Author:
Gressler A. Elisabeth,Volke Daniela,Firacative Carolina,Schnabel Christiane L.,Müller Uwe,Krizsan Andor,Schulze-Richter Bianca,Brock Matthias,Brombacher Frank,Escandón Patricia,Hoffmann Ralf,Alber Gottfried
Abstract
Cryptococcus neoformans, an opportunistic fungal pathogen ubiquitously present in the environment, causes cryptococcal meningitis (CM) mainly in immunocompromised patients, such as AIDS patients. We aimed to identify disease-associated cryptococcal protein antigens targeted by the human humoral immune response. Therefore, we used sera from Colombian CM patients, with or without HIV infection, and from healthy individuals living in the same region. Serological analysis revealed increased titers of anti-cryptococcal IgG in HIV-negative CM patients, but not HIV-positive CM patients, compared to healthy controls. In contrast, titers of anti-cryptococcal IgM were not affected by CM. Furthermore, we detected pre-existing IgG and IgM antibodies even in sera from healthy individuals. The observed induction of anti-cryptococcal IgG but not IgM during CM was supported by analysis of sera from C. neoformans-infected mice. Stronger increase in IgG was found in wild type mice with high lung fungal burden compared to IL-4Rα-deficient mice showing low lung fungal burden. To identify the proteins targeted by human anti-cryptococcal IgG antibodies, we applied a quantitative 2D immunoproteome approach identifying cryptococcal protein spots preferentially recognized by sera from CM patients or healthy individuals followed by mass spectrometry analysis. Twenty-three cryptococcal proteins were recombinantly expressed and confirmed to be immunoreactive with human sera. Fourteen of them were newly described as immunoreactive proteins. Twelve proteins were classified as disease-associated antigens, based on significantly stronger immunoreactivity with sera from CM patients compared to healthy individuals. The proteins identified in our screen significantly expand the pool of cryptococcal proteins with potential for (i) development of novel anti-cryptococcal agents based on implications in cryptococcal virulence or survival, or (ii) development of an anti-cryptococcal vaccine, as several candidates lack homology to human proteins and are localized extracellularly. Furthermore, this study defines pre-existing anti-cryptococcal immunoreactivity in healthy individuals at a molecular level, identifying target antigens recognized by sera from healthy control persons.
Funder
Universität Leipzig
Alexander von Humboldt-Stiftung
Subject
Immunology,Immunology and Allergy
Reference105 articles.
1. Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis;Kwon-Chung;Cold Spring Harb Perspect Med,2014
2. Pathogenesis of Cryptococcosis in Humans;Negroni,2016
3. Isolation of Cryptococcus neoformans and Other Opportunistic Fungi From Pigeon Droppings;Soltani;J Res Med Sci,2013
4. Isolation of Cryptococcus neoformans From Pigeon Droppings in Ahwaz, Iran;Zarrin;Turk J Med Sci,2010
5. Indoor Dust as a Source of Virulent Strains of the Agents of Cryptococcosis in the Rio Negro Micro-Region of the Brazilian Amazon;Brito-Santos;Microorganisms,2020
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献