Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives

Abstract

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as "possible" or "probable" cases but not "proven". Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy.

Keywords: Aspergillus infection; diagnosis; invasive aspergillosis; monoclonal antibody; therapy.

Figure 1

The pathogenesis of invasive aspergillosis. (a) Inhalation. Airborne conidia are inhaled into the respiratory system of the immunosuppressed host. (b) Clearance escape. The resting conidia escape primary clearance and immune attack. (c) Adherence. The rodlet protein cover and melanin of the resting conidia mask the pathogen-associated molecular patterns (PAMPs) and protect the conidia from oxidative stress and the environment (UV) and host (reactive oxygen species, ROS), and from being recognized and attacked by the host. Lectin A and sialic acid residues mediate the adherence and colonization onto the fucose residues of N-glycans and fibronectin of the pulmonary epithelial cells. (d) Internalization. The swollen conidia release the surface hydrophobic layer and melanin, exposing more PAMPs, such as β (1-3)-glucan and calcineurin A (Cal A), to be recognized by dectin-1 and integrin α5β1, respectively, on the epithelial cell wall, inducing the internalization. In addition, the formation of actin polymerization and activation of phospholipase D (PLD) both boost the internalization. (e) Evasion and germination. The swollen conidia in the endosome evade the phagolysosome killing and germinate into tubes and hyphae. Galactosaminogalactan (GAG) on the hyphae wall can be released as a soluble molecule, mediating adhesion, inhibiting phagocytosis and suppressing the host inflammatory responses by masking of β (1,3)-glucan on the hyphal wall. (f) Destruction. GAG released by mature hyphae facilitates the induction of neutrophil apoptosis and prohibits formation of neutrophil extracellular traps (NETosis), and pre-inflammation by induction of IL-IRa. The secreted gliotoxin and fumagillin are involved in pathogen internalization, cell apoptosis, host immune inhibition and tissue degradation. (g) Invasive aspergillosis. The tissue-invasive hyphae penetrate the alveolar epithelia and basement membrane into the blood vessel, disseminating to the whole body and causing IA (h). +: promote; −: inhibit.

Figure 2

Monoclonal antibody-based modes to suppress or eliminate Aspergillus.