Cytokine profiles, apoptosis and pathology of experimental Pasteurella multocida serotype A1 infection in mice

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Abstract

Mice were experimentally infected with Pasteurella multocida serotype A1 to study the cytokine profiles, host cell apoptosis and sequential pathology at different hours of post-infection. Infected mice were dull, anorectic and depressed. A transient leukocytopenia followed by progressive leukocytosis was observed in the course of infection. Serum cytokine profiles showed significantly (P < 0.01) higher amount of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and mouse KC) in the infected mice when compared to control mice. The circulating lymphocytes were apoptotic on annexin V staining. Apoptotic nuclei were detected in splenocytes, hepatocytes and infiltrating leukocytes of the lungs on TUNEL staining. The lungs were grossly congested and hemorrhagic, and showed infiltration with polymorphonuclear cells at early and mononuclear cells in the late hours of infection. Alveolar epithelia, inter-alveolar septa and capillary endothelium of the lungs showed ultrastructural changes. Liver had degenerative changes in histological and ultrathin sections.

Introduction

Pasteurella multocida is a Gram-negative bacterium causing variety of diseases in mammals and birds. P. multocida serogroup A is one of the nasopharyngeal commensal pathogens associated with respiratory diseases in animals. Despite continuing investigations for several decades, the mechanisms by which the isolates of P. multocida incite rapid pathogenesis and acute clinical diseases are poorly understood. The bacterial components such as capsular or outer membrane proteins and endotoxins have been reported as virulence factors responsible for immuno-pathological changes (Boyce and Adler, 2006, Fuller et al., 2000, Hodgson, 2006, Ryu and Kim, 2000), but there is limited information on host factors that play a role in disease pathogenesis in the milieu of host-pathogen interactions. The immuno-pathological changes of endotoxin-producing bacterial infections represent an uncontrolled over-reaction by the host immune system to the endotoxins (Hodgson, 2006, Morrison et al., 1999). This over-reaction takes the form of cascade events, which are mediated by pro-inflammatory cytokines, chemokines and eicosanoids (Hodgson, 2006, Morrison et al., 1999, Yoshie et al., 2001). While these mediators drive the inflammatory reaction, they also aggravate tissue pathology in response to the bacterial components (Hodgson, 2006, Vogel and Hogen, 1990, Yoshie et al., 2001). In addition, bacterial proteins and endotoxins induce host cell apoptosis or cytolysis that results in loss of immunocompetent cells required for combating the infection (Hotchkiss et al., 1997, Stevens and Czuprynski, 1996, Wesche et al., 2005). To understand the pathogenesis of pasteurellosis, it is essential to investigate the profiles of host factors such as pro-inflammatory cytokines and chemokines that are produced in relation to the tissue pathology resulted at various time points of experimental infection. In the present study, we report the pro-inflammatory cytokine profiles, host cell apoptosis and pathology of mice experimentally infected with P. multocida serotype A1.

Section snippets

Animals

Eight week-old Swiss Albino mice (n = 160) of either sex received from the Laboratory Animal Resource centre of the Institute were used in this study. Following 3–4 days of acclimatization period, animals were randomly divided into sixteen groups (n = 10 per group), based on their body weight and size and provided with sterilized food and water ad libitum. Animal care and the experimental procedures were carried out according to the recommendations and specified approval of the Institute Animal

Clinical and hematobiochemical observations

Infected animals were dull and anorectic at early hours of infection (between 6 and 48 h PI). They showed mild crusting around eyes and nose, ruffled hairs and were reluctant to move. During the late hours of infection (between 60 and 96 h PI), animals were depressed, weak and huddled together. Two animals each at 24 and 36 h and one animal at 48 h PI were died due to septicemia. The animals in the control groups appeared normal. Among hematological parameters, the significant changes (P < 0.05) were

Discussion

P. multocida has been associated as a commensal organism in the respiratory tract of mammals and birds, but it is unclear how the bacteria incite acute diseases at times. The current understandings on bacterial interaction with the host suggest that P. multocida establishes a complex interaction in host tissues and utilizes available niches effectively to grow rapidly and cause diseases at favourable circumstances (Boyce and Adler, 2006). However, the mechanisms of acute disease pathogenesis

Acknowledgements

This study was supported by All India Network projects on Bovine Hemorrhagic Septicemia funded by Indian Council of Agricultural Research. Authors are thankful to the technical staffs in Pathology and Bacteriology departments for their help throughout this study.

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