+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Inhibition of Classical and Alternative Modes of Respiration in Candida albicans Leads to Cell Wall Remodeling and Increased Macrophage Recognition


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.


          The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans. We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals.

          Related collections

          Most cited references67

          • Record: found
          • Abstract: found
          • Article: not found

          Nonfilamentous C. albicans mutants are avirulent.

          Candida albicans and Saccharomyces cerevisiae switch from a yeast to a filamentous form. In Saccharomyces, this switch is controlled by two regulatory proteins, Ste12p and Phd1p. Single-mutant strains, ste12/ste12 or phd1/phd1, are partially defective, whereas the ste12/ste12 phd1/phd1 double mutant is completely defective in filamentous growth and is noninvasive. The equivalent cph1/cph1 efg1/efg1 double mutant in Candida (Cph1p is the Ste12p homolog and Efg1p is the Phd1p homolog) is also defective in filamentous growth, unable to form hyphae or pseudohyphae in response to many stimuli, including serum or macrophages. This Candida cph1/cph1 efg1/efg1 double mutant, locked in the yeast form, is avirulent in a mouse model.
            • Record: found
            • Abstract: found
            • Article: not found

            Immune recognition. A new receptor for beta-glucans.

            The carbohydrate polymers known as beta-1,3-d-glucans exert potent effects on the immune system - stimulating antitumour and antimicrobial activity, for example - by binding to receptors on macrophages and other white blood cells and activating them. Although beta-glucans are known to bind to receptors, such as complement receptor 3 (ref. 1), there is evidence that another beta-glucan receptor is present on macrophages. Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of beta-glucans.
              • Record: found
              • Abstract: found
              • Article: not found

              An integrated model of the recognition of Candida albicans by the innate immune system.

              The innate immune response was once considered to be a limited set of responses that aimed to contain an infection by primitive 'ingest and kill' mechanisms, giving the host time to mount a specific humoral and cellular immune response. In the mid-1990s, however, the discovery of Toll-like receptors heralded a revolution in our understanding of how microorganisms are recognized by the innate immune system, and how this system is activated. Several major classes of pathogen-recognition receptors have now been described, each with specific abilities to recognize conserved bacterial structures. The challenge ahead is to understand the level of complexity that underlies the response that is triggered by pathogen recognition. In this Review, we use the fungal pathogen Candida albicans as a model for the complex interaction that exists between the host pattern-recognition systems and invading microbial pathogens.

                Author and article information

                Role: Invited Editor
                Role: Editor
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                29 January 2019
                Jan-Feb 2019
                : 10
                : 1
                : e02535-18
                [a ]Kent Fungal Group, School of Biosciences, University of Kent, Kent, United Kingdom
                [b ]MRC Centre for Medical Mycology at the University of Aberdeen, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
                [c ]Department of Infection, Immunity & Cardiovascular Disease and Bateson Centre, University of Sheffield, Sheffield, United Kingdom
                Monash University
                Tel Aviv University
                Author notes
                Address correspondence to Carol A. Munro, c.a.munro@ 123456abdn.ac.uk , or Campbell W. Gourlay, C.W.Gourlay@ 123456kent.ac.uk .
                Author information
                Copyright © 2019 Duvenage et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                : 15 November 2018
                : 12 December 2018
                Page count
                supplementary-material: 10, Figures: 7, Tables: 0, Equations: 0, References: 69, Pages: 18, Words: 11364
                Funded by: wellcome trust;
                Award Recipient :
                Research Article
                Host-Microbe Biology
                Custom metadata
                January/February 2019

                Life sciences
                candida albicans,cell wall,mitochondria,mycology,yeast
                Life sciences
                candida albicans, cell wall, mitochondria, mycology, yeast


                Comment on this article