Study of the pathogenic Neisseria species has long been hampered by these bacteria’s stringent host specificity, as they express numerous virulence factors that specifically interact with human ligands. Versions of these ligands present in mice are unable to bind these proteins on Neisseria meningitidis or Neisseria gonorrhoeae; thus, infection studies performed in small animal models lack these critical interactions, limiting our understanding of host-pathogen dynamics during natural infection. Advances in mouse models expressing human versions of these ligands now allow us to better interrogate these interactions in vivo.
Here, we utilized transgenic mice expressing human transferrin (hTf) for infection studies. A sublethal systemic infection was performed in mice heterozygous or homozygous for the hTf transgene, which were infected with either N. meningitidis B16B6 wild-type bacteria or B16B6 lacking transferrin binding protein A (TbpA), an integral membrane protein that binds hTf and scavenges iron from the host. After bacterial clearance, mice were allowed to recover, and serum collected three weeks post-infection was tested for the development of antibodies against N. meningitidis and hTf. Surprisingly, systemic infection with wild-type bacteria elicited serum IgG that recognized hTf; this response was attenuated in mice infected with B16B6 lacking TbpA. All mice developed anti-meningococcal antibodies, indicating that the reduced anti-hTf response was not due to a lack of immune activation in mice infected with the TbpA-deficient strain.
As both components of the bacterial transferrin receptor have been considered attractive candidate vaccine antigens, we performed immunizations with recombinant TbpA and TbpB to determine whether the development of antibodies recognizing a host protein can be vaccine-mediated. Transgenic mice expressing hTf immunized with either TbpA or TbpB developed anti-hTf antibodies, whereas wild-type littermates did not, indicating that this effect was due to endogenously expressed hTf rather than a contaminant in the recombinant protein preparation. Importantly, immunization with antigens engineered to lack binding to hTf prevented the development of self-antibodies in transgenic mice. Together, these results highlight an important consideration for future vaccine development, emphasizing the need for safer vaccines that avoid inducing immune responses against host proteins.