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Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients?

Applicant Khanna Nina
Number 163648
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2016 - 31.12.2016
Approved amount 212'098.00
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Keywords (3)

Invasive fungal infections; Interaction of interferon-gamma with neutrophils; Host immune response

Lay Summary (German)

Lead
Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients?
Lay summary

Invasive Pilzinfektionen stellen bei immunsupprimierten Patienten insbesondere nach Transplantation ein grosses Problem dar. Obwohl diese Infektionen im Vergleich zu bakteriellen Infekten deutlich seltener sind, sind die Ausgaben am Universitätsspital Basel mit ca. eineinhalb Millionen Schweizer Franken pro Jahr vergleichbar. Trotz wirksamer Therapien sprechen diese Patienten wegen der eingeschränkten Immunität häufig nur unzureichend an. Als Folge müssen diese lange behandelt werden und es entstehen Nebenwirkungen, Selektion von resistenten Erregern und hohe Kosten. Aus diesen Gründen erforschen wir die Abwehr gegenüber den wichtigsten humanpathogenen Pilzen in den häufigsten Patientenpopulationen mit dem Ziel die Risikopatienten zu identifizieren und die Therapie zu optimieren.

In diesem Fortsetzungsgesuch möchten wir die Interaktion pro-inflammatorischer Zytokine (IFN-γ und GM-CSF) und neutrophiler Granulozyten untersuchen. Dies wird helfen den Zusammenhang zwischen innate und adaptiver Immunantwort zu verstehen. Im weiteren möchten wir die Immunzellen, welche die Pilzläsionen in der Lunge infiltrieren genauer an histologischen Präparaten von Patienten mit einer invasiven Schimmelpilzinfektion untersuchen. Dies wird uns helfen, die beteiligten Zellen im Rahmen der Infektion zu identifizieren.

 

Direct link to Lay Summary Last update: 02.01.2016

Lay Summary (English)

Lead
Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients?
Lay summary

The incidence of opportunistic fungal infections caused in particular by Aspergillus (A.) fumigatus and Candida species has increased over the last decades occurring particularly in severely immune compromised patients [1, 2]. Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity. It is however not clear how fungal-specific immunity influences the individual risk of patients and how this knowledge may be exploited to guide prophylaxis and treatment duration. Within the last two years of the Ambizione-Score grant we (i) identified specific immunological markers that predict development and outcome of fungal infections as well as (ii) developed alternative treatment approaches that could restore or improve fungus-specific immunity for these high-risk patients.

 

During the follow-up grant our first goal is to evaluate the interaction of pro-inflammatory cytokines (i.e. IFN-γ and GM-CSF) on PMN in fungal infection. This will allow bridging the innate and adaptive immune response in the context of fungal infections.  Secondarily, we will investigate the immune cells infiltrating pulmonary mold lesions in histopathological sections of patients with pulmonary IA. This will allow to pinpoint key players in fungal infections.

 

 

Direct link to Lay Summary Last update: 02.01.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Vaccines for Invasive Fungal Infections
Khanna Nina, Stuehler Claudia (2017), Vaccines for Invasive Fungal Infections, Springer New York, New York, NY.
Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage
Schürmann Nura, Forrer Pascal, Casse Olivier, Li Jiagui, Felmy Boas, Burgener Anne-Valérie, Ehrenfeuchter Nikolaus, Hardt Wolf-Dietrich, Recher Mike, Hess Christoph, Tschan-Plessl Astrid, Khanna Nina, Bumann Dirk (2017), Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage, in Nature Microbiology, 2(4), 16268-16268.
Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy
Stuehler Claudia, Bernardini Claudia, Elzi Luigia, Stoeckle Marcel, Zimmerli Stefan, Furrer Hansjakob, Günthard Huldrych F., Leibundgut-Landmann Salomé, Battegay Manuel, Khanna Nina (2016), Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy, in AIDS, 30(12), 1923-1933.

Collaboration

Group / person Country
Types of collaboration
Dr. Jürg Vosbeck, Institut Pathologie, Universitätsspital Basel Switzerland (Europe)
- Publication
- Research Infrastructure
Prof. Salomé Leibundgut-Landmann/ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christoph Hess, Immunobiology, DBM Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Adrian Egli, Applied Microbiology, DBM Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Daniel Goldenberger, Universitätsspital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
142403 Relevance of different CD4+ T-cell subsets for antifungal defense. What is aberrant in immunocompromised patients? 01.01.2013 Ambizione

Abstract

The incidence of opportunistic fungal infections caused in particular by Aspergillus (A.) fumigatus and Candida species has increased over the last decades. These infections are most prevalent in patients suffering from leukemia and in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT), immunosuppressive treatment and patients with HIV infection [1, 2]. Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity. So far, it is unclear, which patients are at highest risk and how long prophylaxis and treatment should be provided. Hence, we aimed at identifying specific immunological markers that predict development and outcome as well as alternative treatment approaches that could restore or boost fungus-specific immunity for these patients. Research during the Ambizione-Score fellowshipStudies in patients after HSCT resulted in two publications in the Journal of Infectious Diseases. In the first study, we investigated the immune reconstitution and function of polymorphonuclear (PMN) cells, NK cells and T lymphocytes. We found that patients with probable or proven invasive aspergillosis (IA) after HSCT have significant defects in polymorphonuclear (PMN) cell function to A. fumigatus and reduced restoration of NK-cell counts over one year. These findings are further strengthened by the fact that in patients with well-controlled IA these immunological parameters recovered faster than in patients with poor outcome. Moreover, NK-cell counts below 200 cells/µl (normal values 200 - 400 cells/µl) were associated with the development of probable and proven IA after HSCT and may therefore serve as immunological biomarker [3]. Secondarily, we showed that patients with IA have increased A. fumigatus-specific IFN-? responses to A. fumigatus and show an expansion of T-cell responses to different Aspergillus proteins at the time of disease resolution [3, 4]. This indicates that an A. fumigatus-specific TH1 response is probably beneficial for fungal clearance. Additionally, we could expand Aspergillus protein-specific T cells using new selection methods to foster adoptive T-cell therapy for fungal infections [4].An additional study of HIV-infected patients with Candida esophagitis will be submitted soon. Currently, two promising studies are ongoing, which are also the reason for the requested extension of the Ambizione-SCORE.Aim 1 To evaluate the impact of Th1 cytokines (i.e. IFN-? and GM-CSF) on PMN in fungal infection. Aim 2To investigate the immune cells infiltrating pulmonary mold lesions in histopathological sections.RationaleThis project carries high potential to get a better understanding of the host immune response that may help to guide the duration of antifungal treatment and prophylaxis and to provide the rational for immunomodulatory and immunotherapeutic strategies in patients at risk for invasive fungal infections, which could complement or replace conventional antifungal therapy.
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