Gene Expression Profiles of Immune Mediators and Histopathological Findings in Animal Models of Leptospirosis: Comparison between Susceptible Hamsters and Resistant Mice

Abstract

Leptospirosis is a widespread zoonosis characterized by multiple organ failure and variable host susceptibility toward pathogenic Leptospira strains. In this study, we put the role of inflammatory mediators in parallel with bacterial burdens and organ lesions by comparing a susceptible animal model, the hamster, and a resistant one, the Oncins France 1 (OF1) mouse, both infected with virulent Leptospira interrogans serovar Icterohaemorrhagiae strain Verdun. Histological observations evidenced edema, congestion, hemorrhage, and inflammatory infiltration in the organs of hamsters, in contrast to limited changes in mice. Using reverse transcription-quantitative PCR techniques, we showed that the relative Leptospira burden progressively increased in hamster tissues, while a rapid clearance was observed in mouse tissues. The early regulation of the proinflammatory mediators interleukin-1␤ (IL-1␤), IL-6, tumor necrosis factor alpha, and cyclo-oxygenase-2 and the chemokines gamma interferon-inducible protein 10 kDa/CXCL10 and macrophage inflammatory protein-1␣/CCL3 in mouse tissues contrasted with their delayed and massive overexpression in hamster tissues. Conversely, the induction of the anti-inflammatory cytokine IL-10 was faster in the resistant than in the susceptible animal model. The role of these cytokines in the pathophysiology of leptospirosis and the implications of their differential regulation in the development of this disease are discussed.

Experimental Hamster Infection with a Strain of Leptospira borgpetersenii Ballum Isolated from a Reservoir Mouse in New Caledonia

“…We described tissue lesions during both the acute and chronic stages of infection. Lethal leptospirosis of hamsters infected with the L. interrogans serovar Icterohaemorrhagiae strain Verdun was previously described 13 and, similarly, led to fatality within 4-6 days, as was also observed for the Ballum B3-13S isolate. This contrasts with the mean period before onset of death observed with another serogroup, Ballum strain 4E, in the same animal model, which died between 8 and 18 days postinfection.…”

“…14 The B3-13S-infected hamsters revealed severe hemorrhaging, as well as edema and congestion in liver, lung, and kidney tissue at the time of death, similar to lesions observed with other strains. 13,15 Hamsters that survived acute disease developed chronic infection with the B3-13S isolate. Indeed, WS staining and specific qPCR techniques confirmed the presence of Leptospira in the kidneys of infected hamsters at 28 days postinfection.…”

Decrease in antithrombin III and prothrombin serum levels contribute to coagulation disorders during leptospirosis

“…Similar to sepsis, human leptospirosis was reported to be associated with high plasma levels of inflammatory cytokines such as TNF-a, IL-6, IL-8, IL-1b and IL-12 (Matsui et al, 2011;Wang et al, 2012;Reis et al, 2013). Indeed, the production of inflammatory cytokines such as TNF-a by CD4+ T-cells after stimulation with antigens of Leptospira was highest in patients with severe disease (Volz et al, 2015).…”

“…Upon Leptospira infection, hamsters that presented features of intense haemorrhage (and, as shown, reduced thrombin inhibitors) also had lower prothrombin levels in the last days of disease, strengthening the activation of the coagulation system, most probably, due to inflammatory cytokines (Matsui et al, 2011). The host response to virulent Leptospira might generate an initial exacerbated coagulation, which would ultimately lead to a lack of coagulation factors and inhibitors during the course of the disease.…”

Genotipificación y evaluación de la dinámica de infección de un aislamiento colombiano de Leptospira santarosai en el modelo experimental hámster

“…(20,(39)(40)(41)(42)(43)(44)(45). Entre estos hallazgos resaltamos los estudios en hámster y tití común (Callithrix jacchus) con especies patógenas de diferente origen y bajo diferentes protocolos de infección.…”