Author | Lindow, Janet C | |
Author | Wunder Junior, Elsio Augusto | |
Author | Popper, Stephen J | |
Author | Min, Jin-Na | |
Author | Mannam, Praveen | |
Author | Srivastava, Anup | |
Author | Yao, Yi | |
Author | Hacker, Kathryn P | |
Author | Raddassi, Khadir | |
Author | Lee, Patty J | |
Author | Montgomery, Ruth R | |
Author | Shaw, Albert C | |
Author | Hagan, Jose E | |
Author | Araújo, Guilherme C | |
Author | Nery, Nivison | |
Author | Relman, David A | |
Author | Kim, Charles C | |
Author | Reis, Mitermayer Galvão dos | |
Author | Ko, Albert Icksang | |
Access date | 2017-03-24T18:32:06Z | |
Available date | 2017-03-24T18:32:06Z | |
Document date | 2016 | |
Citation | LINDOW, J. C. et al. Cathelicidin Insufficiency in Patients with Fatal Leptospirosis. PLoS Pathogens, v. 12, n. 11, p. e1005943, 2016. | pt_BR |
ISSN | 1935-2727 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/18163 | |
Sponsorship | National Institute of Allergy and Infectious Diseases grants U01AI088752 (AIK), R01AI052473 (AIK), and R01
AI121207 (AIK) | pt_BR |
Language | eng | pt_BR |
Publisher | Public Library of Science | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Leptospirose | pt_BR |
Subject in Portuguese | Catelicidina | pt_BR |
Subject in Portuguese | Humano | pt_BR |
Subject in Portuguese | Fatores de Risco | pt_BR |
Subject in Portuguese | Bactericida | pt_BR |
Subject in Portuguese | Sobrevida | pt_BR |
Title | Cathelicidin Insufficiency in Patients with Fatal Leptospirosis | pt_BR |
Type | Article | pt_BR |
DOI | 10.1371/journal.ppat.1005943 | |
Abstract | 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. | pt_BR |
Affilliation | Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Stanford University School of Medicine. Department of Medicine. Stanford, California, USA | pt_BR |
Affilliation | Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Medicine. Department of Internal Medicine.Section of Rheumatology. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Medicine. Department of Neurology. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Medicine. Department of Internal Medicine.Section of Rheumatology. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Medicine. Department of Internal Medicine. Section of Infectious Diseases. New Haven, Connecticut, USA | pt_BR |
Affilliation | Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Stanford University School of Medicine. Department of Medicine. Stanford, California, USA / Stanford University School of Medicine. Department of Microbiology and Immunology. Stanford, California, USA | pt_BR |
Affilliation | University of California. Department of Medicine. Division of Experimental Medicine. San Francisco, California, USA | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Affilliation | Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil | pt_BR |
Subject | Leptospirosis | pt_BR |
Subject | Cathelicidin | pt_BR |
Subject | Human | pt_BR |
Subject | Risk factors | pt_BR |
Subject | Bactericidal | pt_BR |
Subject | Survival | pt_BR |