Adhesion of Neisseria meningitidis to Dermal Vessels Leads to Local Vascular Damage and Purpura in a Humanized Mouse Model

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Abstract
Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia. Certain bacterial pathogens access the bloodstream during infection and this is associated with extremely severe conditions such as septic shock. A central feature of these infections is the rapid alteration of blood vessel function with deregulated inflammation, coagulation and loss of vessel integrity. Studying the mechanisms of infection of Neisseria meningitis in vivo for the first time, we show that the ability of this bacterium to adhere to and proliferate in the blood vessel, a process we refer to as vascular colonization, is a prerequisite to the alteration of vascular function. Previously, circulating bacteria were thought to be responsible. We identified the bacterial factors involved in this process by showing that it is largely dependent on type IV pili, long filamentous appendages that allow bacteria to stick to the vessel walls. To study infection by N. meningitidis, a highly human specific pathogen, we introduced human vessels into mice by grafting human skin onto immunodeficient mice. This work thus also introduces a new animal model of infection that reproduces the cardinal features of meningococcal infections. Such a model will be useful to the scientific community to explore the mechanisms of disease, and test new treatment or preventive strategies.

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