Kinetics of Disease Progression and Host Response in a Rat Model of Bubonic Plague

Abstract

Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease. (Am J Pathol 2005,

Role of the Yersinia pestis plasminogen activator in the incidence of distinct septicemic and bubonic forms of flea-borne plague

“…The bacteria multiply and cause acute lymphadenopathy, resulting in the formation of a pathognomonic bubo, an edematous, necrotic, swollen, and painful lymph node (4,5). Bubonic plague usually progresses rapidly to septicemia, resulting in systemic spread and death caused by severe sepsis.…”

In Vitro Efficacy of Antibiotics Commonly Used To Treat Human Plague against Intracellular Yersinia pestis

“…The necessity of such information has recently become apparent with the appreciation that during the initial phase in plague, Y. pestis resides in host macrophages in which it suppresses immune responsiveness and evades innate immunity (25). Therefore, antibiotics which act effectively against both intracellular and extracellular Y. pestis may have the best potential for efficacy.…”

“…However, another potential cause is the failure of antibiotics to kill intracellular Y. pestis (1,13). During the initial 36-to-72-h phase of infection, Y. pestis invades host macrophages to escape innate immunity (25), and this intracellular Y. pestis may be less sensitive to antibiotic killing (1; J. D. Wendte, D. Ponnusamy, and K. D. Clinkenbeard, presented at the 6th ASM Biodefense and Emerging Diseases Research Meeting, Baltimore, MD, 2008). Prophylactic antibiotic treatment for a mass casualty bioterrorism event may benefit from antibiotics that are efficacious against intracellular Y. pestis.…”

Recent Advancement in the Development of Vaccines Against Y. pestis - A Potential Agent of Bioterrorism

“…Y. pestis replicates within macrophages/ dendritic cells as well as in vitro (Cavanaugh et al, 1959;Janssen et al, 1969;Straley et al;1984;Pujal et al, 2005). Nevertheless, detailed kinetic studies of mice infected intranasally (Lathem et al, 2005) and rats infected intradermally (Sebbane et al, 2005), failed to observe significant numbers of intracellular organisms in vivo. However, Y.pestis bacilli were detected in spleen cells and in CD11b-expressing macrophages when mice were infected subcutaneously (Lukaszewski et al, 2005).…”