Abstract
Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor–associated kinase–3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection.
Highlights
Neisseria meningitidis (Nm) is an exclusively human bacterium that first adheres to the epithelium of the nasopharynx and may be translocated to invade the bloodstream
The bacterial dose of 5*106 CFU of the wild type strain LNP24198 was sublethal for wild-type mice that recovered after 24 h, whereas 17% mortality of infected congenic transgenic mice were scored after the same period of the bacterial challenge (Fig. 1 and Fig. 2)
This decrease was mainly observed for lymphocytes and monocytes that significantly decreased in infected congenic transgenic mice compared to uninfected congenic transgenic mice (Table 3)
Summary
Neisseria meningitidis (Nm) is an exclusively human bacterium that first adheres to the epithelium of the nasopharynx and may be translocated to invade the bloodstream. Bacteria can cross the blood brain barrier to invade the subarachnoidal space of the central nervous system. During these phases of invasive infection, bacteria interact with different cellular barriers and inflammatory cells. We have recently used transgenic C57B6/SJLJ mice expressing the human transferrin (hTf) as an animal model for invasive meningococcal infections [4]. This model allows the growth of N. meningitidis as it provides bacteria with the physiological iron source and should permit a reliable analysis of host-bacteria interactions. This model permitted the analysis of the virulence of an emergent meningococcal strain in France and showed its ability to provoke septicemia in these mice with the induction of cytokine production [5]
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