AuthorLindow, Janet C.
Wunder, Elsio A.
Popper, Stephen J.
Hacker, Kathryn P.
Lee, Patty J.
Montgomery, Ruth R.
Shaw, Albert C.
Hagan, Jose E.
Araújo, Guilherme C.
Relman, David A.
Kim, Charles C.
Reis, Mitermayer G.
Ko, Albert I.
AffiliationUniv Arizona, Dept Med, Div Translat & Regenerat Med
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationCathelicidin Insufficiency in Patients with Fatal Leptospirosis 2016, 12 (11):e1005943 PLOS Pathogens
RightsThis is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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AbstractLeptospirosis 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.
VersionFinal published version
SponsorsNational Institute of Allergy and Infectious Diseases [U01AI088752, R01AI052473, R01 AI121207, F31AI114245-02, U19 AI109761]; Fogarty International Center [R01TW009504]; American Society for Tropical Medicine and Hygiene Gorgas Memorial Institute Research Award; Fogarty International Center, Global Health Fellows and Scholars Research Training Grant [R25 TW009338]; Minsterio da Ciencia, Tecnologia, e Inovacao Ciencias Sem Fronteiras Bolsa; National Institute on Aging [K24 AG042489]
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