Leptospirosis Pathophysiology: Into the Storm of Cytokines

Abstract

Leptospirosis is a neglected tropical zoonosis caused by pathogenic spirochetes of the genus Leptospira. Infected reservoir animals, typically mice and rats, are asymptomatic, carry the pathogen in their renal tubules, and shed pathogenic spirochetes in their urine, contaminating the environment. Humans are accidental hosts of pathogenic Leptospira. Most human infections are mild or asymptomatic. However, 10% of human leptospirosis cases develop into severe forms, including high leptospiremia, multi-organ injuries, and a dramatically increased mortality rate, which can relate to a sepsis-like phenotype. During infection, the triggering of the inflammatory response, especially through the production of cytokines, is essential for the early elimination of pathogens. However, uncontrolled cytokine production can result in a cytokine storm process, followed by a state of immunoparalysis, which can lead to sepsis and associated organ failures. In this review, the involvement of cytokine storm and subsequent immunoparalysis in the development of severe leptospirosis in susceptible hosts will be discussed. The potential contribution of major pro-inflammatory cytokines in the development of tissue lesions and systemic inflammatory response, as well as the role of anti-inflammatory cytokines in contributing to the onset of a deleterious immunosuppressive cascade will also be examined. Data from studies comparing susceptible and resistant mouse models will be included. Lastly, a concise discussion on the use of cytokines for therapeutic purposes or as biomarkers of leptospirosis severity will be provided.

Cytokine response in human leptospirosis with different clinical outcomes: a systematic review

“…In contrast, IL-10 is thought to be the most important antiinflammatory cytokine which restores the immunological homeostasis in leptospirosis [10]. In addition, IL-4 and IL-13 restrict the inflammatory response [10]. The present review revealed elevated levels of the above-mentioned anti-inflammatory cytokines among leptospirosis patients and patients with complicated disease.…”

“…Failure to measure soluble TNF receptor-1 (sTNFR1) might have led to low levels of TNF-α in some studies, as the bound TNF-α will not be included in the analysis [37]. IL-1β, IL-6 and TNF-α were proposed to be pro-inflammatory cytokines which enhance the inflammatory response in leptospirosis [10]. However, the present review found IL-1β to be low among leptospirosis patients, IL-6 to be elevated and TNF-α to be equivocal.…”

“…In contrast, IL-10 is thought to be the most important antiinflammatory cytokine which restores the immunological homeostasis in leptospirosis [10]. In addition, IL-4 and IL-13 restrict the inflammatory response [10].…”

“…Several molecules of the infectious agents like lipopolysaccharides, hemolysins, outer membrane protein and the glycolipoprotein have been implicated with the disease [3,9]. It is proposed that the pathogenesis of leptospirosis is driven through the cytokine response [10].…”

Transbronchial Invasion and Proliferation of Leptospira interrogans in Lung without Inflammatory Cell Infiltration in a Hamster Model

“…Matsui et al (25,26) showed that there was a delay in the expression of the proinflammatory cytokines interleukin 1␤ (IL-1␤), IL-6, and tumor necrosis factor alpha (TNF-␣) and the chemokines CXCL10/IP-1 and CCL3/MIP-1␣ and that a massive overexpression in Leptospira-infected hamsters contrasted with that strictly regulated in mice (asymptomatic carriers). The expression of the antiinflammatory cytokine IL-10 was earlier and greater in mice than in hamsters (27). These findings indicated that in the early stage of Leptospira infection, the hamsters delayed production of cytokines, failed to activate lymphocytes and neutrophils, and allowed leptospires to escape from the host of the immune system.…”