Cathelicidin Insufficiency in Patients with Fatal Leptospirosis
Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10–50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms...
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| Language: | English |
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Public Library of Science
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094754/ |
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pubmed-5094754 |
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pubmed-50947542016-11-18 Cathelicidin Insufficiency in Patients with Fatal Leptospirosis Lindow, Janet C. Wunder, Elsio A. Popper, Stephen J. Min, Jin-na Mannam, Praveen Srivastava, Anup Yao, Yi Hacker, Kathryn P. Raddassi, Khadir Lee, Patty J. Montgomery, Ruth R. Shaw, Albert C. Hagan, Jose E. Araújo, Guilherme C. Nery, Nivison Relman, David A. Kim, Charles C. Reis, Mitermayer G. Ko, Albert I. Research Article Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10–50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis. Public Library of Science 2016-11-03 /pmc/articles/PMC5094754/ /pubmed/27812211 http://dx.doi.org/10.1371/journal.ppat.1005943 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Lindow, Janet C. Wunder, Elsio A. Popper, Stephen J. Min, Jin-na Mannam, Praveen Srivastava, Anup Yao, Yi Hacker, Kathryn P. Raddassi, Khadir Lee, Patty J. Montgomery, Ruth R. Shaw, Albert C. Hagan, Jose E. Araújo, Guilherme C. Nery, Nivison Relman, David A. Kim, Charles C. Reis, Mitermayer G. Ko, Albert I. |
| spellingShingle |
Lindow, Janet C. Wunder, Elsio A. Popper, Stephen J. Min, Jin-na Mannam, Praveen Srivastava, Anup Yao, Yi Hacker, Kathryn P. Raddassi, Khadir Lee, Patty J. Montgomery, Ruth R. Shaw, Albert C. Hagan, Jose E. Araújo, Guilherme C. Nery, Nivison Relman, David A. Kim, Charles C. Reis, Mitermayer G. Ko, Albert I. Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| author_facet |
Lindow, Janet C. Wunder, Elsio A. Popper, Stephen J. Min, Jin-na Mannam, Praveen Srivastava, Anup Yao, Yi Hacker, Kathryn P. Raddassi, Khadir Lee, Patty J. Montgomery, Ruth R. Shaw, Albert C. Hagan, Jose E. Araújo, Guilherme C. Nery, Nivison Relman, David A. Kim, Charles C. Reis, Mitermayer G. Ko, Albert I. |
| author_sort |
Lindow, Janet C. |
| title |
Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| title_short |
Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| title_full |
Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| title_fullStr |
Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| title_full_unstemmed |
Cathelicidin Insufficiency in Patients with Fatal Leptospirosis |
| title_sort |
cathelicidin insufficiency in patients with fatal leptospirosis |
| description |
Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10–50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis. |
| publisher |
Public Library of Science |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094754/ |
| _version_ |
1613712301275217920 |