Lai, R. P. | bioRxiv Science

bioRxiv2019

Elevated LRRK2 and α-synuclein levels in CSF of infectious meningitis patients

Neurodegenerative diseases such as Parkinsons (PD) have a complex aetiology consisting of an interplay of genetic and environmental factors. Inflammation and infection are proposed external factors that trigger disease progression. Tuberculous and cryptococcal meningitis frequently lead to long-term neurological sequelae but their association with the development of PD are unexplored. In this study, we protein profiled the CSF from 76 patients with or without infectious meningitis and found that proteins commonly associated with PD (LRRK2, tau and alpha-synuclein) were significantly elevated, establishing a link between neuroinflammation and infection. Importantly, these findings suggest that LRRK2, tau and alpha-synuclein could represent biomarkers of neuroinflammation.

immunology↗

bioRxiv2019

Mycobacterium tuberculosis cording in the cytosol of live lymphatic endothelial cells

The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. We show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLEC) in vitro and also in the lymph nodes of patients with tuberculosis. We identified via RNA-seq a transcriptional programme in hLEC that activates cellular pro-survival and cytosolic surveillance of intracellular pathogens pathways. Consistent with this, cytosolic access of hLEC is required for intracellular M. tuberculosis cording; and cord formation is dependent on the M. tuberculosis ESX-1 type VII secretion system and the mycobacterial lipid PDIM. Finally, we show that M. tuberculosis cording is a novel size-dependent mechanism used by the pathogen to evade xenophagy in the cytosol of endothelial cells. These results provide a mechanism that explains the long-standing association between M. tuberculosis cording and virulence.

cell biology↗