Antibodies Generated against Streptococci Protect in a Mouse Model of Disseminated Aspergillosis

Abstract

Invasive Aspergillosis (I.A.) resulting from infection by Aspergillus fumagatus (A.f.) is a leading cause of death in immunosuppressed populations. There are limited therapeutic options for this disease and currently no vaccine. There is evidence some anti-A.f. monoclonal antibodies can provide protection against I.A. However, vaccine development has been impeded by a paucity of immunological targets on this organism demonstrated to provide protective responses. Sialylated oligosaccharide epitopes found on a variety of pathogens including fungi and Group B Streptococci (GBS) are thought to be major virulence factors of these organisms facilitating pathogen attachment to host cells and modulating complement activation and phagocytosis. As some of these oligosaccharide structures are conserved across kingdoms, we screened a panel monoclonal antibodies raised against GBS serotypes for reactivity to A.f. This approach revealed that SMB19, a GBSIb type-specific mAb, reacts with A.f. conidia and hyphae. The presence of this antibody in mice, as a result of passive or active immunization, or by enforced expression of the SMB19 heavy chain as a transgene, results in significant protection in both intravenous and airway-induced models of I.A. This study demonstrates that some antibodies generated against bacterial polysaccharides engage fungal pathogens and promote their clearance in vivo and thus provide rationale of alternative strategies for the development of vaccines or therapeutic monoclonal antibodies against these organisms.

Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals

“…Similarly, the Group B streptococci type Ib repeating unit (53) is identical to the oligosaccharide sialyl-lactoneotetraosyl-ceramide (44), and has the potential to share epitopes with other gangliosides, including GD1a, expressed on mouse TH2 cells and GD1α expressed preferentially on mouse TH1 cells (54). Anti-Group B streptococcal antibodies raised by immunization of mice with the Group B streptococci type III or type Ib does not appear to cause neuromuscular paralysis or affect T cell functions (55). Another striking characteristic of these antibodies is that their binding to target acidic polysaccharides is calcium dependent (44) such that these antibodies may not bind to oligosaccharides expressed as gangliosides on host cells.…”

“…Since the generation of antibodies to fungal epitopes is difficult, we hypothesized that generating antibodies to a bacterial epitope that is also expressed by fungi would stimulate the production of immunoprotective antibodies. Mice vaccinated with a Group B Streptococci 1b strain containing sialyl-lacto-N-tetraose were protected in a model of disseminated aspergillosis (55). Additionally, i.v., infusion of antibodies against sialyl-lacto-N-tetraose (clone SMB19) or use of SMB19 B cell transgenic mice expressing high levels of endogenous antibodies against sialyl-lacto-N-tetraose without deliberate bacterial immunization resulted in protection.…”

“…Additionally, i.v., infusion of antibodies against sialyl-lacto-N-tetraose (clone SMB19) or use of SMB19 B cell transgenic mice expressing high levels of endogenous antibodies against sialyl-lacto-N-tetraose without deliberate bacterial immunization resulted in protection. Interestingly, J558 B cell transgenic mice with a high frequency of B cells specific for α-1,3-glucan and increased levels of antibody against α-1,3-glucan, which is also a major component of the A. fumigatus hyphal cell wall, were not protected against disseminated aspergillosis (55). Compared with antibodies against α-1,3-glucan, the SMB19 antibody is unique because it preferentially binds the tip of the germinating hyphae (24, 55).…”

“…Interestingly, J558 B cell transgenic mice with a high frequency of B cells specific for α-1,3-glucan and increased levels of antibody against α-1,3-glucan, which is also a major component of the A. fumigatus hyphal cell wall, were not protected against disseminated aspergillosis (55). Compared with antibodies against α-1,3-glucan, the SMB19 antibody is unique because it preferentially binds the tip of the germinating hyphae (24, 55). Calcium pumps and channels regulate the growing tip of the hyphae, and dysregulation of these calcium gradients may inhibit hyphal growth (89).…”

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…149 In a more recent study, administration of a monoclonal IgM antibody targeting a sialylated b-1,3-linked oligosaccharide was found to protect mice from intravenous challenge with A. fumigatus. 150 Excitingly, treatment with this antibody also improved the survival of neutropenic mice infected intratracheally with A. fumigatus though not when these mice were infected intravenously. The mechanism by which this monoclonal antibody mediates protection in neutropenic mice is unclear, but may involve complement and/or enhancing phagocytic killing by non-neutrophil leukocytes.…”