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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 101691

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Prof. Dr. Toshio Hattori

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Guest Editor

Visiting Professor, Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka 420-0881, Japan
Interests: dengue; malaria; leptospirosis; HIV; tuberculosis; inflammation; galectins; osteopontin
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Special Issue Information

Dear Colleagues,

The acute infection of pathogens elicits strong immune responses in the host to clear invading pathogens and infected cells. These innate and adaptive immune responses lead to the eventual recovery of most infected individuals. Numerous proteins from pathogens, signal molecules, receptors, cytokines, and chemokines have been known to be involved in this process. Each pathogen has unique ways to infect, and has employed mechanisms to escape and/or evade the host immune responses. In some cases, acute symptoms develop into fatal systemic deterioration showing coagulation abnormality or immunological tolerance. Systemic reactions can lead to poor understanding of underlying biological events during the acute phase of immune response. Emerging knowledge of new inflammatory molecules revealed a novel aspect of the pathophysiology of acute infectious diseases. For example, matricellular proteins (MCPs) that are usually present in the extracellular space were found to be elevated in patients with acute infection. However, their exact roles in this context are poorly understood because MCPs have diverse functions including interactions with cell surface receptors, such as integrins, growth factors, and protease. In this Special Issue, we will focus on the novel molecules involved in infection to have a better understanding of infectious diseases.

Prof. Dr. Toshio Hattori
Guest Editor

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Keywords

Dengue
Malaria
Leptospirosis
HIV
Tuberculosis
Cytokine
Matrix protein
Coagulation
Sepsis
Influenza

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Published Papers (11 papers)

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11 pages, 2789 KiB

Open AccessArticle

Synthesis of a Cleaved Form of Osteopontin by THP-1 Cells and Its Alteration by Phorbol 12-Myristate 13-Acetate and BCG Infection

by Gaowa Bai, Hirotoshi Motoda, Ryo Ozuru, Haorile Chagan-Yasutan, Toshio Hattori and Takashi Matsuba

Int. J. Mol. Sci. 2018, 19(2), 418; https://doi.org/10.3390/ijms19020418 - 31 Jan 2018

Cited by 11 | Viewed by 5019

Abstract

The protease-cleaved osteopontin (OPN) was proposed to enhance the migration of memory T cells to granulomas in tuberculosis. Various forms of OPN were identified in human monocytic THP-1 cells stimulated by phorbol 12-myristate 13-acetate (PMA). Antibodies O-17, 10A16 and 34E3, which recognize N-terminus, the C-half, and thrombin-cleaved site of OPN, respectively, all detected distinct bands on Western blots following PMA stimulation. Bands corresponding to 18 and 30 kD were detected by antibodies 34E3 and 10A16, indicating that OPN cleavage occurred by endogenous proteases in the PMA-stimulated THP-1 cells. In immune-fluorescence (IF) assay, 34E3 positive signals were detected in intracellular space of non-infected and bacillus Calmette-Guérin (BCG)-infected cells; however, 10A16 positive signals were confirmed in extracellular area in PMA-stimulated cells followed by BCG infection. Small amounts of full-length (FL) and thrombin-cleaved (Tr) OPN were detected by ELISA in the supernatants of non-PMA-stimulated cells, and increased levels of all forms, including undefined (Ud) OPN, in PMA-stimulated cells. ELISA showed a decrease in OPN synthesis during BCG infection. To our knowledge, this is the first report of OPN cleavage in THP-1 macrophages after PMA stimulation, and of enhanced cleavage induced by BCG infection. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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Open AccessCommunication

RSV Infection in Human Macrophages Promotes CXCL10/IP-10 Expression during Bacterial Co-Infection

by Daniela Machado, Jonathan Hoffmann, Marie Moroso, Manuel Rosa-Calatrava, Hubert Endtz, Olivier Terrier and Glaucia Paranhos-Baccalà

Int. J. Mol. Sci. 2017, 18(12), 2654; https://doi.org/10.3390/ijms18122654 - 7 Dec 2017

Cited by 10 | Viewed by 4979

Abstract

Respiratory syncytial virus (RSV), a major etiologic agent of acute lower respiratory infection constitutes the most important cause of death in young children worldwide. Viral/bacterial mixed infections are related to severity of respiratory inflammatory diseases, but the underlying mechanisms remain poorly understood. We have previously investigated the intracellular mechanisms that mediate the immune response in the context of influenza virus/Streptococcus pneumoniae (Sp) co-infection using a model of human monocyte-derived macrophages (MDMs). Here, we set up and characterized a similar model of MDMs to investigate different scenarios of RSV infection and co-infection with Sp. Our results suggest that Sp contributes to a faster and possibly higher level of CXCL10/IP-10 expression induced by RSV infection in human MDMs. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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2883 KiB

Open AccessArticle

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

by Olga V. Masalova, Ekaterina I. Lesnova, Pavel N. Solyev, Natalia F. Zakirova, Vladimir S. Prassolov, Sergey N. Kochetkov, Alexander V. Ivanov and Alla A. Kushch

Int. J. Mol. Sci. 2017, 18(11), 2346; https://doi.org/10.3390/ijms18112346 - 6 Nov 2017

Cited by 12 | Viewed by 5165

Abstract

The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full-length HCV genome or transient expression of its core, Е1/Е2, NS3 and NS5B led to the death of 20–47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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1295 KiB

Open AccessCommunication

Secretion of Galectin-9 as a DAMP during Dengue Virus Infection in THP-1 Cells

by Isolde C. Dapat, Dyshelly Nurkartika Pascapurnama, Hiroko Iwasaki, Hannah Karen Labayo, Haorile Chagan-Yasutan, Shinichi Egawa and Toshio Hattori

Int. J. Mol. Sci. 2017, 18(8), 1644; https://doi.org/10.3390/ijms18081644 - 28 Jul 2017

Cited by 25 | Viewed by 8591

Abstract

Damage-associated molecular patterns (DAMPs) are endogenous cellular molecules released to the extracellular environment in response to stress conditions such as virus infection. Galectins are β-galactoside-binding proteins that are widely expressed in cells and tissues of the immune system, are localized in the cell cytoplasm, and have roles in inflammatory responses and immune responses against infection. Elevated levels of galectin-9 (Gal-9) in natural human infections have been documented in numerous reports. To investigate the effect of dengue virus (DENV) infection on expression of endogenous Gal-9, monocytic THP-1 cells were infected with varying doses of DENV-3 (multiplicity of infection (MOI) 0.01, 0.03 and 0.1) and incubated at varying time points (Day 1, Day 2, Day 3). Results showed augmentation of Gal-9 levels in the supernatant, reduction of Gal-9 levels in the cells and decreased expression of LGALS9 mRNA, while DENV-3 mRNA copies for all three doses remained stable through time. Dengue virus induced the secretion of Gal-9 as a danger response; in turn, Gal-9 and other inflammatory factors, and stimulated effector responses may have limited further viral replication. The results in this pilot experiment add to the evidence of Gal-9 as a potential DAMP. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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14 pages, 1157 KiB

Open AccessReview

Programmed Cell Death in the Pathogenesis of Influenza

by Daisuke Fujikura and Tadaaki Miyazaki

Int. J. Mol. Sci. 2018, 19(7), 2065; https://doi.org/10.3390/ijms19072065 - 16 Jul 2018

Cited by 48 | Viewed by 11644

Abstract

Influenza is a respiratory disease induced by infection by the influenza virus, which is a member of Orthomyxoviridae family. This infectious disease has serious impacts on public health systems and results in considerable mortality and economic costs throughout the world. Based on several experimental studies, massive host immune reaction is associated with the disease severity of influenza. Programmed cell death is typically induced during virus infection as a consequence of host immune reaction to limit virus spread by eliminating niches for virus propagation without causing inflammation. However, in some viral infectious diseases, such as influenza, in the process of immune reaction, aberrant induction of programmed cell death disturbs the maintenance of organ function. Current reports show that there are different types of programmed cell death that vary in terms of molecular mechanisms and/or associations with inflammation. In addition, these novel types of programmed cell death are associated with pathogenesis rather than suppressing virus propagation in the disease course. Here, we review our current understanding of mechanisms of programmed cell death in the pathogenesis of influenza. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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28 pages, 1574 KiB

Open AccessReview

Neutrophils: Beneficial and Harmful Cells in Septic Arthritis

by Daiane Boff, Helena Crijns, Mauro M. Teixeira, Flavio A. Amaral and Paul Proost

Int. J. Mol. Sci. 2018, 19(2), 468; https://doi.org/10.3390/ijms19020468 - 5 Feb 2018

Cited by 33 | Viewed by 25212

Abstract

Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable in the first-line defense to kill invading pathogens in the early stage of disease. However, on the other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible damage to the infected joint, which is known as an important complication in septic arthritis patients. Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an efficient therapy to reduce tissue damage in septic arthritis. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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13 pages, 898 KiB

Open AccessReview

Infectious Agents as Stimuli of Trained Innate Immunity

by Paulina Rusek, Mateusz Wala, Magdalena Druszczyńska and Marek Fol

Int. J. Mol. Sci. 2018, 19(2), 456; https://doi.org/10.3390/ijms19020456 - 3 Feb 2018

Cited by 74 | Viewed by 14117

Abstract

The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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29 pages, 2366 KiB

Open AccessReview

Regulation of Three Virulence Strategies of Mycobacterium tuberculosis: A Success Story

by Niels A. Zondervan, Jesse C. J. Van Dam, Peter J. Schaap, Vitor A. P. Martins dos Santos and Maria Suarez-Diez

Int. J. Mol. Sci. 2018, 19(2), 347; https://doi.org/10.3390/ijms19020347 - 24 Jan 2018

Cited by 32 | Viewed by 8977

Abstract

Tuberculosis remains one of the deadliest diseases. Emergence of drug-resistant and multidrug-resistant M. tuberculosis strains makes treating tuberculosis increasingly challenging. In order to develop novel intervention strategies, detailed understanding of the molecular mechanisms behind the success of this pathogen is required. Here, we review recent literature to provide a systems level overview of the molecular and cellular components involved in divalent metal homeostasis and their role in regulating the three main virulence strategies of M. tuberculosis: immune modulation, dormancy and phagosomal rupture. We provide a visual and modular overview of these components and their regulation. Our analysis identified a single regulatory cascade for these three virulence strategies that respond to limited availability of divalent metals in the phagosome. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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18 pages, 843 KiB

Open AccessReview

Implication of Soluble Forms of Cell Adhesion Molecules in Infectious Disease and Tumor: Insights from Transgenic Animal Models

by Etsuro Ono and Toshimitsu Uede

Int. J. Mol. Sci. 2018, 19(1), 239; https://doi.org/10.3390/ijms19010239 - 13 Jan 2018

Cited by 13 | Viewed by 4967

Abstract

Cell adhesion molecules (CAMs) are surface ligands, usually glycoproteins, which mediate cell-to-cell adhesion. They play a critical role in maintaining tissue integrity and mediating migration of cells, and some of them also act as viral receptors. It has been known that soluble forms of the viral receptors bind to the surface glycoproteins of the viruses and neutralize them, resulting in inhibition of the viral entry into cells. Nectin-1 is one of important CAMs belonging to immunoglobulin superfamily and herpesvirus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF) receptor family. Both CAMs also act as alphaherpesvirus receptor. Transgenic mice expressing the soluble form of nectin-1 or HVEM showed almost complete resistance against the alphaherpesviruses. As another CAM, sialic acid-binding immunoglobulin-like lectins (Siglecs) that recognize sialic acids are also known as an immunoglobulin superfamily member. Siglecs play an important role in the regulation of immune cell functions in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer. Siglec-9 is one of Siglecs and capsular polysaccharide (CPS) of group B Streptococcus (GBS) binds to Siglec-9 on neutrophils, leading to suppress host immune response and provide a survival advantage to the pathogen. In addition, Siglec-9 also binds to tumor-produced mucins such as MUC1 to lead negative immunomodulation. Transgenic mice expressing the soluble form of Siglec-9 showed significant resistance against GBS infection and remarkable suppression of MUC1 expressing tumor proliferation. This review describes recent developments in the understanding of the potency of soluble forms of CAMs in the transgenic mice and discusses potential therapeutic interventions that may alter the outcomes of certain diseases. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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The Roles of Matricellular Proteins in Oncogenic Virus-Induced Cancers and Their Potential Utilities as Therapeutic Targets

by Naoyoshi Maeda and Katsumi Maenaka

Int. J. Mol. Sci. 2017, 18(10), 2198; https://doi.org/10.3390/ijms18102198 - 21 Oct 2017

Cited by 15 | Viewed by 5807

Abstract

Matricellular proteins differ from other classical extracellular matrix proteins; for instance, they are transiently expressed as soluble proteins rather than being constitutively expressed in pathological conditions, such as acute viral infections. Accumulating studies have revealed that matricellular proteins, including osteopontin and tenascin-C, both of which interact with integrin heterodimers, are involved in inflammatory diseases, autoimmune disorders, and cancers. The concentrations of these matricellular proteins are elevated in the plasma of patients with certain types of cancers, indicating that they play important roles in oncogenesis. Chronic viral infections are associated with certain cancers, which are distinct from non-viral cancers. Viral oncogenes play critical roles in the development and progression of such cancers. It is vital to investigate the mechanisms of tumorigenesis and, particularly, the mechanism by which viral proteins induce tumor progression. Viral proteins have been shown to influence not only the viral-infected cancer cells, but also the stromal cells and matricellular proteins that constitute the extracellular matrix that surrounds tumor tissues. In this review, we summarize the recent progress on the involvement of matricellular proteins in oncogenic virus-induced cancers to elucidate the mechanism of oncogenesis and consider the possible role of matricellular proteins as therapeutic targets in virus-induced cancers. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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Open AccessCase Report

Secretion of IFN-γ Associated with Galectin-9 Production by Pleural Fluid Cells from a Patient with Extrapulmonary Tuberculosis

by Jingge Zhao, Beata Shiratori, Haorile Chagan-Yasutan, Makoto Matsumoto, Toshiro Niki, Michinori Tanaka, Yayoi Takahashi, Osumu Usami, Yugo Ashino and Toshio Hattori

Int. J. Mol. Sci. 2017, 18(7), 1382; https://doi.org/10.3390/ijms18071382 - 28 Jun 2017

Cited by 10 | Viewed by 5486

Abstract

In this study, we investigated the role of a matricellular protein galectin-9 (Gal-9) in pleural effusion related to tuberculosis (TB). Plasma and pleural fluid of a patient with extrapulmonary TB were analyzed for cytokine content by ELISA and Luminex. Peripheral blood mononuclear cells (PBMCs) and pleural fluid cells (PFCs) were examined for interferon-γ (IFN-γ) secretion by the enzyme-linked immunospot (ELISPOT) assay or IFN-γ ELISA, for apoptosis and necrosis by Cell Death Detection ELISA, and also underwent cell sorting. The results indicate that compared to plasma, pleural fluid had increased levels of IFN-γ (1.6 vs. 55.5 pg/mL), IL-10, IL-12p40, vascular endothelial growth factor (VEGF), and Gal-9 (3.0 vs. 936.0 pg/mL), respectively. PFCs culture supernatant exhibited higher concentration of Gal-9 compared to PBMCs in culture, consistent with enriched Gal-9 staining in the granuloma that is in closer vicinity to PFCs compared to PBMCs. PFCS displayed higher IFN-γ secretion after stimulation with TB antigens ESAT-6/CFP-10. Furthermore, in PFCs, Gal-9 alone could stimulate IFN-γ synthesis in culture or ELISPOT, which was inhibited by a Gal-9 antagonist lactose, and which may promote apoptosis and necrosis. These findings suggest that Gal-9 could modulate immune responses and participate in immunopathology of pleural effusion during TB. Full article

(This article belongs to the Special Issue Molecular Mechanism of Infectious Disease)

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