Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/18163
Title: Cathelicidin Insufficiency in Patients with Fatal Leptospirosis
Authors: Lindow, Janet C
Wunder Junior, Elsio Augusto
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 Galvão dos
Ko, Albert Icksang
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
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
Stanford University School of Medicine. Department of Medicine. Stanford, California, USA
Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA
Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA
Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA
Yale School of Medicine. Department of Internal Medicine.Section of Rheumatology. New Haven, Connecticut, USA
Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, Connecticut, USA
Yale School of Medicine. Department of Neurology. New Haven, Connecticut, USA
Yale University School of Medicine. Critical Care and Sleep Medicine. Section of Pulmonary. New Haven, Connecticut, USA
Yale School of Medicine. Department of Internal Medicine.Section of Rheumatology. New Haven, Connecticut, USA
Yale School of Medicine. Department of Internal Medicine. Section of Infectious Diseases. New Haven, Connecticut, USA
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
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Stanford University School of Medicine. Department of Medicine. Stanford, California, USA / Stanford University School of Medicine. Department of Microbiology and Immunology. Stanford, California, USA
University of California. Department of Medicine. Division of Experimental Medicine. San Francisco, California, USA
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
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
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.
Keywords: Leptospirosis
Cathelicidin
Human
Risk factors
Bactericidal
Survival
keywords: Leptospirose
Catelicidina
Humano
Fatores de Risco
Bactericida
Sobrevida
Issue Date: 2016
Publisher: Public Library of Science
Citation: LINDOW, J. C. et al. Cathelicidin Insufficiency in Patients with Fatal Leptospirosis. PLoS Pathogens, v. 12, n. 11, p. e1005943, 2016.
DOI: 10.1371/journal.ppat.1005943
ISSN: 1935-2727
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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