Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome

TL;DR

This study finds that increased Notch pathway activity is linked to severe illness and poor outcomes in patients with scrub typhus.

Contribution

The study is the first to investigate canonical Notch activation in scrub typhus and link it to disease severity and outcomes.

Findings

Plasma DLL1 levels were significantly higher in scrub typhus patients at admission and decreased during recovery.

NOTCH4 RNA expression was reduced in whole blood of scrub typhus patients at admission.

Higher admission DLL1 levels correlated with disease severity and poor short-term survival.

Abstract

The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus.

Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O. tsutsugamushi infection (n = 31) and in healthy controls (n = 31); all from the same area of South India.

Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of NOTCH4 was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and NOTCH4 was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in O. tsutsugamushi-infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of NOTCH4.

Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.

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