Respiratory impairment during Pneumocystis Pneumonia (PcP) is closely related to exuberant pulmonary inflammation in response to the organism. Anti-inflammatory corticosteroids (in addition to antibiotics) improves outcome during PcP, but are associated with further immune suppression and co-infection. Our recent studies demonstrate that Pneumocystis cell wall components including 2-glucans (PCBG) interact with alveolar macrophages and epithelial cells stimulating release of cytokines and chemokines that promote inflammatory cell recruitment in the lungs. We further demonstrated that host cell lactosylceramide mediates inflammatory activation in response to Pneumocystis and purified PCBG. Furthermore, glucosylceramide synthase (GCS) inhibitors, which reduce lactosylceramide, not only strongly suppress lung inflammation during PcP, but also strongly suppress the numbers of Pneumocystis organisms in treated mice. Our data further support that Pc itself possesses GCS synthetic molecules necessary for organism viability. Thus, GCS inhibitors represent a potential new class of anti-Pneumocystis agents with both beneficial immune modulating activity as well as direct suppressive effects on Pc. We currently hypothesize that Pneumocystis activates deleterious inflammatory signaling in epithelial cells and macrophages through lactosylceramide mediated MAPK signaling with subsequent cytokine/chemokine generation. We further postulate that glycosphingolipid synthesis in the organism itself occurs through a PCGCS-1 synthetase essential for Pneumocystis viability. These concepts will be addressed through three independent, interrelated, aims.
Aim 1 will evaluate the mechanisms by which Pneumocystis and PCBG activate MAPK signaling in macrophages and epithelial cells, resulting in release of inflammatory cytokines and chemokines.
In Aim 2, we will define the GCS synthetic machinery of Pneumocystis by characterizing GSC-1 synthetase, and its role in Pc viability. Finally, Aim 3 will evaluate specific GCS inhibitors as both prophylactic and therapeutic regimens for PcP, defining their impact on lung inflammation, gas exchange, and organism burdens. Better understanding the roles of lactosylceramide related signaling during PcP will better define mechanisms of lung injury during this infection. More over, this proposal also represents the potential to develop a new class of anti-pneumocystis agents with important effects both on the organism, as well as on organism-driven lung inflammation, during this important infection.

Public Health Relevance

. Pneumocystis pneumonia remains a major cause of illness and death in patients with impaired host defenses, and is therefore of significant relevance for public health particularly in patients with AIDS, malignancies, and following organ transplantation. Lung inflammation during Pneumocystis pneumonia strongly contributes to lung injury and death during this infection. The following studies encompass the development of a new means to suppress both lung inflammation as well as the Pneumocystis organisms themselves during pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062150-17
Application #
7635861
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Peavy, Hannah H
Project Start
1993-07-10
Project End
2013-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
17
Fiscal Year
2009
Total Cost
$377,750
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Cheon, In Su; Son, Young Min; Jiang, Li et al. (2018) Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses. J Allergy Clin Immunol 142:1100-1112
Burnham-Marusich, Amanda R; Hubbard, Breeana; Kvam, Alexander J et al. (2018) Conservation of Mannan Synthesis in Fungi of the Zygomycota and Ascomycota Reveals a Broad Diagnostic Target. mSphere 3:
Nandakumar, Vijayalakshmi; Hebrink, Deanne; Jenson, Paige et al. (2017) Differential Macrophage Polarization from Pneumocystis in Immunocompetent and Immunosuppressed Hosts: Potential Adjunctive Therapy during Pneumonia. Infect Immun 85:
Kottom, Theodore J; Hebrink, Deanne M; Jenson, Paige E et al. (2017) The Interaction of Pneumocystis with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense against Infection. J Immunol 198:3515-3525
Kottom, Theodore J; Hebrink, Deanne M; Jenson, Paige E et al. (2017) Characterization of N-Acetylglucosamine Biosynthesis in Pneumocystis species. A New Potential Target for Therapy. Am J Respir Cell Mol Biol 56:213-222
Kottom, Theodore J; Limper, Andrew H (2016) Evidence for a Pneumocystis carinii Flo8-like transcription factor: insights into organism adhesion. Med Microbiol Immunol 205:73-84
Calero-Bernal, Maria L; Martin-Garrido, Isabel; Donazar-Ezcurra, Mikel et al. (2016) Intermittent Courses of Corticosteroids Also Present a Risk for Pneumocystis Pneumonia in Non-HIV Patients. Can Respir J 2016:2464791
Kottom, Theodore J; Hebrink, Deanne M; Jenson, Paige E et al. (2015) Evidence for Proinflammatory ?-1,6 Glucans in the Pneumocystis carinii Cell Wall. Infect Immun 83:2816-26
Ali, Mohamed F; Driscoll, Christopher B; Walters, Paula R et al. (2015) ?-Glucan-Activated Human B Lymphocytes Participate in Innate Immune Responses by Releasing Proinflammatory Cytokines and Stimulating Neutrophil Chemotaxis. J Immunol 195:5318-26

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