Waddell, S. J. | 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

Protein kinase B controls Mycobacterium tuberculosis growth via phosphorylation of the global transcriptional regulator Lsr2

Mycobacterium tuberculosis is able to persist in the body through months of multi-drug therapy. Mycobacteria possess a wide range of regulatory proteins, including the essential protein kinase B (PknB), that control transitions between growth states. Here, we establish that depletion of PknB in replicating M. tuberculosis results in transcriptional adaptations that implicate the DNA-binding protein Lsr2 in coordinating these changes. We show that Lsr2 is phosphorylated by PknB, and that phosphorylation of Lsr2 at threonine 112 is important for M. tuberculosis growth and survival under hypoxic conditions. Fluorescence anisotropy and electrophoretic mobility shift assays demonstrate that phosphorylation reduces Lsr2 binding to DNA, and ChIP-sequencing confirms increased DNA binding of a phosphoablative (T112A) Lsr2 mutant in M. tuberculosis. Altered expression of target genes in T112A Lsr2 compared to wild type Lsr2 M. tuberculosis offers further evidence that phosphorylation mediates expression of the Lsr2 regulon. Structural studies reveal increased dynamics of the Lsr2 DNA binding domain from a T112D phosphomimetic Lsr2 mutant, providing a molecular basis for decreased DNA binding by phosphorylated Lsr2. Our findings suggest that, the essential protein kinase, PknB controls M. tuberculosis growth and adaptations to the changing host environment by phosphorylating the global transcriptional regulator Lsr2.

microbiology↗