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Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory

Chan, Liana C. ; Rossetti, Maura ; Miller, Lloyd S. ; [et al.]

Proceedings of the National Academy of Sciences ; 2018

In: Proceedings of the National Academy of Sciences Vol. 115, No. 47 ( 2018-11-20)

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 47 ( 2018-11-20)

Abstract: Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Our prior studies discovered a role for protective innate memory against recurrent methicillin-resistant S. aureus (MRSA) SSSI. In the present study, the dynamics and mechanisms of this response were explored in recurrent SSSI in WT mice. Priming by prior infection reduced skin lesion severity and MRSA burden, and protected against dissemination at day 7 but not day 2. Cytokine and cellular signatures in SSSI differed at day 2 versus 7, and were distinct in skin versus blood or spleen. Cytokines associated with protection in skin included increased IL-17, IL-6, monokine inducible by IFN-γ (MIG), and RANTES, while increased IP-10 correlated with protection from dissemination. Cellular signatures of protection included increased Th17, M1 macrophage, and dendritic cell populations in abscesses, and total macrophages in lymph nodes. Priming potentiated S. aureus -specific phagocytic killing by bone marrow-derived macrophages in vitro, and their adoptive transfer into naïve skin afforded protective efficacy in vivo. Present findings indicate that protective immunity in recurrent S. aureus infection is locally targeted, and involves specific memory conferred by macrophages. These insights provide targets for vaccine and immunotherapeutic development against MRSA.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1808353115

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2018

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

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Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients

Mba Medie, Felix ; Sharma-Kuinkel, Batu K. ; Ruffin, Felicia ; [et al.]

Proceedings of the National Academy of Sciences ; 2019

In: Proceedings of the National Academy of Sciences Vol. 116, No. 40 ( 2019-10), p. 20087-20096

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 40 ( 2019-10), p. 20087-20096

Abstract: The role of the host in development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus bacteremia (RB) matched by sex, age, race, hemodialysis status, diabetes mellitus, and presence of implantable medical device was studied to gain insights into this question. One heterozygous g.25498283A 〉 C polymorphism located in the DNMT3A intronic region of chromosome 2p with no impact in messenger RNA (mRNA) expression was more common in RB (21 of 34, 61.8%) than PB (3 of 34, 8.8%) patients ( P = 7.8 × 10 −6 ). Patients with MRSA bacteremia and g.25498283A 〉 C genotype exhibited significantly higher levels of methylation in gene-regulatory CpG island regions (Δmethylation = 4.1%, P 〈 0.0001) and significantly lower serum levels of interleukin-10 (IL-10) than patients with MRSA bacteremia without DNMT3A mutation (A/C: 9.7038 pg/mL vs. A/A: 52.9898 pg/mL; P = 0.0042). Expression of DNMT3A was significantly suppressed in patients with S. aureus bacteremia and in S. aureus -challenged primary human macrophages. Small interfering RNA (siRNA) silencing of DNMT3A expression in human macrophages caused increased IL-10 response upon S. aureus stimulation. Treating macrophages with methylation inhibitor 5-Aza-2′-deoxycytidine resulted in increased levels of IL-10 when challenged with S. aureus . In the murine sepsis model, methylation inhibition increased susceptibility to S. aureus . These findings indicate that g.25498283A 〉 C genotype within DNMT3A contributes to increased capacity to resolve MRSA bacteremia, potentially through a mechanism involving increased methylation of gene-regulatory regions and reduced levels of antiinflammatory cytokine IL-10.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1909849116

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2019

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

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Identification of Candida glabrata Transcriptional Regulators That Govern Stress Resistance and Virulence

Filler, Elan E. ; Liu, Yaoping ; Solis, Norma V. ; [et al.]

American Society for Microbiology ; 2021

In: Infection and Immunity Vol. 89, No. 3 ( 2021-02-16)

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In: Infection and Immunity, American Society for Microbiology, Vol. 89, No. 3 ( 2021-02-16)

Abstract: The mechanisms by which Candida glabrata resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable C. glabrata to withstand these classes of stressors, a library of 215 C. glabrata transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified eight mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, six were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were ADA2 , GCN5 , SPT8 , HOS2 , RPD3 , and SPP1 . Deletion of ADA2 , GCN5 , and RPD3 also increased susceptibility to mammalian host defense peptides. The Δ ada2 and Δ gcn5 mutants had increased susceptibility to other stressors, such as H 2 O 2 and SDS. In the Galleria mellonella model of disseminated infection, the Δ ada2 and Δ gcn5 mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δ ada2 and Δ rpd3 mutants was decreased. Thus, histone modification plays a central role in enabling C. glabrata to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.

Type of Medium: Online Resource

ISSN: 0019-9567 , 1098-5522

URL: Article

DOI: 10.1128/IAI.00146-20

RVK:

XA 10000

Language: English

Publisher: American Society for Microbiology

Publication Date: 2021

detail.hit.zdb_id: 1483247-1

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Cryptococcus gattii VGIII Isolates Causing Infections in HIV/AIDS Patients in Southern California: Identification of the Local Environmental Source as Arboreal

Springer, Deborah J. ; Billmyre, R. Blake ; Filler, Elan E. ; [et al.]

Public Library of Science (PLoS) ; 2014

In: PLoS Pathogens Vol. 10, No. 8 ( 2014-8-21), p. e1004285-

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In: PLoS Pathogens, Public Library of Science (PLoS), Vol. 10, No. 8 ( 2014-8-21), p. e1004285-

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1004285

DOI: 10.1371/journal.ppat.1004285.g001

DOI: 10.1371/journal.ppat.1004285.g002

DOI: 10.1371/journal.ppat.1004285.g003

DOI: 10.1371/journal.ppat.1004285.g004

DOI: 10.1371/journal.ppat.1004285.g005

DOI: 10.1371/journal.ppat.1004285.g006

DOI: 10.1371/journal.ppat.1004285.g007

DOI: 10.1371/journal.ppat.1004285.g008

DOI: 10.1371/journal.ppat.1004285.g009

DOI: 10.1371/journal.ppat.1004285.s001

DOI: 10.1371/journal.ppat.1004285.s002

DOI: 10.1371/journal.ppat.1004285.s003

DOI: 10.1371/journal.ppat.1004285.s004

DOI: 10.1371/journal.ppat.1004285.s005

DOI: 10.1371/journal.ppat.1004285.s006

DOI: 10.1371/journal.ppat.1004285.s007

DOI: 10.1371/journal.ppat.1004285.s008

DOI: 10.1371/journal.ppat.1004285.s009

DOI: 10.1371/journal.ppat.1004285.s010

DOI: 10.1371/journal.ppat.1004285.s011

DOI: 10.1371/journal.ppat.1004285.s012

DOI: 10.1371/journal.ppat.1004285.s013

DOI: 10.1371/journal.ppat.1004285.s014

DOI: 10.1371/journal.ppat.1004285.s015

DOI: 10.1371/journal.ppat.1004285.s016

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2014

detail.hit.zdb_id: 2205412-1

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Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

Snarr, Brendan D. ; Baker, Perrin ; Bamford, Natalie C. ; [et al.]

Proceedings of the National Academy of Sciences ; 2017

In: Proceedings of the National Academy of Sciences Vol. 114, No. 27 ( 2017-07-03), p. 7124-7129

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 27 ( 2017-07-03), p. 7124-7129

Abstract: Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa , respectively. These exopolysaccharides both contain 1,4-linked N -acetyl- d -galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3 h from A. fumigatus and PelA h from P. aeruginosa ) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3 h disrupted A. fumigatus biofilms with an EC 50 of 0.4 nM. PelA h treatment also disrupted preformed A. fumigatus biofilms with EC 50 values similar to those obtained for Sph3 h . In contrast, Sph3 h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3 h or PelA h significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus -induced cell damage for up to 24 h. Intratracheal administration of Sph3 h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1702798114

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2017

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

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Infliximab attenuates early myocardial dysfunction after resuscitation in a swine cardiac arrest model

Niemann, James T. ; Youngquist, Scott ; Rosborough, John P. ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2010

In: Critical Care Medicine Vol. 38, No. 4 ( 2010-04), p. 1162-1167

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In: Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. 4 ( 2010-04), p. 1162-1167

Type of Medium: Online Resource

ISSN: 0090-3493

URL: Article

DOI: 10.1097/CCM.0b013e3181d44324

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2010

detail.hit.zdb_id: 2034247-0

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AtrR Is an Essential Determinant of Azole Resistance in Aspergillus fumigatus

Paul, Sanjoy ; Stamnes, Mark ; Thomas, Grace Heredge ; [et al.]

American Society for Microbiology ; 2019

In: mBio Vol. 10, No. 2 ( 2019-04-30)

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In: mBio, American Society for Microbiology, Vol. 10, No. 2 ( 2019-04-30)

Abstract: Aspergillosis associated with azole-resistant Aspergillus fumigatus has a mortality rate that can approach 90% in certain patient populations. The best-understood avenue for azole resistance involves changes in the cyp51A gene that encodes the target of azole drugs, lanosterol α-14 demethylase. The most common azole resistance allele currently described is a linked change corresponding to a change in the coding sequence of cyp51A and a duplication of a 34-bp region in the promoter leading to a tandem repeat (TR). Our previous studies identified a positively acting transcription factor called AtrR that binds to the promoter of cyp51A as well as that of an important membrane transporter protein gene called abcG1 . In this work, we characterize two different mutant alleles of atrR , either an overproducing or an epitope-tagged form, causing constitutive activation of this factor. Using an epitope-tagged allele of atrR for chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), the genomic binding sites for AtrR were determined. Close to 900 genes were found to have an AtrR response element (ATRE) in their promoter regions. Transcriptome evaluation by RNA sequencing (RNA-seq) indicated that both alleles led to elevated transcription of a subset of target genes. An electrophoretic mobility shift assay and DNase I protection mapping localized the ATREs in both the abcG1 and cyp51A promoters. The ATRE in cyp51A was located within the 34-bp repeat element. Virulence in a murine model was compromised when AtrR was either deleted or overproduced, indicating that the proper dosage of this factor is key for pathogenesis. IMPORTANCE Aspergillus fumigatus is the major filamentous fungal pathogen in humans. Infections associated with A. fumigatus are often treated with azole drugs, but resistance to these antifungal agents is increasing. Mortality from aspergillosis associated with azole-resistant fungi is extremely high. Previous work has identified transcriptional control of the azole drug target-encoding gene cyp51A as an important contributor to resistance in A. fumigatus . Here, we demonstrate that the transcription factor AtrR binds to a region in the cyp51A promoter that is associated with alleles of this gene conferring clinically important azole resistance. Using high-throughput genomic technologies, we also uncover a large suite of target genes controlled by AtrR. These data indicate that AtrR coordinately regulates many different processes involved in drug resistance, metabolism, and virulence. Our new understanding of AtrR function provides important new insight into the pathogenesis of A. fumigatus .

Type of Medium: Online Resource

ISSN: 2161-2129 , 2150-7511

URL: Article

DOI: 10.1128/mBio.02563-18

Language: English

Publisher: American Society for Microbiology

Publication Date: 2019

detail.hit.zdb_id: 2557172-2

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Cardiac Function and the Proinflammatory Cytokine Response After Recovery From Cardiac Arrest in Swine

Niemann, James T. ; Rosborough, John P. ; Youngquist, Scott ; [et al.]

Mary Ann Liebert Inc ; 2009

In: Journal of Interferon & Cytokine Research Vol. 29, No. 11 ( 2009-11), p. 749-758

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In: Journal of Interferon & Cytokine Research, Mary Ann Liebert Inc, Vol. 29, No. 11 ( 2009-11), p. 749-758

Type of Medium: Online Resource

ISSN: 1079-9907 , 1557-7465

URL: Article

DOI: 10.1089/jir.2009.0035

Language: English

Publisher: Mary Ann Liebert Inc

Publication Date: 2009

detail.hit.zdb_id: 1483128-4

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Predictive Value of HIV-1 Viral Load on Risk for Opportunistic Infection

Swindells, Susan ; Evans, Scott ; Zackin, Robert ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2002

In: JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 30, No. 2 ( 2002-06), p. 154-158

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In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 2 ( 2002-06), p. 154-158

Type of Medium: Online Resource

ISSN: 1525-4135

URL: Article

DOI: 10.1097/00042560-200206010-00003

RVK:

XA 10000

RVK:

XA 51942

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2002

detail.hit.zdb_id: 2038673-4

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The Tetraspanin Protein CD37 Regulates IgA Responses and Anti-Fungal Immunity

van Spriel, Annemiek B. ; Sofi, Mariam ; Gartlan, Kate H. ; [et al.]

Public Library of Science (PLoS) ; 2009

In: PLoS Pathogens Vol. 5, No. 3 ( 2009-3-13), p. e1000338-

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In: PLoS Pathogens, Public Library of Science (PLoS), Vol. 5, No. 3 ( 2009-3-13), p. e1000338-

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1000338

DOI: 10.1371/journal.ppat.1000338.g001

DOI: 10.1371/journal.ppat.1000338.g002

DOI: 10.1371/journal.ppat.1000338.g003

DOI: 10.1371/journal.ppat.1000338.g004

DOI: 10.1371/journal.ppat.1000338.g005

DOI: 10.1371/journal.ppat.1000338.s001

DOI: 10.1371/journal.ppat.1000338.s002

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2009

detail.hit.zdb_id: 2205412-1

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