Cell death and infection: a double-edged sword for host and pathogen survival

Host cell death is an intrinsic immune defense mechanism in response to microbial infection. However, bacterial pathogens use many strategies to manipulate the host cell death and survival pathways to enhance their replication and survival. This manipulation is quite intricate, with pathogens often suppressing cell death to allow replication and then promoting it for dissemination. Frequently, these effects are exerted through modulation of the mitochondrial pro-death, NF-κB-dependent pro-survival, and inflammasome-dependent host cell death pathways during infection. Understanding the molecular details by which bacterial pathogens manipulate cell death pathways will provide insight into new therapeutic approaches to control infection.     

Current status of immune mechanisms of killing of intracellular microorganisms

The interaction between intracellular pathogens and the mammalian host follows different pathways that reflect evolved survival mechanisms of both the pathogen and the host to assure each one's own survival. From the host's perspective, different immune mechanisms predominate at different stages of infection. Both phagocytic and non-phagocytic target cells participate in microbial uptake and, in some cases, intracellular destruction. In addition, the development of specific immunity ensures sustained activation of intracellular microbicidal mechanisms in the target cells, and induction of apoptotic or lytic target cell death by cytotoxic T lymphocytes. From the pathogen's perspective, different evasion strategies are employed to counteract host defenses. Understanding microbial survival strategies and the immune mechanisms that result in killing of intracellular pathogens will deepen our insight into the pathogenesis of infection that could be applied towards the development of effective vaccination and immunotherapy.     

Signaling of apoptosis through TLRs critically involves toll/IL-1 receptor domain-containing adapter inducing IFN-beta, but not MyD88, in bacteria-infected murine macrophages

TLRs are important sensors of the innate immune system that serve to identify conserved microbial components to mount a protective immune response. They furthermore control the survival of the challenged cell by governing the induction of pro- and antiapoptotic signaling pathways. Pathogenic Yersinia spp. uncouple the balance of life and death signals in infected macrophages, which compels the macrophage to undergo apoptosis. The initiation of apoptosis by Yersinia infection specifically involves TLR4 signaling, although Yersinia can activate TLR2 and TLR4. In this study we characterized the roles of downstream TLR adapter proteins in the induction of TLR-responsive apoptosis. Experiments using murine macrophages defective for MyD88 or Toll/IL-1R domain-containing adapter inducing IFN-beta (TRIF) revealed that deficiency of TRIF, but not of MyD88, provides protection against Yersinia-mediated cell death. Similarly, apoptosis provoked by treatment of macrophages with the TLR4 agonist LPS in the presence of a proteasome inhibitor was inhibited in TRIF-defective, but not in MyD88-negative, cells. The transfection of macrophages with TRIF furthermore potently promoted macrophage apoptosis, a process that involved activation of a Fas-associated death domain- and caspase-8-dependent apoptotic pathway. These data indicate a crucial function of TRIF as proapoptotic signal transducer in bacteria-infected murine macrophages, an activity that is not prominent for MyD88. The ability to elicit TRIF-dependent apoptosis was not restricted to TLR4 activation, but was also demonstrated for TLR3 agonists. Together, these results argue for a specific proapoptotic activity of TRIF as part of the host innate immune response to bacterial or viral infection.     

Manipulation of the host cell death pathway by Shigella

Host cells deploy multiple defences against microbial infection. One prominent host defence mechanism, the death of infected cells, plays a pivotal role in clearing damaged cells, eliminating pathogens, removing replicative niches, exposing intracellular bacterial pathogens to extracellular immune surveillance and presenting bacteria‐derived antigens to the adaptive immune system. Although cell death can occur under either physiological or pathophysiological conditions, it acts as an innate defence mechanism against bacterial pathogens by limiting their persistent colonization. However, many bacterial pathogens, including Shigella, have evolved mechanisms that manipulate host cell death for their own benefit.     

Role of autophagy in disease resistance and hypersensitive response-associated cell death

Ancient autophagy pathways are emerging as key defense modules in host eukaryotic cells against microbial pathogens. Apart from actively eliminating intracellular intruders, autophagy is also responsible for cell survival, for example by reducing the deleterious effects of endoplasmic reticulum stress. At the same time, autophagy can contribute to cellular suicide. The concurrent engagement of autophagy in these processes during infection may sometimes mask its contribution to differing pro-survival and pro-death decisions. The importance of autophagy in innate immunity in mammals is well documented, but how autophagy contributes to plant innate immunity and cell death is not that clear. A few research reports have appeared recently to shed light on the roles of autophagy in plant-pathogen interactions and in disease-associated host cell death. We present a first attempt to reconcile the results of this research.     

病原体调控宿主细胞周期致病机制的研究进展

病原体在长期进化中形成多种策略以利于自身增殖,进而导致多种疾病.这些策略包括干扰宿主免疫反应、调控细胞周期与凋亡等.近年来,人们越来越关注病原体通过干扰宿主细胞周期致病的机制,有助于更好了解病原体与宿主的相互作用.本文综述了病原体引起宿主细胞周期停滞在不同时期的机制,特别是一些细菌分泌毒力因子引起宿主细胞周期紊乱并导致...     

Programmed cell death in the plant immune system

Cell death has a central role in innate immune responses in both plants and animals. Besides sharing striking convergences and similarities in the overall evolutionary organization of their innate immune systems, both plants and animals can respond to infection and pathogen recognition with programmed cell death. The fact that plant and animal pathogens have evolved strategies to subvert specific cell death modalities emphasizes the essential role of cell death during immune responses. The hypersensitive response (HR) cell death in plants displays morphological features, molecular architectures and mechanisms reminiscent of different inflammatory cell death types in animals (pyroptosis and necroptosis). In this review, we describe the molecular pathways leading to cell death during innate immune responses. Additionally, we present recently discovered caspase and caspase-like networks regulating cell death that have revealed fascinating analogies between cell death control across both kingdoms.     

Why should cell biologists study microbial pathogens?

One quarter of all deaths worldwide each year result from infectious diseases caused by microbial pathogens. Pathogens infect and cause disease by producing virulence factors that target host cell molecules. Studying how virulence factors target host cells has revealed fundamental principles of cell biology. These include important advances in our understanding of the cytoskeleton, organelles and membrane-trafficking intermediates, signal transduction pathways, cell cycle regulators, the organelle/protein recycling machinery, and cell-death pathways. Such studies have also revealed cellular pathways crucial for the immune response. Discoveries from basic research on the cell biology of pathogenesis are actively being translated into the development of host-targeted therapies to treat infectious diseases. Thus there are many reasons for cell biologists to incorporate the study of microbial pathogens into their research programs.     

Cell death in the host response to infection

Infections elicit diverse responses in the host that include activation of the innate immune system, inflammation and cell death. Pathogen-triggered cell death is manifested by various morphologies indicative of apoptosis, pyroptosis, oncosis or autophagic cell death. The question of whether cell death performs a physiologic function during infection is key to understanding host-pathogen interactions and pathogenesis, and devising targeted therapeutic strategies for infectious diseases. In this review, we examine the different modes of cell death employed by the host during infection, the strategies used by pathogens to manipulate the cell death process and the outcome of cell death, that is, whether it is protective for the host or on the contrary favorable for pathogen dissemination. The pathways leading to cell death by infection are discussed with a focus on the role of pattern recognition receptors in the activation of survival and death effectors.     

Modulation of inflammasome pathways by bacterial and viral pathogens

Inflammasomes are emerging as key regulators of the host response against microbial pathogens. These cytosolic multiprotein complexes recruit and activate the cysteine protease caspase-1 when microbes invade sterile tissues or elicit cellular damage. Inflammasome-activated caspase-1 induces inflammation by cleaving the proinflammatory cytokines IL-1β and IL-18 into their biologically active forms and by releasing the alarmin HMGB1 into the extracellular milieu. Additionally, inflammasomes counter bacterial replication and clear infected immune cells through an inflammatory cell death program termed pyroptosis. As a countermeasure, bacterial and viral pathogens evolved virulence factors to antagonize inflammasome pathways. In this review, we discuss recent progress on how inflammasomes contribute to host defense against bacterial and viral pathogens, and we review how viruses and bacteria modulate inflammasome function to their benefit.     

Microbe-derived non-necrotic glycoside hydrolase family 12 proteins act as immunogenic signatures triggering plant defenses

Plant pattern recognition receptors(PRRs) are sentinels at the cell surface sensing microbial invasion and activating innate immune responses. During infection, certain microbial apoplastic effectors can be recognized by plant PRRs, culminating in immune responses accompanied by cell death. However, the intricated relationships between the activation of immune responses and cell death are unclear.Here, we studied the glycoside hydrolase family12(GH12) protein, Ps109281, secreted by Phytophthora ...     

Role of Bruton’s tyrosine kinase in macrophage apoptosis

Macrophages and polymorphonuclear cells (PMNs) rapidly respond to microbial and immune inflammatory stimuli and die during these responses. We have shown earlier that many macrophage and PMN functions are compromised in x-linked immunodeficient (Xid) mice with functional deficiency in Bruton’s tyrosine kinase (Btk). We now report that Btk-deficient macrophages show enhanced susceptibility to apoptotic death on exposure to the microbial and immune inflammatory signals bacterial lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in vitro. In vivo in mixed bone marrow (BM) chimeras Btk deficiency leads primarily to loss of peripheral macrophage numbers without affecting BM development, suggesting a role of inflammation-induced apoptosis in regulating macrophage life span. Surprisingly, Btk deficiency does not affect macrophage apoptosis induced by DNA damage or CD95 engagement. Reactive nitrogen and oxygen species also do not contribute to inflammation-induced apoptosis, but apoptotic process involves loss of mitochondrial potential, shows increased activation of caspase 9 and enhanced loss of Bcl-xL. The lack of pro-survival signaling through the Btk-phosphotidylinositol 3-kinase-Akt pathway, and persistent MEK signaling, lead to enhanced death in Btk-deficient macrophages only downstream of inflammatory triggers. These data underline the complex role of Btk in the regulation of macrophage survival and function.     

Signaling pathways bridging microbial-triggered inflammation and cancer

Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable secondary damage to host tissues that can result in tissue fibrosis and carcinogenesis, if persistent. In addition to classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce inflammation-associated cancer following the alterations of their microenvironment. Emerging experimental evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic pathogens can cause DNA damage in various cell types. In addition, the inflammatory response induced by chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A microenvironment including active immune cells releasing high amounts of inflammatory signaling molecules can favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations, whereas pro-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation in cancer prevention are herein summarized and discussed.     

Co‐opting oxylipin signals in microbial disease

Oxylipins, or oxygenated lipids, are universal signalling molecules across all kingdoms of life. These molecules, either produced by microbial pathogens or their mammalian host, regulate inflammation during microbial infection. In this review, we summarise current literature on the biosynthesis pathways of microbial oxylipins and their biological activity towards mammalian cells. Collectively, these studies have illustrated how microbial pathogens can modulate immune rsponse and disease outcome via oxylipin‐mediated mechanisms.     

Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni,Vidi, Vici!!

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the “code of conduct” of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.     

Neutrophils, dendritic cells and Toxoplasma

Toxoplasma gondii rapidly elicits strong Type 1 cytokine-based immunity. The necessity for this response is well illustrated by the example of IFN-gamma and IL-12 gene knockout mice that rapidly succumb to the effects of acute infection. The parasite itself is skilled at sparking complex interactions in the innate immune system that lead to protective immunity. Neutrophils are one of the first cell types to arrive at the site of infection, and the cells release several proinflammatory cytokines and chemokines in response to Toxoplasma. Dendritic cells are an important source of IL-12 during infection with T. gondii and other microbial pathogens, and they are also specialized for high-level antigen presentation to T lymphocytes. Tachyzoites express at least two types of molecules that trigger innate immune cell cytokine production. One of these involves Toll-like receptor/MyD88 pathways common to many microbial pathogens. The second pathway is less conventional and involves molecular mimicry between a parasite cyclophilin and host CC chemokine receptor 5-binding ligands. Neutrophils, dendritic cells and Toxoplasma work together to elicit the immune response required for host survival. Cytokine and chemokine cross-talk between parasite-triggered neutrophils and dendritic cells results in recruitment, maturation and activation of the latter. Neutrophil-empowered dendritic cells possess properties expected of highly potent antigen presenting cells that drive T helper 1 generation.     

Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing

Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a proprotein, Caspase-1 undergoes autoproteolysis within multiprotein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and for release of the cytokines interleukin-1β and interleukin-18, and it can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial pathogens can be separated genetically and that two distinct inflammasome complexes mediate these events. Inflammasomes containing the signaling adaptor Asc form a single large "focus" in which Caspase-1 undergoes autoproteolysis and processes IL-1β/IL-18. In contrast, Asc-independent inflammasomes activate Caspase-1 without autoproteolysis and do not form any large structures in the cytosol. Caspase-1 mutants unable to undergo autoproteolysis promoted rapid cell death, but processed IL-1β/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.