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.
Author Summary Leptospirosis causes over one million cases and nearly 60,000 deaths annually. Infection with the spirochetal bacterium results in a spectrum of symptoms, ranging from mild febrile illness to life-threatening pulmonary hemorrhage syndrome and acute kidney injury. Despite leptospirosis being a leading cause of zoonotic morbidity worldwide, little is known about the human immune response to Leptospira infections, and less about the pathogenic mechanisms resulting in severe disease outcomes. Here, we used a systems biology approach to discover transcripts and immunoprofiles associated with case fatality. We identified new risk factors for high bacterial loads and fatal leptospirosis, including the antimicrobial peptide, cathelicidin, which we validated in an animal model. Cathelicidin therefore represents a potential novel treatment for severe cases of leptospirosis.