Melican, K. | Search bioRxiv

bioRxiv2024

Tissue resident cells differentiate S. aureus from S. epidermidis via IL-1beta following barrier disruption in healthy human skin disruption in healthy human skin

The Staphylococcus species are a dominant part of the human skin microbiome and present across all body sites. Staphylococcus epidermidis is a ubiquitous skin commensal, while S. aureus is thought to colonize at least 30% of the population. S. aureus are not only colonizers but a leading cause of skin and soft tissue infections and a critical healthcare concern. To understand how healthy human skin may differentiate commensal bacteria, such as S. epidermidis, from the potential pathogen methicillin-resistant S. aureus (MRSA),, we use ex vivo human skin models that allows us to study this host-bacterial interaction in the most clinically relevant environment. Our work highlights the role of the outer stratum corneum as a protective physical barrier against invasion by colonizing Staphylococci. We show how the structural cells of the skin can internalize and respond to different Staphylococci with increasing sensitivity. Disruption of the protective stratum corneum triggered an increased and discriminative immune response led by strong IL-1{beta} expression. We identified and localized tissue resident Langerhans cells (LCs) as a potential source of this IL-1{beta} and go on to show a dose dependent response of MUTZ-LCs to S. aureus but not S. epidermidis. This suggests an important role of LCs in sensing and discriminating between bacteria in healthy human skin. This work provides a detailed snapshot of how human skin differentiates between friend and potential foe. With the rise in antibiotic resistance, understanding the innate immune response of healthy skin may help us find ways to enhance or manipulate these natural defenses to help prevent invasive infection. Author SummaryHow healthy human skin can differentiate between commensal bacteria which live harmoniously on our skin and those bacteria which have the potential to cause invasive infection is of great interest. Here we use ex vivo human skin models to show how the outer layers of human skin resists bacterial invasion and that disruption of this layer leads to increased infection and inflammation. We show how colonization of disrupted skin by the potentially pathogenic Staphyloccus aureus causes an increased IL-1{beta} signaling compared to the commensal S. epidermidis. We show that tissue resident Langerhans cells are well positioned throughout the skin epidermis and can differentiate commensal from pathogen via IL-1{beta}. This work identifies one of the subtle, yet effective pathways by which human skin differentiates commensals and pathogens. Understanding these mechanisms could lead to potential new treatment and prevention targets, mechanisms by which we can enhance innate immunity.

microbiology↗

bioRxiv2021

Colonization of dermal arterioles by Neisseria meningitidis provides a safe haven from neutrophils

Neisseria meningitidis, a human-specific bacterium, is responsible for meningitis and fatal fulminant systemic disease. Bacteria colonize blood vessels, rapidly causing devastating vascular damage despite a neutrophil-rich inflammatory infiltrate. How this pathogen escapes the neutrophil response is unknown. Using a humanized mouse model, we show that vascular colonization leads to the recruitment of neutrophils, partially reducing bacterial burden and vascular damage. This partial effect is due to the ability of bacteria to indiscriminately colonize capillaries, venules and arterioles, as observed in human samples. In venules, potent neutrophil recruitment allows efficient bacterial phagocytosis. In contrast, in infected capillaries and arterioles adhesion molecules such as E-Selectin are not expressed on the endothelium and intravascular neutrophil recruitment is minimal. These results show that colonization of capillaries and arterioles by N. meningitidis create an intravascular niche that preclude the action of neutrophils, resulting in immune escape and subsequent fulminant progression of the infection.

microbiology↗

bioRxiv2018

Adhesion to nanofibers drives cell membrane remodeling through 1D wetting

The shape of cellular membranes is highly regulated by a set of conserved mechanisms. These mechanisms can be manipulated by bacterial pathogens to infect cells. Human endothelial cell plasma membrane remodeling by the bacterium Neisseria meningitidis is thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unknown. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a novel physical mechanism we term \" onedimensional\" membrane wetting. We provide a theoretical model that gives the physical basis of 1D wetting and show that this mechanism occurs in model membranes interacting with model nanofibers, and in human cells interacting with model extracellular matrices. It is thus a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococcus during infection.

cell biology↗