Monoclonal IgM Antibodies Targeting Candida albicans Hyr1 Provide Cross-Kingdom Protection Against Gram-Negative Bacteria

Abstract

Recent years have seen an unprecedented rise in the incidence of multidrug-resistant (MDR) Gram-negative bacteria (GNBs) such as Acinetobacter and Klebsiella species. In view of the shortage of novel drugs in the pipeline, alternative strategies to prevent, and treat infections by GNBs are urgently needed. Previously, we have reported that the Candida albicans hypha-regulated protein Hyr1 shares striking three-dimensional structural homology with cell surface proteins of Acinetobacter baumannii. Moreover, active vaccination with rHyr1p-N or passive immunization with anti-Hyr1p polyclonal antibody protects mice from Acinetobacter infection. In the present study, we use molecular modeling to guide design of monoclonal antibodies (mAbs) generated against Hyr1p and show them to bind to priority surface antigens of Acinetobacter and Klebsiella pneumoniae. The anti-Hyr1 mAbs block damage to primary endothelial cells induced by the bacteria and protect mice from lethal pulmonary infections mediated by A. baumannii or K. pneumoniae. Our current studies emphasize the potential of harnessing Hyr1p mAbs as a cross-kingdom immunotherapeutic strategy against MDR GNBs.

Pathogenesis of Respiratory Viral and Fungal Coinfections

“…Therefore, studies focusing on understanding the role of humoral immunity during viral and fungal coinfections are scarce. Of note, monoclonal antibodies targeting Candida albicans can confer protection against lethal pulmonary infections by Gram-negative bacteria in mice ( 486 ), while Pneumocystis infection can protect mice against subsequent influenza infection due to the enhancement of the influenza virus-specific antibody response ( 487 ). Susceptibility mechanisms could include the activation of low-affinity cellular responses and/or production of nonneutralizing antibodies that could facilitate coinfections ( 488 – 490 ).…”

The threat of multidrug-resistant/extensively drug-resistant Gram-negative respiratory infections: another pandemic

“…Panobacumab and AR-105 target polysaccharides produced by P. aeruginosa and are under investigation as adjuncts with standard-of-care antibiotics for nosocomial P. aeruginosa infections [ 95 , 96 ]. Continued advancements in molecular modelling and bioinformatics are likely to yield additional targets for pathogens associated with MDR Gram-negative respiratory infections [ 97 ].…”

Heterologous immunity induced by 1st generation COVID-19 vaccines and its role in developing a pan-coronavirus vaccine

“…A study by Youssef et al. identified a Hyrl antigen specific IgM antibody from a fungal infection, Candida albicans , that was able to cross-react with two Gram-negative bacteria, Acinetobacter baumannii and Klebsiella pneumoniae ( 11 ). The study found there was structural homology between the hypha-regulated protein (Hyr1) of C. albicans and the cell surface protein of A. baumannii.…”

“…The study found there was structural homology between the hypha-regulated protein (Hyr1) of C. albicans and the cell surface protein of A. baumannii. Furthermore, the study found that active vaccination with Hyr1p-N protein or passive immunization with the IgM antibody to that protein protects mice from A. baumannii infections and prevents severe bacteremia ( 11 ). This IgM antibody illustrates a cross-kingdom humoral response that is not only capable of cross-reacting with both a bacterial and fungal protein, but is also functionally protective against A. baumannii infections and their pathologies.…”