Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

PLoS Pathogens

Jin-na Min¹  Mitermayer G. Reis¹  Elsio A. Wunder Jr¹  David A. Relman¹  Charles C. Kim¹  Patty J. Lee²  Janet C. Lindow²  Stephen J. Popper²  Nivison Nery Jr²  Albert I. Ko³  Praveen Mannam³  Ruth R. Montgomery⁴  Guilherme C. Araújo⁵  Yi Yao⁶  Anup Srivastava⁶  Albert C. Shaw⁶  Kathryn P. Hacker⁶  Khadir Raddassi⁷  Jose E. Hagan⁷ 

[1] Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil;Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America;Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America;Department of Neurology, Yale School of Medicine, New Haven, Connecticut, United States of America;Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America;Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America;Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America

关键词: Leptospirosis;    Immune response;    Blood;    Leptospira;    Antibodies;    Microarrays;    Hamsters;    T cells;   

DOI  :  10.1371/journal.ppat.1005943

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY