustained activation of the staphylococcal agr system. Finally, we correlated ⍺-toxin production with significant increases in biomarkers of liver and kidney damage during coinfection and determined that functional toxin was required for morbidity and mortality. We next sought to determine the candidal effector(s) mediating this enhanced virulence by employing an unbiased screening approach. C. albicans transcription factor mutants were evaluated for their ability to induce S. aureus agr activation in polymicrobial culture. Incredibly, we identified several mutants that displayed defects in augmenting S. aureus agr activity in vitro. Two of the mutants failed to completely synergize with S. aureus in vivo and further analysis revealed the necessity of the uncharacterized C. albicans transcription factor, ZCF13, in driving enhanced toxin production both in vitro and in vivo. Collectively, we identified a novel effector by which C. albicans augments S. aureus virulence and identified a potential mechanism of fungal-bacterial lethal synergism.

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

2016 ◽  
Vol 84 (3) ◽  
pp. 782-789 ◽  
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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