The multiple mechanisms of Ca2+signalling by listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes

Cholesterol-dependent cytolysins (CDCs) represent a large family of conserved pore-forming toxins produced by several Gram-positive bacteria such as Listeria monocytogenes, Streptococcus pyrogenes and Bacillus anthracis. These toxins trigger a broad range of cellular responses that greatly influence pathogenesis. Using mast cells, we demonstrate that listeriolysin O (LLO), a prototype of CDCs produced by L. monocytogenes, triggers cellular responses such as degranulation and cytokine synthesis in a Ca2+-dependent manner. Ca2+ signalling by LLO is due to Ca2+ influx from extracellular milieu and release of from intracellular stores. We show that LLO-induced release of Ca2+ from intracellular stores occurs via at least two mechanisms: (i) activation of intracellular Ca2+ channels and (ii) a Ca2+ channels independent mechanism. The former involves PLC-IP3R operated Ca2+ channels activated via G-proteins and protein tyrosine kinases. For the latter, we propose a novel mechanism of intracellular Ca2+ release involving injury of intracellular Ca2+ stores such as the endoplasmic reticulum. In addition to Ca2+ signalling, the discovery that LLO causes damage to an intracellular organelle provides a new perspective in our understanding of how CDCs affect target cells during infection by the respective bacterial pathogens

Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local anti-viral response.

Vector-borne flaviviruses such as tick-borne encephalitis virus (TBEV), West Nile virus and dengue virus cause millions of infections in humans. TBEV causes a broad range of pathological symptoms ranging from meningitis to severe encephalitis or even hemorrhagic fever with high mortality. Despite the availability of an effective vaccine, incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuro-inflammation in LGTV-infected mice characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that a coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE: The type I interferon (IFN) system is important to control viral infections, however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system is poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection: first in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). Secondly, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis