A number of infectious agents, including emerging pathogens and agents responsible for nosocomial infections, reach the blood during infection. Colonization of the bloodstream induces different types of severe pathological consequences such as septicemia and meningitis. Despite the availability of antibiotics these infections resulting in sequels and high death rates remain a major concern in intensive care units and emergency rooms. A better understanding of the mechanisms of disease is a necessary step to the identification of innovative treatments. We study the pathogenesis of Neisseria meningitidis (or meningococcus), a Gram-negative bacterium that recapitulates these different pathological effects. This bacterium asymptomatically colonizes the human nasopharynx and pathology is initiated when the bacterium crosses the nasopharynx epithelium and reaches the bloodstream where they survive and proliferate.
Outstanding questions in terms of understanding N. meningitidis pathogenesis include: how do bacteria cross the epithelium and reach the bloodstream? How do they survive in the blood? How do they damage vessels and reach the cerebrospinal fluid (i.e. cause septic shock and meningitis)?
We have recently identified a mechanism that facilitates the crossing of the epithelium by the bacterium. This mechanism relies on the activity of a bacterial transferase that modifies the major component of type IV pili.
We are now extensively characterizing this enzyme at the structural and biochemical level to design inhibitors. To study the blood phase of the infection we take advantage of in vitro models to explore the biogenesis and function of type IV pili and how they mediate intricate cross-talk with human endothelial cells in culture. Perhaps most importantly we have developed an animal model based on the xenograft of human skin onto immunodeficient mice. Because of its strict human specificity N. meningitidis type IV pili bind only to capillaries present in the human tissue. Strikingly, adhesion along vessels triggers local inflammation, coagulation and loss of vascular integrity, the three typical histological observations in human cases of infection. Availability of such a model of infection recapitulating the cardinal features of the blood phase of the infection now allows us to address key questions in terms of the bacterial and host processes involved in N. meningitidis-caused vascular damage. These results point out the importance of the interaction between bacteria and the endothelium in the context of Neisseria meningitidis sepsis. The role of these interactions in sepsis caused by other bacteria will now be explored.
We are thus well engaged in a global and multidisciplinary approach combining microbiology with cell biology, vascular biology, chemistry and physics to study the pathogenesis of N. meningitidis infection.
Whenever possible our basic findings are exploited to design preventive and therapeutic approaches in collaboration with pharmacological companies. It is also essential to us to take advantage of our progress in the knowledge of N. meningitidis to the study of other bacterial pathogens involved in similar pathologies.
