PANoptosis: A New Insight Into Oral Infectious Diseases

The oral microbiome, one of the most complex and intensive microbial ecosystems in the human body, comprises bacteria, archaea, fungi, protozoa, and viruses. Dysbiosis of the oral microbiome is the initiating factor that leads to oral infectious diseases. Infection is a sophisticated biological process involving interplay between the pathogen and the host, which often leads to activation of programmed cell death. Studies suggest that pyroptosis, apoptosis, and necroptosis are involved in multiple oral infectious diseases. Further understanding of crosstalk between cell death pathways has led to pyroptosis, apoptosis, and necroptosis being integrated into a single term: PANoptosis. PANoptosis is a multifaceted agent of the immune response that has important pathophysiological relevance to infectious diseases, autoimmunity, and cancer. As such, it plays an important role in innate immune cells that detect and eliminate intracellular pathogens. In addition to the classical model of influenza virus-infected and Yersinia-infected macrophages, other studies have expanded the scope of PANoptosis to include other microorganisms, as well as potential roles in cell types other than macrophages. In this review, we will summarize the pathophysiological mechanisms underlying inflammation and tissue destruction caused by oral pathogens. We present an overview of different pathogens that may induce activation of PANoptosis, along with the functional consequences of PANoptosis in the context of oral infectious diseases. To advance our understanding of immunology, we also explore the strategies used by microbes that enable immune evasion and replication within host cells. Improved understanding of the interplay between the host and pathogen through PANoptosis will direct development of therapeutic strategies that target oral infectious diseases.

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Distinct and Atypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in Cone Photoreceptors

PLoS Genetics ◽

10.1371/journal.pgen.1003555 ◽

2013 ◽

Vol 9 (6) ◽

pp. e1003555 ◽

Cited By ~ 21

Author(s):

Kyoung-in Cho ◽

MdEmdadul Haque ◽

Jessica Wang ◽

Minzhong Yu ◽

Ying Hao ◽

...

Keyword(s):

Cell Death ◽

Photoreceptor Cell ◽

Cell Types ◽

Cone Photoreceptors ◽

Cell Death Pathways

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Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis

Journal of Virology ◽

10.1128/jvi.02404-16 ◽

2017 ◽

Vol 91 (6) ◽

Cited By ~ 25

Author(s):

Angela K. Berger ◽

Bradley E. Hiller ◽

Deepti Thete ◽

Anthony J. Snyder ◽

Encarnacion Perez ◽

...

Keyword(s):

Cell Death ◽

Immune System ◽

Virus Infection ◽

De Novo ◽

Rna Virus ◽

Viral Rna ◽

Host Cells ◽

Type I ◽

Tissue Destruction ◽

Reovirus Infection

ABSTRACT Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to the de novo synthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus. IMPORTANCE An appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis.

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Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

Pathogens ◽

10.3390/pathogens7010008 ◽

2018 ◽

Vol 7 (1) ◽

pp. 8 ◽

Cited By ~ 8

Author(s):

Courtney McDougal ◽

John-Demian Sauer

Keyword(s):

Cell Death ◽

Listeria Monocytogenes ◽

Host Cell ◽

Acute Infection ◽

Host Cells ◽

Cell Mediated Immunity ◽

Cell Death Pathways ◽

Host Cell Death ◽

The Impact

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications on the development of disease and the subsequent immune response. Although L. monocytogenes can activate multiple pathways of host cell death, including necrosis, apoptosis, and pyroptosis, like most intracellular pathogens L. monocytogenes has evolved a series of adaptations that minimize host cell death to promote its virulence. Understanding how L. monocytogenes modulates cell death during infection could lead to novel therapeutic approaches. In addition, as L. monocytogenes is currently being developed as a tumor immunotherapy platform, understanding how cell death pathways influence the priming and quality of cell-mediated immunity is critical. This review will focus on the mechanisms by which L. monocytogenes modulates cell death, as well as the implications of cell death on acute infection and the generation of adaptive immunity.

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Intracellular Staphylococcus aureus employs the cysteine protease staphopain A to induce host cell death in epithelial cells

10.1101/2020.02.10.936575 ◽

2020 ◽

Cited By ~ 2

Author(s):

Kathrin Stelzner ◽

Tobias Hertlein ◽

Aneta Sroka ◽

Adriana Moldovan ◽

Kerstin Paprotka ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Cell Death ◽

Epithelial Cells ◽

Host Cell ◽

Cysteine Protease ◽

Host Cells ◽

Upper Respiratory Tract ◽

Intracellular Replication ◽

Tissue Destruction ◽

Host Cell Death

AbstractStaphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Intracellularity is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death by intracellular S. aureus after translocation into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. Our study suggests that staphopain A is utilized by S. aureus to mediate escape from the host cell and thus contributes to tissue destruction and dissemination of infection.Author SummaryStaphylococcus aureus is a well-known antibiotic-resistant pathogen that emerges in hospital and community settings and can cause a variety of diseases ranging from skin abscesses to lung inflammation and blood poisoning. The bacterium asymptomatically colonizes the upper respiratory tract and skin of about one third of the human population and takes advantage of opportune conditions, like immunodeficiency or breached barriers, to cause infection. Although S. aureus is not regarded as a professional intracellular bacterium, it can be internalized by human cells and subsequently exit the host cells by induction of cell death, which is considered to cause tissue destruction and spread of infection. The bacterial virulence factors and underlying molecular mechanisms involved in the intracellular lifestyle of S. aureus remain largely unknown. We identified a bacterial cysteine protease to contribute to host cell death mediated by intracellular S. aureus. Staphopain A induced killing of the host cell after translocation of the pathogen into the cell cytosol, while bacterial proliferation was not required. Further, the protease enhanced survival of the pathogen during lung infection. These findings reveal a novel, intracellular role for the bacterial protease staphopain A.

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Presenilin-interacting proteins

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399402005008 ◽

2002 ◽

Vol 4 (19) ◽

pp. 1-18 ◽

Cited By ~ 26

Author(s):

Qi Chen ◽

David Schubert

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Cell Types ◽

Cellular Adhesion ◽

Interacting Proteins ◽

Missense Mutations ◽

Cell Death Pathways ◽

Physiological Relevance ◽

Genes Encoding

Familial Alzheimer's disease (FAD) accounts for 5–10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to missense mutations in three genes, encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Of these, the vast majority of FAD-linked mutations are within PS1. There has been an extensive effort to identify proteins that functionally interact with PS1 and PS2 because of their clear roles in FAD. The goal of this review is to describe these proteins and to discuss in more detail the probable biological functions of a subset of the better-studied interacting proteins. In particular, the review examines APP, Notch, nicastrin, modifier of cellular adhesion (MOCA), β-catenin, and the group of proteins involved in cell death, calcium metabolism and cell adhesion. We argue that, although a few of the interacting proteins are unambiguously involved in well-studied cellular pathways, their exact roles within these pathways have not been clearly defined, and indeed might vary between cell types. We also question the physiological relevance of some of the work linking PS to cell death pathways. Finally, we point out the value of using flies and worms to sort out the often contradictory work in the PS field, and we mention how knowledge of PS-interacting pathways will contribute to the development of new therapeutic strategies in AD.

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Why should cell biologists study microbial pathogens?

Molecular Biology of the Cell ◽

10.1091/mbc.e15-03-0144 ◽

2015 ◽

Vol 26 (24) ◽

pp. 4295-4301 ◽

Cited By ~ 11

Author(s):

Matthew D. Welch

Keyword(s):

Infectious Diseases ◽

Virulence Factors ◽

Membrane Trafficking ◽

Cell Biology ◽

Basic Research ◽

Host Cells ◽

Microbial Pathogens ◽

Cell Cycle Regulators ◽

Cell Death Pathways ◽

Cellular Pathways

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.

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Mesenchymal Stromal/Stem Cells-Derived Exosomes as an Antimicrobial Weapon for Orodental Infections

Frontiers in Microbiology ◽

10.3389/fmicb.2021.795682 ◽

2022 ◽

Vol 12 ◽

Author(s):

Nazanin Jafari ◽

Arezoo Khoradmehr ◽

Reza Moghiminasr ◽

Mina Seyed Habashi

Keyword(s):

Stem Cells ◽

Oral Cavity ◽

Infectious Diseases ◽

Immune Cells ◽

The Body ◽

Oral Microbiome ◽

Host Cells ◽

Therapeutic Effects ◽

Different Types ◽

Stromal Stem Cells

The oral cavity as the second most various microbial community in the body contains a broad spectrum of microorganisms which are known as the oral microbiome. The oral microbiome includes different types of microbes such as bacteria, fungi, viruses, and protozoa. Numerous factors can affect the equilibrium of the oral microbiome community which can eventually lead to orodental infectious diseases. Periodontitis, dental caries, oral leukoplakia, oral squamous cell carcinoma are some multifactorial infectious diseases in the oral cavity. In defending against infection, the immune system has an essential role. Depending on the speed and specificity of the reaction, immunity is divided into two different types which are named the innate and the adaptive responses but also there is much interaction between them. In these responses, different types of immune cells are present and recent evidence demonstrates that these cell types both within the innate and adaptive immune systems are capable of secreting some extracellular vesicles named exosomes which are involved in the response to infection. Exosomes are 30–150 nm lipid bilayer vesicles that consist of variant molecules, including proteins, lipids, and genetic materials and they have been associated with cell-to-cell communications. However, some kinds of exosomes can be effective on the pathogenicity of various microorganisms and promoting infections, and some other ones have antimicrobial and anti-infective functions in microbial diseases. These discrepancies in performance are due to the origin of the exosome. Exosomes can modulate the innate and specific immune responses of host cells by participating in antigen presentation for activation of immune cells and stimulating the release of inflammatory factors and the expression of immune molecules. Also, mesenchymal stromal/stem cells (MSCs)-derived exosomes participate in immunomodulation by different mechanisms. Ease of expansion and immunotherapeutic capabilities of MSCs, develop their applications in hundreds of clinical trials. Recently, it has been shown that cell-free therapies, like exosome therapies, by having more advantages than previous treatment methods are emerging as a promising strategy for the treatment of several diseases, in particular inflammatory conditions. In orodental infectious disease, exosomes can also play an important role by modulating immunoinflammatory responses. Therefore, MSCs-derived exosomes may have potential therapeutic effects to be a choice for controlling and treatment of orodental infectious diseases.

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Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence

Frontiers in Immunology ◽

10.3389/fimmu.2020.621733 ◽

2021 ◽

Vol 11 ◽

Author(s):

Dominique Missiakas ◽

Volker Winstel

Keyword(s):

Staphylococcus Aureus ◽

Cell Death ◽

Host Cell ◽

Intervention Strategies ◽

Host Cells ◽

Intracellular Killing ◽

Mammalian Development ◽

Cell Responses ◽

Cell Death Pathways ◽

Host Cell Death

Host cell death programs are fundamental processes that shape cellular homeostasis, embryonic development, and tissue regeneration. Death signaling and downstream host cell responses are not only critical to guide mammalian development, they often act as terminal responses to invading pathogens. Here, we briefly review and contrast how invading pathogens and specifically Staphylococcus aureus manipulate apoptotic, necroptotic, and pyroptotic cell death modes to establish infection. Rather than invading host cells, S. aureus subverts these cells to produce diffusible molecules that cause death of neighboring hematopoietic cells and thus shapes an immune environment conducive to persistence. The exploitation of cell death pathways by S. aureus is yet another virulence strategy that must be juxtaposed to mechanisms of immune evasion, autophagy escape, and tolerance to intracellular killing, and brings us closer to the true portrait of this pathogen for the design of effective therapeutics and intervention strategies.

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Impairment in inflammasome signaling by the chronic Pseudomonas aeruginosa isolates from cystic fibrosis patients results in an increase in inflammatory response

Cell Death and Disease ◽

10.1038/s41419-021-03526-w ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Melissa S. Phuong ◽

Rafael E. Hernandez ◽

Daniel J. Wolter ◽

Lucas R. Hoffman ◽

Subash Sad

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Cell Death ◽

Inflammatory Cytokines ◽

Immune Cell ◽

Host Cells ◽

Respiratory Pathogen ◽

Cell Death Pathways ◽

The Relationship

AbstractPseudomonas aeruginosa is a common respiratory pathogen in cystic fibrosis (CF) patients which undergoes adaptations during chronic infection towards reduced virulence, which can facilitate bacterial evasion of killing by host cells. However, inflammatory cytokines are often found to be elevated in CF patients, and it is unknown how chronic P. aeruginosa infection can be paradoxically associated with both diminished virulence in vitro and increased inflammation and disease progression. Thus, we investigated the relationship between the stimulation of inflammatory cell death pathways by CF P. aeruginosa respiratory isolates and the expression of key inflammatory cytokines. We show that early respiratory isolates of P. aeruginosa from CF patients potently induce inflammasome signaling, cell death, and expression of IL-1β by macrophages, yet little expression of other inflammatory cytokines (TNF, IL-6 and IL-8). In contrast, chronic P. aeruginosa isolates induce relatively poor macrophage inflammasome signaling, cell death, and IL-1β expression but paradoxically excessive production of TNF, IL-6 and IL-8 compared to early P. aeruginosa isolates. Using various mutants of P. aeruginosa, we show that the premature cell death of macrophages caused by virulent bacteria compromises their ability to express cytokines. Contrary to the belief that chronic P. aeruginosa isolates are less pathogenic, we reveal that infections with chronic P. aeruginosa isolates result in increased cytokine induction due to their failure to induce immune cell death, which results in a relatively intense inflammation compared with early isolates.

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Delivery of Toxins and Effectors by Bacterial Membrane Vesicles

Toxins ◽

10.3390/toxins13120845 ◽

2021 ◽

Vol 13 (12) ◽

pp. 845

Author(s):

Adrian Macion ◽

Agnieszka Wyszyńska ◽

Renata Godlewska

Keyword(s):

Virulence Factors ◽

Pathogenic Bacteria ◽

Membrane Vesicles ◽

Cell Types ◽

Oral Bacteria ◽

Host Cells ◽

Target Cells ◽

Tissue Destruction ◽

Secretion Systems ◽

The Central Nervous System

Pathogenic bacteria interact with cells of their host via many factors. The surface components, i.e., adhesins, lipoproteins, LPS and glycoconjugates, are particularly important in the initial stages of colonization. They enable adhesion and multiplication, as well as the formation of biofilms. In contrast, virulence factors such as invasins and toxins act quickly to damage host cells, causing tissue destruction and, consequently, organ dysfunction. These proteins must be exported from the bacterium and delivered to the host cell in order to function effectively. Bacteria have developed a number of one- and two-step secretion systems to transport their proteins to target cells. Recently, several authors have postulated the existence of another transport system (sometimes called “secretion system type zero”), which utilizes extracellular structures, namely membrane vesicles (MVs). This review examines the role of MVs as transporters of virulence factors and the interaction of toxin-containing vesicles and other protein effectors with different human cell types. We focus on the unique ability of vesicles to cross the blood–brain barrier and deliver protein effectors from intestinal or oral bacteria to the central nervous system.

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