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 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.
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Janet C
http://orcid.org/0000-0003-3235-3698
JC
Lindow
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Elsio A
EA
Wunder
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
Stephen J
http://orcid.org/0000-0002-2001-945X
SJ
Popper
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Jin-Na
JN
Min
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Praveen
P
Mannam
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Anup
A
Srivastava
Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.
Yi
Y
Yao
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
Kathryn P
KP
Hacker
Department of Neurology, Yale School of Medicine, New Haven, Connecticut, United States of America.
Khadir
K
Raddassi
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Patty J
http://orcid.org/0000-0001-9906-1628
PJ
Lee
Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.
Ruth R
RR
Montgomery
Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.
Albert C
AC
Shaw
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Jose E
http://orcid.org/0000-0002-1837-6319
JE
Hagan
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Guilherme C
GC
Araújo
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Nivison
N
Nery
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
David A
DA
Relman
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
Charles C
http://orcid.org/0000-0001-6474-8227
CC
Kim
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Mitermayer G
MG
Reis
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, Bahia, Brazil.
Albert I
AI
Ko
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism*; D001938:Brazil; D016000:Cluster Analysis; D006224:Cricetinae; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007922:Leptospirosis / Q000276:immunology*; D008647:Mesocricetus; D020411:Oligonucleotide Array Sequence Analysis; D012307:Risk Factors; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins