The finding that the Warburg effect observed in proliferating cancer cells is also observed during immune responses renewed the interest in the study of metabolic reprogramming of immune cells, a ...field of investigation called immunometabolism. However, the specific mechanisms and processes underlying metabolic changes of host cells upon bacterial infection remain poorly understood. Several recent reports have reported that mammalian cells infected with intracellular bacteria have an altered metabolism that resembles the Warburg effect seen in cancer cells. In this Review, we will summarize current knowledge on metabolic reprogramming and discuss putative causes underlying the preferential remodelling of host cells to Warburg‐like metabolic programs during infection by intracellular bacteria.
Metabolic changes of host cells upon bacterial infection remain poorly understood. Several recent reports revealed that mammalian cells infected with intracellular bacteria have an altered metabolism that resembles the Warburg effect seen in cancer cells. Here, we review current knowledge on metabolic reprogramming and discuss causes underlying the preferential remodelling of host cells to Warburg‐like metabolic programs during bacterial infection.
Many bacterial pathogens have evolved the ability to subvert and exploit host functions in order to enter and replicate in eukaryotic cells. For example, bacteria have developed specific mechanisms ...to target eukaryotic organelles such as the nucleus, the mitochondria, the endoplasmic reticulum and the Golgi apparatus. In this Review, we highlight the most recent advances in our understanding of the mechanisms that bacterial pathogens use to target these organelles. We also discuss how these strategies allow bacteria to manipulate host functions and to ultimately enable bacterial infection.
Legionella
species are environmental gram-negative bacteria able to cause a severe form of pneumonia in humans known as Legionnaires' disease. Since the identification of
Legionella pneumophila
in ...1977, four decades of research on
Legionella
biology and Legionnaires' disease have brought important insights into the biology of the bacteria and the molecular mechanisms that these intracellular pathogens use to cause disease in humans. Nowadays,
Legionella
species constitute a remarkable model of bacterial adaptation, with a genus genome shaped by their close coevolution with amoebae and an ability to exploit many hosts and signaling pathways through the secretion of a myriad of effector proteins, many of which have a eukaryotic origin. This review aims to discuss current knowledge of
Legionella
infection mechanisms and future research directions to be taken that might answer the many remaining open questions. This research will without a doubt be a terrific scientific journey worth taking.
The study of virulence of Legionella pneumophila and its interactions with its hosts has been predominantly conducted in cellulo in the past decades. Although easy to implement and allowing the ...dissection of molecular pathways underlying host-pathogen interactions, these cellular models fail to provide conditions of the complex environments encountered by the bacteria during the infection of multicellular organisms. To improve our understanding of human infection, several animal models have been developed. This review provides an overview of the invertebrate and vertebrate models that have been established to study L. pneumophila infection and that are alternatives to the classical mouse model, which does not recall human infection with L. pneumophila well. Finally we provide insight in the main contributions made by these models along with their pros and cons.
Legionella pneumophila is an intracellular bacterial pathogen that can cause a severe form of pneumonia in humans, a phenotype evolved through interactions with aquatic protozoa in the environment. ...Here, we show that L. pneumophila uses extracellular vesicles to translocate bacterial small RNAs (sRNAs) into host cells that act on host defence signalling pathways. The bacterial sRNA RsmY binds to the UTR of ddx58 (RIG-I encoding gene) and cRel, while tRNA-Phe binds ddx58 and irak1 collectively reducing expression of RIG-I, IRAK1 and cRel, with subsequent downregulation of IFN-β. Thus, RsmY and tRNA-Phe are bacterial trans-kingdom regulatory RNAs downregulating selected sensor and regulator proteins of the host cell innate immune response. This miRNA-like regulation of the expression of key sensors and regulators of immunity is a feature of L. pneumophila host-pathogen communication and likely represents a general mechanism employed by bacteria that interact with eukaryotic hosts.
is a gram-negative bacterium that inhabits freshwater ecosystems, where it is present in biofilm or as planktonic form.
is mainly found associated with protozoa, which serve as protection from ...hostile environments and as replication niche. If inhaled within aerosols,
is also able to infect and replicate in human alveolar macrophages, eventually causing the Legionnaires' disease. The transition between intracellular and extracellular environments triggers a differentiation program in which metabolic as well as morphogenetic changes occur. We here describe the current knowledge on how the different developmental states of this bacterium are regulated, with a particular emphasis on the stringent response activated during the transition from the replicative phase to the infectious phase and the metabolic features going in hand. We propose that the cellular differentiation of this intracellular pathogen is closely associated to key metabolic changes in the bacterium and the host cell, which together have a crucial role in the regulation of
virulence.
Abstract
FIC proteins regulate molecular processes from bacteria to humans by catalyzing post-translational modifications (PTM), the most frequent being the addition of AMP or AMPylation. In many ...AMPylating FIC proteins, a structurally conserved glutamate represses AMPylation and, in mammalian FICD, also supports deAMPylation of BiP/GRP78, a key chaperone of the unfolded protein response. Currently, a direct signal regulating these FIC proteins has not been identified. Here, we use X-ray crystallography and in vitro PTM assays to address this question. We discover that
Enterococcus faecalis
FIC (EfFIC) catalyzes both AMPylation and deAMPylation and that the glutamate implements a multi-position metal switch whereby Mg
2+
and Ca
2+
control AMPylation and deAMPylation differentially without a conformational change. Remarkably, Ca
2+
concentration also tunes deAMPylation of BiP by human FICD. Our results suggest that the conserved glutamate is a signature of AMPylation/deAMPylation FIC bifunctionality and identify metal ions as diffusible signals that regulate such FIC proteins directly.
Abstract
In this review, we propose that certain modifications in cellular metabolism might function as danger signals triggering inflammasome-mediated immune responses. We propose to call them ...danger-associated metabolic modifications (DAMMs). As intracellular bacteria can actively modulate macrophage metabolism for their benefit, infected host cells might sense bacteria-induced metabolic alterations and activate immune reactions. Here we report the known metabolic interactions that occur during infection of macrophages by intracellular bacteria and discuss the possible emergence of DAMMs upon bacteria-induced alterations of cellular metabolism.
Legionella pneumophila,
the causative agent of Legionnaires’ disease, a severe pneumonia, injects via a type 4 secretion system (T4SS) more than 300 proteins into macrophages, its main host cell in ...humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here. we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δ
ψ
m
) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that
L. pneumophila
reverses the ATP-synthase activity of the mitochondrial F
O
F
1
-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δ
ψ
m
, preserves mitochondrial polarization, and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that
Lp
Spl is partially involved in conserving the Δ
ψ
m
, but not LncP and MitF. The inhibition of the
L. pneumophila
-induced ‘reverse mode’ of the F
O
F
1
-ATPase collapsed the Δ
ψ
m
and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δ
ψ
m
and showed delayed cell death. This direct manipulation of the mode of activity of the F
O
F
1
-ATPase is a newly identified feature of
L. pneumophila
allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.
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