Rapid reprogramming of haemoglobin structure-function exposes multiple dual-antimicrobial potencies.
The intrinsic cytotoxicity of cell-free haemoglobin (Hb) has hampered the development of reliable Hb-based blood substitutes for over seven decades. Notably, recent evidence shows that the Hb deploys this cytotoxic attack against invading microbes, albeit, through an unknown mechanism. Here, we unraveled a rapid molecular reprogramming of the Hb structure-function triggered by virulent haemolytic pathogens that feed on the haem-iron. On direct contact with the microbe, the Hb unveils its latent antimicrobial potency, where multiple antimicrobial fragments are released, each harbouring coordinated 'dual-action centres': microbe binding and pseudoperoxidase (POX) cycle activity. The activated Hb fragments anchor onto the microbe while the juxtaposed POX instantly unleashes a localized oxidative shock, killing the pathogen-in-proximity. This concurrent action conceivably restricts the diffusion of free radicals. Furthermore, the host astutely protects itself from self-cytotoxicity by simultaneously releasing endogenous antioxidants. We found that this decryption mechanism of antimicrobial potency is conserved in the ancient invertebrate respiratory protein, indicating its fundamental significance. Our definition of dual-antimicrobial centres in the Hb provides vital clues for designing a safer Hb-based oxygen carrier blood substitute.
Du
Ruijuan
R
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
Ho
Bow
B
Ding
Jeak Ling
JL
D000220:Adaptation, Biological / Q000502:physiology; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001802:Blood Substitutes / Q000494:pharmacology; D006454:Hemoglobins / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D006737:Horseshoe Crabs; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008958:Models, Molecular; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D001802:Blood Substitutes; D006454:Hemoglobins; D009195:Peroxidase