Mechanisms directing stress-specific outputs from a regulatory hub - Hog1 in Candida albicans
Lead Research Organisation:
University of Aberdeen
Department Name: School of Medical Sciences
Abstract
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Technical Summary
Stress-activated protein kinase (SAPK) pathways are important stress signalling modules found in all eukaryotic cells. These pathways comprise of a protein kinase cascade that activates the SAPK by phosphorylation at a conserved TGY motif. However, TGY phosphorylation alone is not sufficient to explain how SAPKs programme stress-specific outputs in response to diverse stress inputs. The Hog1 SAPK is critical for the adaptation of the pathogenic fungus Candida albicans to a diverse range of stresses, and is essential for its virulence. Notably, in addition to TGY phosphorylation, we have found that C. albicans Hog1 is subjected to three further posttranslational modifications in a stress-specific fashion: (a) phosphorylation at T179, (b) oxidation, and (c) S-nitrosylation. Our working hypothesis is that these stress-specific SAPK modifications modulate the stress-specific outputs of Hog1. In this project we will test this, firstly by establishing the impact of blocking these modifications upon the ability of Hog1 to drive stress-specific adaptation in C. albicans. We will then perform complementary interaction, expression and chemogenetic screens to define the Hog1 interactome under different stress conditions. This will allow us to test our prediction that Hog1 phosphorylation, oxidation and S-nitrosylation programme stress-dependent interactions. In addition, the global characterisation of environmentally contingent outputs of the Hog1 interactome will facilitate the identification of those components vital in mediating stress-specific downstream responses. Finally we will establish the impact of the novel posttranslational modifications of Hog1, and the Hog1-dependent stress-specific responses identified in this study, on C. albicans-host interactions and disease progression using well established tools and infection models.
Planned Impact
To achieve the maximum impact for our project we will:
1. Ensure that our scientific observations and datasets are disseminated effectively across the academic community
2. Protect and exploit commercially valuable intellectual property that arises during the course of the project.
3. Contribute to public outreach programmes with a view to enhancing the public understanding of science
4. Further enhance our collaborations in the UK and abroad.
5. Provide an excellent training for our PDRAs in medical mycology, molecular biology, genomics and infection biology.
ACADEMIC DISSEMINATION: We will ensure that our work is disseminated broadly across the academic community through publication in leading journals, presentations at the top international conferences in our field, collaboration with international colleagues, the release of datasets through recognised public repositories and our personal websites, and through the activities of the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology.
RELEVANCE TO HUMAN HEALTH AND COMMERCIAL EXPLOITATION: This project addresses an important biological question of relevance to human health and we will protect and exploit potentially valuable findings. The relevance to human health lies at two levels.
A. We will establish how the Hog1 SAPK regulates key fitness attributes in a major pathogen of humans. Fungal infections represent a significant and understudied medical problem (Science vol 336, 647). C. albicans is widespread in humans, a frequent cause of oral thrush and vaginitis, and the most prevalent cause of life-threatening systemic fungal infections in immunocompromised patients. Candida is the fourth leading cause of hospital-acquired bloodstream infections with a mortality rate above 40%, exceeding that of all Gram-negative bacterial septicaemias. Furthermore, systemic fungal infections significantly extend the average length of stay of intensive care patients, having a major impact upon medical care budgets (~1000 Euros per day per infected patient). Efforts to extend and improve the efficacy of antifungal therapies depend on a better understanding of fungal pathobiology. This project directly addresses this need because stress adaptation is critical for fungal virulence and disease progression, and our project is likely to provide information that leads to improvements in antifungal therapies. This view is reinforced by the support from NovoBiotics, an SME developing novel antimicrobial peptides. Our work will reveal mechanisms by which Hog1-related mechanisms promote the resistance of Candida to these peptides, thereby allowing Novabiotics to develop approaches that circumvent these resistance mechanisms. This principle can be extended to other antifungal therapies because Hog1 also promotes resistance to other types of antifungal drug.
B. SAPKs are highly conserved and the mechanisms we are examining in C. albicans are conserved in human cells. Hence, our findings will be translatable to human systems where the SAPKs p38 and JNK1 regulate cytokine responses, T cell proliferation, apoptosis and differentiation as well as stress adaptation. All of these processes underpin human health and represent attractive therapeutic targets.
PUBLIC OUTREACH: We will continue our contributions to local and national public outreach programmes as detailed in the Pathways to Impact.
COLLABORATIONS: This project involves the establishment of a new international collaboration (with Morten Grotli, University of Gothenburg) which provides access to novel molecules that facilitate a chemogenomic screen for Hog1 interactors. This new collaboration strengthens our network of eminent international collaborators.
TRAINING: We will provide an excellent research training in fungal genomics, molecular and cell biology and infection biology for our PDRAs. Also, we will enhance their career prospects by providing training in transferable skills and networking.
1. Ensure that our scientific observations and datasets are disseminated effectively across the academic community
2. Protect and exploit commercially valuable intellectual property that arises during the course of the project.
3. Contribute to public outreach programmes with a view to enhancing the public understanding of science
4. Further enhance our collaborations in the UK and abroad.
5. Provide an excellent training for our PDRAs in medical mycology, molecular biology, genomics and infection biology.
ACADEMIC DISSEMINATION: We will ensure that our work is disseminated broadly across the academic community through publication in leading journals, presentations at the top international conferences in our field, collaboration with international colleagues, the release of datasets through recognised public repositories and our personal websites, and through the activities of the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology.
RELEVANCE TO HUMAN HEALTH AND COMMERCIAL EXPLOITATION: This project addresses an important biological question of relevance to human health and we will protect and exploit potentially valuable findings. The relevance to human health lies at two levels.
A. We will establish how the Hog1 SAPK regulates key fitness attributes in a major pathogen of humans. Fungal infections represent a significant and understudied medical problem (Science vol 336, 647). C. albicans is widespread in humans, a frequent cause of oral thrush and vaginitis, and the most prevalent cause of life-threatening systemic fungal infections in immunocompromised patients. Candida is the fourth leading cause of hospital-acquired bloodstream infections with a mortality rate above 40%, exceeding that of all Gram-negative bacterial septicaemias. Furthermore, systemic fungal infections significantly extend the average length of stay of intensive care patients, having a major impact upon medical care budgets (~1000 Euros per day per infected patient). Efforts to extend and improve the efficacy of antifungal therapies depend on a better understanding of fungal pathobiology. This project directly addresses this need because stress adaptation is critical for fungal virulence and disease progression, and our project is likely to provide information that leads to improvements in antifungal therapies. This view is reinforced by the support from NovoBiotics, an SME developing novel antimicrobial peptides. Our work will reveal mechanisms by which Hog1-related mechanisms promote the resistance of Candida to these peptides, thereby allowing Novabiotics to develop approaches that circumvent these resistance mechanisms. This principle can be extended to other antifungal therapies because Hog1 also promotes resistance to other types of antifungal drug.
B. SAPKs are highly conserved and the mechanisms we are examining in C. albicans are conserved in human cells. Hence, our findings will be translatable to human systems where the SAPKs p38 and JNK1 regulate cytokine responses, T cell proliferation, apoptosis and differentiation as well as stress adaptation. All of these processes underpin human health and represent attractive therapeutic targets.
PUBLIC OUTREACH: We will continue our contributions to local and national public outreach programmes as detailed in the Pathways to Impact.
COLLABORATIONS: This project involves the establishment of a new international collaboration (with Morten Grotli, University of Gothenburg) which provides access to novel molecules that facilitate a chemogenomic screen for Hog1 interactors. This new collaboration strengthens our network of eminent international collaborators.
TRAINING: We will provide an excellent research training in fungal genomics, molecular and cell biology and infection biology for our PDRAs. Also, we will enhance their career prospects by providing training in transferable skills and networking.
People |
ORCID iD |
Al Brown (Principal Investigator) |
Publications
Ballard E
(2019)
Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism.
in Fungal genetics and biology : FG & B
Ballard E
(2018)
In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis.
in Fungal genetics and biology : FG & B
Ballard E
(2020)
Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus.
in Journal of fungi (Basel, Switzerland)
Ballou ER
(2016)
Lactate signalling regulates fungal ß-glucan masking and immune evasion.
in Nature microbiology
Bohovych I
(2016)
Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses.
in Molecular and cellular biology
Brown AJ
(2014)
Stress adaptation in a pathogenic fungus.
in The Journal of experimental biology
Brown AJ
(2014)
Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels.
in Trends in microbiology
Brown AJP
(2017)
Stress Adaptation.
in Microbiology spectrum
Description | Hog1 is an evolutionarily conserved regulatory hub that controls cellular responses to a variety of different types of stress. The universally accepted paradigm is that Hog1 (which is related to the p38 protein kinase in humans), becomes activated in response to stress by being phosphorylated. As predicted in our original proposal, we have demonstrated that Hog1 becomes differentially modified in response to different stress inputs, and that this tunes the molecular outputs from Hog1, thereby tuning the cellular responses to the particular environmental stress that was imposed. Compromising certain stress-specific functions of Hog1 in Candida albicans attenuates the virulence of this model pathogenic yeast. This was a collaboration with Professor Jan Quinn's group (Newcastle University). |
Exploitation Route | The data could potentially be used by the pharmaceutical companies interested in developing antifungal therapies that target stress sensitivities in Candida albicans. |
Sectors | Pharmaceuticals and Medical Biotechnology |
URL | http://www.abdn.ac.uk/ims/research/profiles/al.brown |
Description | Our non-academic impacts relate to our public outreach activities, which are listed under our Outputs. |
First Year Of Impact | 2016 |
Impact Types | Societal |
Description | Collaboration with Dr Quinn, Newcastle University, |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our collaboration was used to study oxidative stress responses in Candida spec. |
Collaborator Contribution | Our collaboration was used to study oxidative stress responses in Candida spec. |
Impact | Outputs - lots of joint papers |
Description | Collaboration with other Group Leaders in the Aberdeen Fungal Group |
Organisation | University of Aberdeen |
Department | Aberdeen Fungal Group |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Multifarious contributions relating to Candida albicans genomics, molecular biology, systems biology |
Collaborator Contribution | Multifarious contributions relating to Candida albicans cell wall, drug tolerance, immunology and infection biology |
Impact | Outputs - numerous successful collaborations leading to >100 joint papers. |
Description | Adaptation of a fungal pathogen to complex niches in its human host - EMBL Conference: Frontiers in Fungal Systems Biology - September 2014 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Yeast and filamentous fungi are widely used as model eukaryotic organisms and as cell factories for biochemical and protein production. Moreover, various fungal species are leading cause of pathogenic infections in both animals and plants. The main objective of the proposed meeting is to bring together leading experts in various aspects of fungal molecular biology and review the recent progresses driven by the current "OMICS" technologies. The meeting will facilitate interactions between cell biology, structural biology, systems biology and mathematical modelling communities. Moreover new strategies to maximize the impact of "OMICS" approaches on the holistic understanding and system-level modelling of fungal systems and processes will be addressed. This includes cellular architecture (incl. macro-molecular assemblies, compartmentalisation and localisation of proteins and pathways), metabolism (incl. secondary metabolism, protein-metabolite interactions and metabolic engineering), pathogenicity (incl. regulation of virulence and effect of environmental factors), adaptation to extreme environment (esp. thermophily) and genetic engineering. - |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.embl.de/training/events/2014/FUN14-01/introduction/ |
Description | Adaptation of a fungal pathogen to host-imposed stresses - International Conference on Systems, Stiges, Spain: Nov 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation to international community on systems biology |
Year(s) Of Engagement Activity | 2015 |
Description | Blog for Nature Microbiology paper |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This blog described the background to our study described in Nature Microbiology (vol 2, article 16238). |
Year(s) Of Engagement Activity | 2016 |
URL | https://naturemicrobiologycommunity.nature.com/ |
Description | Carbon source-conditional modulation of Candida stress responses - Intl Course on Human Pathogens, La Colle sur Loup, France: May 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation at an Advanced Course |
Year(s) Of Engagement Activity | 2015 |
Description | Fungal Kingdom exhibit at Explorathon during European Researchers Night |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Contribution to the presentation of the "Fungal Kingdom" exhibit at Explorathon in the Aberdeen Science Museum during European Researchers Night [30 September], which was attended by hundreds. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.explorathon.co.uk/aberdeen |
Description | Fungal adaptation affects immune surveillance - Cold Spring Harbor Conference, USA: Sept 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk to international community and postgrad students |
Year(s) Of Engagement Activity | 2015 |
Description | Fungal adaptation, pathogenesis and disease - Infectious Diseases Conference, Putrajaya, Malaysia - April 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk to Far Eastern Community including clinicians |
Year(s) Of Engagement Activity | 2015 |
Description | GRC on Cellular & Molecular Fungal Biology 2016 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Co-Deputy Chair Gordon Research Conference on Cellular & Molecular Fungal Biology |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.grc.org/programs.aspx?id=11335 |
Description | Invited Lecture at Mycology Course, Szeged Hungary |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Lecture at Mycology Course, Szeged Hungary on "Impact of metabolic adaptation upon Candida albicans pathogenicity" |
Year(s) Of Engagement Activity | 2016 |
Description | Invited Lecture at Mycology Systems Biology Course, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Lecture at Mycology Systems Biology Course, UK on "How is Systems Biology increasing our understanding of Candida albicans pathobiology?" |
Year(s) Of Engagement Activity | 2016 |
Description | Invited Talk - University of Dusseldorf, September 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Al Brown presented and Invited talk on "Metabolic adaptation in Candida albicans impacts pathogenicity at multiple levels" at a Molecules of Infection Symposium at the University of Dusseldorf, Germany, in September 2017 |
Year(s) Of Engagement Activity | 2017 |
Description | Invited seminar (NIMR) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Seminar at National Institute for Medical Research, Mill Hill on "Impact of metabolic adaptation on the pathogenicity of Candida albicans" |
Year(s) Of Engagement Activity | 2016 |
Description | Killer Fungus exhibit at Royal Society Summer Science Exhibition |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Contribution to the presentation of the successful "Killer Fungus" exhibit at the Royal Society Summer Science Exhibition in London, which was attended by thousands. Our feedback indicated that this exhibit increased awareness of the impact of fungal diseases upon human health and of the types of research that are being done by UK researchers to address this impact. |
Year(s) Of Engagement Activity | 2016 |
URL | https://royalsociety.org/science-events-and-lectures/summer-science-exhibition/exhibits/killer-fungu... |
Description | Managing stress in a fungal pathogen - Intl Systems Biology Advanced Course, Innsbruck, Austria: Feb 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Lectures and tutorial at Advanced Course on Systems Biology |
Year(s) Of Engagement Activity | 2016 |
Description | Metabolic adaptation affects Candida albicans pathogenicity - Intl Fungal Genetics Conference: Asilomar USA, March 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Outreach to international community |
Year(s) Of Engagement Activity | 2015 |
Description | Podcast for Nature Microbiology paper |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | This podcast described the rationale behind our study described in Nature Microbiology (vol 2, article 16238). |
Year(s) Of Engagement Activity | 2016 |
URL | https://soundcloud.com/mrccmm/lactate-signalling-regulates-glucan-masking-and-immune-evasion |
Description | ProkaGENOMICS Plenary Talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Al Brown presented the Plenary Talk at the ProkaGENOMICS Conference in Gottingen, Germany, in September 2017. the talk was on "Fungus-host interactions during Candida colonisation and infection" |
Year(s) Of Engagement Activity | 2017 |