Cryptococcus neoforman s rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

• DOI: 10.1128/mbio.03078-23
• Publication Date: 2024-03-21T13:01:02Z
• Authors: Vanessa I. Francis; Corin Liddle; Emma Camacho; Madhura Kulkarni; Samuel R. S. Junior; Jamie A. Harvey; Elizabeth R. Ballou; Darren D. Thomson; Gordon D. Brown; J. Marie Hardwick; Arturo Casadevall; Jonathan Witton; Carolina Coelho
• Keywords: Phagocytic Cell; Lamina propria

ABSTRACT Cryptococcus neoformans causes lethal meningitis and accounts for approximately 10%–15% of AIDS-associated deaths worldwide. There are major gaps in our understanding how this fungus invades the mammalian brain. To investigate dynamics C. tissue invasion, we mapped fungal localization host cell interactions infected brain, lung, upper airways using mouse models systemic airway infection. enable this, developed an situ imaging pipeline capable measuring large volumes while preserving anatomical cellular information by combining thick sections, clarification, confocal imaging. We confirm high burden after nasal inoculation. Yeast turbinates were frequently titan cells, with faster kinetics than reported lungs. Importantly, observed one instance cells enmeshed lamina propria airways, suggesting penetration mucosa as a possible route invasion dissemination to bloodstream. extend previous literature positing bloodstream , finding viable fungi mice few days intranasal As early 24 h post infection, majority traversed blood-brain barrier, engulfed or close proximity microglia. Our work presents new method investigating microbial establishes that can breach multiple barriers within first demonstrates microglia responding IMPORTANCE Cryptococcal globally. Still, brain-specific immunity cryptococci is conundrum. By employing innovative imaging, study reveals what occurs during infection brain airways. found predominate mucosa, which implies that, at least mice, site dissemination. This would signify mucosal needs be better understood. also show microglia, brain-resident macrophages, responders clusters formed surrounding cryptococci. opens field detailed molecular investigations on immune response, traverses respond ultimately monitor barrier preserve function.