Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of , leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-09, Vol.118 (37)
Main Authors: Keshari, Ravi Shankar, Popescu, Narcis Ioan, Silasi, Robert, Regmi, Girija, Lupu, Cristina, Simmons, Joe H, Ricardo, Alonso, Coggeshall, K Mark, Lupu, Florea
Format: Article
Language:English
Subjects:
Acute Kidney Injury - etiology
Acute Kidney Injury - pathology
Acute Kidney Injury - prevention & control
Anemia
Anemia, Hemolytic - etiology
Anemia, Hemolytic - pathology
Anemia, Hemolytic - prevention & control
Animals
Anthrax
Anthrax - microbiology
Anthrax - pathology
Baboons
Bacillus anthracis - chemistry
Bacteremia
Biological Sciences
Cell Wall - chemistry
Cell walls
Complement
Complement activation
Complement C5 - antagonists & inhibitors
Complement component C5
Cytotoxicity
Erythrocytes
Etiology
Failure
Female
Fibrinolysis
Hematocrit
Heme
Hemolysis
Hemolytic anemia
Hemolytic uremic syndrome
Immune response
Infections
Inflammation
Injury prevention
Kidneys
Male
Neutralization
Papio
Pathology
Peptidoglycan - toxicity
Peptidoglycans
Renal failure
Sepsis
Sepsis - chemically induced
Sepsis - complications
Toxicity
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Summary:Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of , leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2104347118