Cryptococcosis

Interactions of the immune system with the human pathogenic fungus Cryptococcus neoformans

Cryptococcus neoformans is a single-cell encapsulated fungus that occurs ubiquitously in the environment. The inhalation of fungal spores is the most important source of infection for humans. In humans with an intact immune system, the ingestion of the fungus does not lead to any direct disease. However, recent findings indicate an association between permanent lung exposure to the fungus and the development of bronchial asthma (1). Cryptococcus neoformans can proliferate in the lungs, spread to the brain and cause life-threatening cryptococcal meningoencephalitis in individuals with an impaired immune system, particularly AIDS patients. More than 160,000 people die of this disease every year worldwide.

The Institute of Immunology has been investigating the interaction of the fungus with the immune system for more than 20 years, focusing in particular on pathogenetic, allergy-associated factors. The studies of the Institute of Immunology have helped to answer important questions about the involvement of the immune system in the disease. Thus it could be shown that messenger substances of the immune system, which play an important role also with allergies, complicate the immunological fight of the mushroom by the body. This misdirected immune response is accompanied by the activation of allergy-associated T-helper cells, which in turn activate alternative-activated macrophages that do not kill the pathogen as usual but leave the fungus undisturbed. It has also been shown that eosinophilic granulocytes release messenger substances during cryptococcosis which additionally promote the allergy-associated T-helper cells (2-6). In this context, a subpopulation of T-helper cells was also investigated, which have a regulatory effect and attempt to counteract the fatal allergy-associated T-helper cell response triggered by the fungus (7). Research projects of this kind can help to develop therapies to prevent a pathological immune response against the fungus (8). Other projects dealt with a phenomenon known as inflammatory immune reconstitution syndrome (IRIS). Immunosuppressed HIV patients receiving antiretroviral therapy and previously infected with Cryptococcus develop an uncontrolled, life-threatening immune response in some cases. The research of the Institute of Immunology has helped to elucidate the mechanisms of this fatal overreaction (9).

References:

(1) Grahnert A, Med Mycol. 2015 Aug;53(6):576-86
(2) Müller U, J Immunol. 2007 Oct 15;179(8):5367-77
(3) Müller U, J Infect Dis. 2008 Dec 1;198(11):1714-21
(4) Müller U, Mucosal Immunol. 2012 May;5(3):299-310
(5) Müller U, Int Immunol. 2013 Aug;25(8):459-70
(6) Piehler D, Am J Pathol. 2011 Aug;179(2):733-44
(7) Schulze B, Eur J Immunol. 2014 Dec;44(12):3596-604
(8) Schulze B, Pathog Dis. 2016 Jun;74(4):ftw020
(9) Eschke M, Eur J Immunol. 2015 Dec;45(12):3339-50

Proposed and approved projects:

DFG:

• "Mechanismen der Interleukin-12p75- und Interleukin-12p40-abhängigen Immunantwort gegen Cryptococcus neoformans und Salmonella enteritidis" (Projekt: 5233484)

• "Funktionsanalyse des Interleukin-4-Rezeptors in der Abwehr von Cryptococcus neoformans anhand von zellspezifischen gendefizienten Mäusen" (Projekt: 5281860)

• "Rolle von Interleukin(IL)-22 in der pulmonalen Abwehr gegen Cryptococcus neoformans" (Projekt: 169376706)

• "Linking early IL-4 producing cell types with allergic pulmonary inflammation induced by infection with Cryptococcus neoformans" (Projekt: 172924446)

• "Identifikation und Charakterisierung von frühen Interleukin (IL)-5/IL-13-produzierenden Zellen und deren induzierende Faktoren im Modell der pulmonalen Kryptokokkose" (Projekt: 220277515)

• "Analyse der Pathomechanismen im Mausmodell des Immunrekonstitutions-Inflammations-Syndroms bei der Infektion mit Cryptococcus neoformans " (Projekt: 221792892)

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Cooperations:

• Prof. Dr. Frank Brombacher (Cape Town, South Africa)

• Dr. Andrew McKenzie, PhD (Cambridge, Great Britain)

• Prof. Dr. Gabriele Köhler (Fulda, Germany)

• Dr. Robert Sabat (Berlin, Germany)

• Prof. Dr. Werner Stenzel (Berlin, Germany)

• Prof. Dr. Regina Treudler (Leipzig, Germany)

Current investigations deal a) with the interactions of Cryptococcus neoformans with pulmonary epithelial cells, which act as mediators between the fungus and the immune system, and b) with the humoral immune response against Cryptococcus neoformans.

Until now, cryptococcal research has always focused on the direct interaction of the fungus with immune cells. However, the first cells that come into contact with the fungal spores after inhalation are the epithelial cells of the lung. For this reason, this interaction between fungus, epithelia and immune cells has been focused on at the Institute of Immunology. Important findings on the involvement of the epithelium in allergy-inducing immune responses during cryptococcosis have already been published (1). Based on this, the interaction of the epithelium with individual cell types of the immune system is investigated using newly established in vitro models. This research is intended to provide a better understanding of the processes during the onset of lung infection and also to answer fundamental questions that are also relevant to the development of allergic asthma.

Proposed and approved projects:

• "In vitro-System zur Charakterisierung des allergischen Potentials human- und tierpathogener Pilze" (Zoonosen-Netz: 01KI1904)

Publications:

(1) Heyen, L, Pathog Dis. 2016 Oct;74(7). pii: ftw086

Cooperations:

• Dr. Matthias Brock (Nottingham, Großbritannien)

Persons involved:

PD Dr. Uwe Müller
Dr. Martina Protschka
Silke Lehnert

Alumni:

Dr. Laura Heyen
Dr. Daniel Piehler

 

In past studies, antibodies against both proteins and capsule components (capsular polysaccharides) of the fungus could be detected in the serum of individuals infected with cryptococci. In the current project, the humoral immune response is examined in more detail in two aspects. In the first part of the project, the reactivity of different antibody isotypes and classes against Cryptococcus neoformans proteins and capsule components is quantified. Following a published study on antibodies in murine sera (1), these investigations will now be continued with human sera. In the second part of the project, immunoreactive proteins of the fungus are identified by immunoproteomic methods. Both approaches should contribute to a better understanding of crypocococcosis and show approaches for new therapeutic strategies.

The project is completed.

Approved projects and scholarships:

• Doktoranden-Förderplatz for Elisabeth Greßler

Publications:

(1) Firacative C, Gressler AE, Sci Rep. 2018 Feb 8;8(1):2681
(2) Gressler AE, Front Immunol. 2021 Jul 23;12:709695

Cooperations:

• Prof. Dr. Ralf Hoffmann (Leipzig, Germany)
• Prof. Dr. Martin von Bergen (Leipzig, Germany)

Persons involved:

Alumni:

Dr. Bianca Schulze
Elisabeth Greßler
Dr. Caroline Firacative