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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.
Highlights
Cryptococcus neoformans, an encapsulated opportunistic fungal pathogen, is the main agent causing cryptococcosis, a fatal systemic disease [1]
Each individual serum was pre-absorbed with C. neoformans H99 or Candida albicans SC5314 cells prior to detection of IgG and IgM antibodies directed against intact cryptococcal cells
We used wild type (WT) Balb/c mice which are susceptible to disseminated cryptococcal infection, and IL-4Ra-deficient (IL-4Ra-/-) Balb/c mice which do not succumb to cryptococcal infection, but develop a latent pulmonary infection [75], after intranasal infection with the C. neoformans serotype D strain 1841
Summary
Cryptococcus neoformans, an encapsulated opportunistic fungal pathogen, is the main agent causing cryptococcosis, a fatal systemic disease [1]. The main risk factor for development of systemic cryptococcal disease is impaired cell-mediated immunity [8], typically occurring in HIV-positive patients with AIDS. These patients account for 80-95% of all cases [7, 8], but individuals receiving immunosuppressive drugs are at risk [8]. Several case reports describe CM or other forms of disseminated cryptococcal disease in persons with humoral immunity defects like immunoglobulin (Ig)G-deficiencies [11,12,13,14] or X-linked hyperIgM syndrome, which is characterized by reduced IgG and IgA serum levels and normal or elevated serum IgM [15,16,17,18]. CM has been found in patients with reduced percentage of IgMproducing memory B cells [19], indicating the contribution of humoral immunity in anti-cryptococcal defense for control of C. neoformans
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