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  • 1.
    Lopes, José Pedro
    et al.
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
    Stylianou, Marios
    Örebro University, School of Science and Technology.
    Backman, Emelie
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
    Holmberg, Sandra
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Claesson, Rolf
    Section Oral Microbiology, Department of Odontology, Umeå University, Umeå, Sweden.
    Urban, Constantin F.
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden; Umeå Centre for Microbial Research, Umeå, Sweden; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
    Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence2018In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 6, article id e02120-18Article in journal (Refereed)
    Abstract [en]

    Microbial colonizers of humans have evolved to adapt to environmental cues and to sense nutrient availability. Oxygen is a constantly changing environmental parameter in different host tissues and in different types of infection. We describe how Candida albicans, an opportunistic fungal pathogen, can modulate the host response under hypoxia and anoxia. We found that high infiltration of polymorphonuclear leukocytes (PMNs) to the site of infection contributes to a low oxygen milieu in a murine subdermal abscess. A persistent hypoxic environment did not affect viability or metabolism of PMNs. Under oxygen deprivation, however, infection with C. albicans disturbed specific PMN responses. PMNs were not able to efficiently phagocytose, produce ROS, or release extracellular DNA traps. Failure to launch an adequate response was caused by C. albicans cell wall masking of β-glucan upon exposure to low oxygen levels which hindered PAMP sensing by Dectin-1 on the surfaces of PMNs. This in turn contributed to immune evasion and enhanced fungal survival. The cell wall masking effect is prolonged by the accumulation of lactate produced by PMNs under low oxygen conditions. Finally, adaptation to oxygen deprivation increased virulence of C. albicans which we demonstrated using a Caenorhabditis elegans infection model.

    IMPORTANCE

    Successful human colonizers have evolved mechanisms to bypass immune surveillance. Infiltration of PMNs to the site of infection led to the generation of a low oxygen niche. Exposure to low oxygen levels induced fungal cell wall masking, which in turn hindered pathogen sensing and antifungal responses by PMNs. The cell wall masking effect was prolonged by increasing lactate amounts produced by neutrophil metabolism under oxygen deprivation. In an invertebrate infection model, C. albicans was able to kill infected C. elegans nematodes within 2 days under low oxygen conditions, whereas the majority of uninfected controls and infected worms under normoxic conditions survived. These results suggest that C. albicans benefited from low oxygen niches to increase virulence. The interplay of C. albicans with innate immune cells under these conditions contributed to the overall outcome of infection. Adaption to low oxygen levels was in addition beneficial for C. albicans by reducing susceptibility to selected antifungal drugs. Hence, immunomodulation of host cells under low oxygen conditions could provide a valuable approach to improve current antifungal therapies.

  • 2.
    Vincent, Leah R.
    et al.
    Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda MD, United States; NIAID, Bethesda MD, United States.
    Kerr, Samuel R.
    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill NC, United States; Yale University, New Haven CT, United States.
    Tan, Yang
    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill NC, United States.
    Tomberg, Joshua
    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill NC, United States.
    Raterman, Erica L.
    Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda MD, United States.
    Hotopp, Julie C. Dunning
    Department of Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore MD, United States.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. World Health Organization Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Swedish Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Nicholas, Robert A.
    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill NC, United States; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill NC, United States.
    Jerse, Ann E.
    Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda MD, United States.
    In Vivo-Selected Compensatory Mutations Restore the Fitness Cost of Mosaic penA Alleles That Confer Ceftriaxone Resistance in Neisseria gonorrhoeae2018In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 2, article id e01905-17Article in journal (Refereed)
    Abstract [en]

    Resistance to ceftriaxone in Neisseria gonorrhoeae is mainly conferred by mosaic penA alleles that encode penicillin-binding protein 2 (PBP2) variants with markedly lower rates of acylation by ceftriaxone. To assess the impact of these mosaic penA alleles on gonococcal fitness, we introduced the mosaic penA alleles from two ceftriaxone-resistant (Cro(r)) clinical isolates (H041 and F89) into a Cro(s) strain (FA19) by allelic exchange and showed that the resultant Cro(r) mutants were significantly outcompeted by the Cro(s) parent strain in vitro and in a murine infection model. Four Cro(r) compensatory mutants of FA19 penA41 were isolated independently from mice that outcompeted the parent strain both in vitro and in vivo. One of these compensatory mutants (LV41C) displayed a unique growth profile, with rapid log growth followed by a sharp plateau/gradual decline at stationary phase. Genome sequencing of LV41C revealed a mutation (G348D) in the acnB gene encoding the bifunctional aconitate hydratase 2/2 methylisocitrate dehydratase. Introduction of the acnB G348D allele into FA19 penA41 conferred both a growth profile that phenocopied that of LV41C and a fitness advantage, although not as strongly as that exhibited by the original compensatory mutant, suggesting the existence of additional compensatory mutations. The mutant aconitase appears to be a functional knockout with lower activity and expression than wild-type aconitase. Transcriptome sequencing (RNA-seq) analysis of FA19 penA41 acnB(G348D) revealed a large set of upregulated genes involved in carbon and energy metabolism. We conclude that compensatory mutations can be selected in Cro(r) gonococcal strains that increase metabolism to ameliorate their fitness deficit.

    IMPORTANCE: The emergence of ceftriaxone-resistant (Cro(r)) Neisseria gonorrhoeae has led to the looming threat of untreatable gonorrhea. Whether Cro resistance is likely to spread can be predicted from studies that compare the relative fitnesses of susceptible and resistant strains that differ only in the penA gene that confers Cro resistance. We showed that mosaic penA alleles found in Cro(r) clinical isolates are outcompeted by the Cro(s) parent strain in vitro and in vivo but that compensatory mutations that allow ceftriaxone resistance to be maintained by increasing bacterial fitness are selected during mouse infection. One compensatory mutant that was studied in more detail had a mutation in acnB, which encodes the aconitase that functions in the tricarboxylic acid (TCA) cycle. This study illustrates that compensatory mutations can be selected during infection, which we hypothesize may allow the spread of Cro resistance in nature. This study also provides novel insights into gonococcal metabolism and physiology.

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