The Hyr1 protein from the fungus Candida albicans is a cross kingdom immunotherapeutic target for Acinetobacter bacterial infection

Abstract

Different pathogens share similar medical settings and rely on similar virulence strategies to cause infections. We have previously applied 3-D computational modeling and bioinformatics to discover novel antigens that target more than one human pathogen. Active and passive immunization with the recombinant N-terminus of Candida albicans Hyr1 (rHyr1p-N) protect mice against lethal candidemia. Here we determine that Hyr1p shares homology with cell surface proteins of the multidrug resistant Gram negative bacterium, Acinetobacter baumannii including hemagglutinin (FhaB) and outer membrane protein A (OmpA). The A. baumannii OmpA binds to C. albicans Hyr1p, leading to a mixed species biofilm. Deletion of HYR1, or blocking of Hyr1p using polyclonal antibodies, significantly reduce A. baumannii binding to C. albicans hyphae. Furthermore, active vaccination with rHyr1p-N or passive immunization with polyclonal antibodies raised against specific peptide motifs of rHyr1p-N markedly improve survival of diabetic or neutropenic mice infected with A. baumannii bacteremia or pneumonia. Antibody raised against one particular peptide of the rHyr1p-N sequence (peptide 5) confers majority of the protection through blocking A. baumannii invasion of host cells and inducing death of the bacterium by a putative iron starvation mechanism. Anti-Hyr1 peptide 5 antibodies also mitigate A. baumannii /C. albicans mixed biofilm formation in vitro. Consistent with our bioinformatic analysis and structural modeling of Hyr1p, anti-Hyr1p peptide 5 antibodies bound to A. baumannii FhaB, OmpA, and an outer membrane siderophore binding protein. Our studies highlight the concept of cross-kingdom vaccine protection against high priority human pathogens such as A. baumannii and C. albicans that share similar ecological niches in immunocompromised patients.

Monoclonal IgM antibodies raised againstCandida albicansHyr1 provide cross-kingdom protection against Gram negative bacteria

“…Our group uses advanced computational molecular modeling and bioinformatic approaches to discover novel vaccine antigen candidates that target more than one high priority human pathogens 14,25,26 . This strategy, known as unnatural or heterologous immunity, has been previously applied in the development of viral and bacterial vaccines in which an antigen protects against another pathogen from the same or from a different kingdom 25 .…”

“…A recombinant form of N-terminus of the Als3p (rAls3p-N) elicits robust Tand B-cell responses and protects mice from both Candida and MRSA infections 26,[28][29][30][31][32][33] . Most recently, we reported that another hyphal cell surface protein of C. albicans, Hyr1p, has 3-D structural homologies with candidate antigens of the MDR GNB A. baumannii 14 . Indeed, using different mouse models, active or passive immunization (with pAb) targeting either Als3p or Hyr1p, protected mice from S. aureus or A. baumannii infections, respectively 14,26,28 .…”

“…Most recently, we reported that another hyphal cell surface protein of C. albicans, Hyr1p, has 3-D structural homologies with candidate antigens of the MDR GNB A. baumannii 14 . Indeed, using different mouse models, active or passive immunization (with pAb) targeting either Als3p or Hyr1p, protected mice from S. aureus or A. baumannii infections, respectively 14,26,28 . In particular, antibodies against one specific surface exposed and highly antigenic15-mer peptide of Hyr1p offered the highest protection to host cells from A. baumannii both in vitro and in vivo 14 .…”

“…baumannii's ability to damage mammalian cells 14 . Thus, we hypothesized that binding of GNB with mAbs would similarly block the invasion and damage of host cells by the MDR GNB, A. baumannii (HUMC1), KP-QR and KPC-RM.…”

“…Recently, we found that the Hyr1p protein shares striking 3D structural, and immunological homologies to antigens present on the Gram negative bacteria (GNB) A. baumannii, including with the putative hemagglutinin/hemolysin protein FhaB, and a number of siderophore-binding proteins 14 . Polyclonal antibodies (pAbs) against peptides derived from the Hyr1p N-terminus blocked A. baumannii-mediated lung epithelial cell invasion, and killed the bacterium in vitro 14 . Importantly, anti-Hyr1p pAb completely protected mice from A. baumannii infections.…”