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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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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2021-09, Vol.118 (37) |
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| creator | Keshari, Ravi Shankar Popescu, Narcis Ioan Silasi, Robert Regmi, Girija Lupu, Cristina Simmons, Joe H Ricardo, Alonso Coggeshall, K Mark Lupu, Florea |
| description | 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. |
| doi_str_mv | 10.1073/pnas.2104347118 |
| format | article |
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, 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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2104347118</identifier><identifier>PMID: 34507997</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-09, Vol.118 (37)</ispartof><rights>Copyright National Academy of Sciences Sep 14, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-9aae33bc16dac754645ba4acc3b22e629f6d95cd90da23b9631fbd293005c1b13</citedby><cites>FETCH-LOGICAL-c421t-9aae33bc16dac754645ba4acc3b22e629f6d95cd90da23b9631fbd293005c1b13</cites><orcidid>0000-0002-4177-9095 ; 0000-0003-1249-9278 ; 0000-0003-1815-6831 ; 0000-0003-4797-9095 ; 0000-0002-4809-9885 ; 0000-0001-6827-3783 ; 0000-0001-8619-0893</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449412/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449412/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34507997$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Keshari, Ravi Shankar</creatorcontrib><creatorcontrib>Popescu, Narcis Ioan</creatorcontrib><creatorcontrib>Silasi, Robert</creatorcontrib><creatorcontrib>Regmi, Girija</creatorcontrib><creatorcontrib>Lupu, Cristina</creatorcontrib><creatorcontrib>Simmons, Joe H</creatorcontrib><creatorcontrib>Ricardo, Alonso</creatorcontrib><creatorcontrib>Coggeshall, K Mark</creatorcontrib><creatorcontrib>Lupu, Florea</creatorcontrib><title>Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Acute Kidney Injury - etiology</subject><subject>Acute Kidney Injury - pathology</subject><subject>Acute Kidney Injury - prevention & control</subject><subject>Anemia</subject><subject>Anemia, Hemolytic - etiology</subject><subject>Anemia, Hemolytic - pathology</subject><subject>Anemia, Hemolytic - prevention & control</subject><subject>Animals</subject><subject>Anthrax</subject><subject>Anthrax - microbiology</subject><subject>Anthrax - pathology</subject><subject>Baboons</subject><subject>Bacillus anthracis - chemistry</subject><subject>Bacteremia</subject><subject>Biological Sciences</subject><subject>Cell Wall - chemistry</subject><subject>Cell walls</subject><subject>Complement</subject><subject>Complement activation</subject><subject>Complement C5 - antagonists & inhibitors</subject><subject>Complement component C5</subject><subject>Cytotoxicity</subject><subject>Erythrocytes</subject><subject>Etiology</subject><subject>Failure</subject><subject>Female</subject><subject>Fibrinolysis</subject><subject>Hematocrit</subject><subject>Heme</subject><subject>Hemolysis</subject><subject>Hemolytic anemia</subject><subject>Hemolytic uremic syndrome</subject><subject>Immune response</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Injury prevention</subject><subject>Kidneys</subject><subject>Male</subject><subject>Neutralization</subject><subject>Papio</subject><subject>Pathology</subject><subject>Peptidoglycan - toxicity</subject><subject>Peptidoglycans</subject><subject>Renal failure</subject><subject>Sepsis</subject><subject>Sepsis - chemically induced</subject><subject>Sepsis - complications</subject><subject>Toxicity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdkUlvFDEQhS1ERIbAmRuyxIVLJ9568QUJjdikSLkkZ6u8zIyHbrux3Yj5Afxv3EoIy-kd6qunevUQekXJJSU9v5oD5EtGieCip3R4gjaUSNp0QpKnaEMI65tBMHGOnud8JITIdiDP0DkXLeml7Dfo5zZO8-gmFwrettiHg9e--BjwnGJxpmQMe_AhF3xwUxxPxRsMwU0eqlgMZikOf_U2uFPdPi5plToqhwQ_8Ozm4m3cjycDofHBLsZZnN2cfV45DTrGkF-gsx2M2b180At09_HD7fZzc33z6cv2_XVjBKOlkQCOc21oZ8H0rehEq0GAMVwz5jomd52VrbGSWGBcy47TnbZMckJaQzXlF-jdve-86MlZU1MnGNWc_ATppCJ49e8k-IPax-9qEEIKyqrB2weDFL8tLhc1-WzcONaXxCUr1vZU0m4gK_rmP_QYlxRqvJXigyRC8kpd3VMmxZyT2z0eQ4laK1ZrxepPxXXj9d8ZHvnfnfJfAk6mdw</recordid><startdate>20210914</startdate><enddate>20210914</enddate><creator>Keshari, Ravi Shankar</creator><creator>Popescu, Narcis Ioan</creator><creator>Silasi, Robert</creator><creator>Regmi, Girija</creator><creator>Lupu, Cristina</creator><creator>Simmons, Joe H</creator><creator>Ricardo, Alonso</creator><creator>Coggeshall, K Mark</creator><creator>Lupu, Florea</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4177-9095</orcidid><orcidid>https://orcid.org/0000-0003-1249-9278</orcidid><orcidid>https://orcid.org/0000-0003-1815-6831</orcidid><orcidid>https://orcid.org/0000-0003-4797-9095</orcidid><orcidid>https://orcid.org/0000-0002-4809-9885</orcidid><orcidid>https://orcid.org/0000-0001-6827-3783</orcidid><orcidid>https://orcid.org/0000-0001-8619-0893</orcidid></search><sort><creationdate>20210914</creationdate><title>Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons</title><author>Keshari, Ravi Shankar ; Popescu, Narcis Ioan ; Silasi, Robert ; Regmi, Girija ; Lupu, Cristina ; Simmons, Joe H ; Ricardo, Alonso ; Coggeshall, K Mark ; Lupu, Florea</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-9aae33bc16dac754645ba4acc3b22e629f6d95cd90da23b9631fbd293005c1b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acute Kidney Injury - etiology</topic><topic>Acute Kidney Injury - pathology</topic><topic>Acute Kidney Injury - prevention & control</topic><topic>Anemia</topic><topic>Anemia, Hemolytic - etiology</topic><topic>Anemia, Hemolytic - pathology</topic><topic>Anemia, Hemolytic - prevention & control</topic><topic>Animals</topic><topic>Anthrax</topic><topic>Anthrax - microbiology</topic><topic>Anthrax - pathology</topic><topic>Baboons</topic><topic>Bacillus anthracis - chemistry</topic><topic>Bacteremia</topic><topic>Biological Sciences</topic><topic>Cell Wall - chemistry</topic><topic>Cell walls</topic><topic>Complement</topic><topic>Complement activation</topic><topic>Complement C5 - antagonists & inhibitors</topic><topic>Complement component C5</topic><topic>Cytotoxicity</topic><topic>Erythrocytes</topic><topic>Etiology</topic><topic>Failure</topic><topic>Female</topic><topic>Fibrinolysis</topic><topic>Hematocrit</topic><topic>Heme</topic><topic>Hemolysis</topic><topic>Hemolytic anemia</topic><topic>Hemolytic uremic syndrome</topic><topic>Immune response</topic><topic>Infections</topic><topic>Inflammation</topic><topic>Injury prevention</topic><topic>Kidneys</topic><topic>Male</topic><topic>Neutralization</topic><topic>Papio</topic><topic>Pathology</topic><topic>Peptidoglycan - toxicity</topic><topic>Peptidoglycans</topic><topic>Renal failure</topic><topic>Sepsis</topic><topic>Sepsis - chemically induced</topic><topic>Sepsis - complications</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Keshari, Ravi Shankar</creatorcontrib><creatorcontrib>Popescu, Narcis Ioan</creatorcontrib><creatorcontrib>Silasi, Robert</creatorcontrib><creatorcontrib>Regmi, Girija</creatorcontrib><creatorcontrib>Lupu, Cristina</creatorcontrib><creatorcontrib>Simmons, Joe H</creatorcontrib><creatorcontrib>Ricardo, Alonso</creatorcontrib><creatorcontrib>Coggeshall, K Mark</creatorcontrib><creatorcontrib>Lupu, Florea</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Keshari, Ravi Shankar</au><au>Popescu, Narcis Ioan</au><au>Silasi, Robert</au><au>Regmi, Girija</au><au>Lupu, Cristina</au><au>Simmons, Joe H</au><au>Ricardo, Alonso</au><au>Coggeshall, K Mark</au><au>Lupu, Florea</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2021-09-14</date><risdate>2021</risdate><volume>118</volume><issue>37</issue><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Author contributions: R.S.K., N.I.P., C.L., K.M.C., and F.L. designed research; R.S.K., N.I.P., R.S., G.R., C.L., J.H.S., and F.L. performed research; A.R. contributed new reagents/analytic tools; R.S.K., N.I.P., R.S., G.R., C.L., J.H.S., K.M.C., and F.L. analyzed data; and R.S.K., N.I.P., K.M.C., and F.L. wrote the paper.</notes><notes>2K.M.C. and F.L. contributed equally to this work.</notes><notes>Edited by Arturo Casadevall, Johns Hopkins University, Baltimore, MD, and accepted by Editorial Board Member John Collier July 14, 2021 (received for review March 8, 2021)</notes><notes>1R.S.K. and N.I.P. contributed equally to this work.</notes><abstract>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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>34507997</pmid><doi>10.1073/pnas.2104347118</doi><orcidid>https://orcid.org/0000-0002-4177-9095</orcidid><orcidid>https://orcid.org/0000-0003-1249-9278</orcidid><orcidid>https://orcid.org/0000-0003-1815-6831</orcidid><orcidid>https://orcid.org/0000-0003-4797-9095</orcidid><orcidid>https://orcid.org/0000-0002-4809-9885</orcidid><orcidid>https://orcid.org/0000-0001-6827-3783</orcidid><orcidid>https://orcid.org/0000-0001-8619-0893</orcidid><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons |
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