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Fulltext Immune Checkpoint Molecules and Glucose Metabolism in HIV-Induced T Cell Exhaustion

Chan YT, Cheong HC, Tang TF, Rajasuriar R, Cheng KK, Looi CY, et al.

Biomedicines, 2022 Nov 04;10(11).
PMID: 36359329 DOI: 10.3390/biomedicines10112809

The progressive decline of CD8+ cytotoxic T cells in human immunodeficiency virus (HIV)-infected patients due to infection-triggered cell exhaustion and cell death is significantly correlated with disease severity and progression into the life-threatening acquired immunodeficiency syndrome (AIDS) stage. T cell exhaustion is a condition of cell dysfunction despite antigen engagement, characterized by augmented surface expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1), which suppress T cell receptor (TCR) signaling and negatively impact the proliferative and effector activities of T cells. T cell function is tightly modulated by cellular glucose metabolism, which produces adequate energy to support a robust reaction when battling pathogen infection. The transition of the T cells from an active to an exhausted state following pathogen persistence involves a drastic change in metabolic activity. This review highlights the interplay between immune checkpoint molecules and glucose metabolism that contributes to T cell exhaustion in the context of chronic HIV infection, which could deliver an insight into the rational design of a novel therapeutic strategy.
Zika Virus Vaccine: The Current State of Affairs and Challenges Posed by Antibody-Dependent Enhancement Reaction

Cheong HC, Cheok YY, Chan YT, Sulaiman S, Looi CY, Alshanon AF, et al.

Viral Immunol, 2022 Nov;35(9):586-596.
PMID: 36301533 DOI: 10.1089/vim.2022.0082

Infection caused by the Zika virus (ZIKV) can lead to serious neurological complications such as microcephaly in neonates. At present, no approved ZIKV vaccine is available, but few vaccine candidates are undergoing clinical trial. One major challenge faced is antibody-dependent enhancement (ADE) reaction that may provoke severe outcome in subsequent infection by ZIKV or other flaviviruses. Thus, more efforts should be dedicated to understanding ADE in designing a safe and effective vaccine to minimize the consequence of the potentially fatal infection's complications and to tackle potential ZIKV reemergence. This review discusses different types of ZIKV vaccine candidates that are currently underway in various stages of preclinical and clinical evaluations.
Fulltext Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection

Cheok YY, Tan GMY, Fernandez KC, Chan YT, Lee CYQ, Cheong HC, et al.

Front Immunol, 2021;12:702156.
PMID: 34707599 DOI: 10.3389/fimmu.2021.702156

Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.
Chlamydia trachomatis plasmid-encoding Pgp3 protein induces secretion of distinct inflammatory signatures from HeLa cervical epithelial cells

Cheong HC, Cheok YY, Chan YT, Tang TF, Sulaiman S, Looi CY, et al.

BMC Microbiol, 2023 Mar 04;23(1):58.
PMID: 36870960 DOI: 10.1186/s12866-023-02802-3

BACKGROUND: Genital Chlamydia trachomatis infection is the most common bacterial sexual transmitted disease that causes severe complications including pelvic inflammatory disease, ectopic pregnancy, and infertility in females. The Pgp3 protein encoded by C. trachomatis plasmid has been speculated to be an important player in chlamydial pathogenesis. However, the precise function of this protein is unknown and thus remains to be thoroughly investigated.
METHODS: In this study, we synthesized Pgp3 protein for in vitro stimulation in the Hela cervical carcinoma cells.
RESULTS AND CONCLUSION: We showed that Pgp3 induced prominent expression of host inflammatory cytokine genes including interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and chemokine C-X-C motif ligand 1 (CXCL1), implying a possible role of Pgp3 in modulating the inflammatory reaction in the host.
Influx of podoplanin-expressing inflammatory macrophages into the genital tract following Chlamydia infection

Chan YT, Cheok YY, Cheong HC, Tan GMY, Seow SR, Tang TF, et al.

Immunol Cell Biol, 2023 Apr;101(4):305-320.
PMID: 36658328 DOI: 10.1111/imcb.12621

Genital Chlamydia trachomatis infection remains a major health issue as it causes severe complications including pelvic inflammatory disease, ectopic pregnancy and infertility in females as a result of infection-associated chronic inflammation. Podoplanin, a transmembrane receptor, has been previously reported on inflammatory macrophages. Thus, strategies that specifically target podoplanin might be able to reduce local inflammation. This study investigated the expression level and function of podoplanin in a C. trachomatis infection model. C57BL/6 mice infected with the mouse pathogen Chlamydia muridarum were examined intermittently from days 1 to 60 using flow cytometry analysis. Percentages of conventional macrophages (CD11b+ CD11c- F4/80+ ) versus inflammatory macrophages (CD11b+ CD11c+ F4/80+ ), and the expression of podoplanin in these cells were investigated. Subsequently, a podoplanin-knockout RAW264.7 cell was used to evaluate the function of podoplanin in C. trachomatis infection. Our findings demonstrated an increased CD11b+ cell volume in the spleen at day 9 after the infection, with augmented podoplanin expression, especially among the inflammatory macrophages. A large number of podoplanin-expressing macrophages were detected in the genital tract of C. muridarum-infected mice. Furthermore, analysis of the C. trachomatis-infected patients demonstrated a higher percentage of podoplanin-expressing monocytes than that in the noninfected controls. Using an in vitro infection in a transwell migration assay, we identified that macrophages deficient in podoplanin displayed defective migratory function toward C. trachomatis-infected HeLa 229 cells. Lastly, using immunoprecipitation-mass spectrometry method, we identified two potential podoplanin interacting proteins, namely, Cofilin 1 and Talin 1 actin-binding proteins. The present study reports a role of podoplanin in directing macrophage migration to the chlamydial infection site. Our results suggest a potential for reducing inflammation in individuals with chronic chlamydial infections by targeting podoplanin.
Critical review on airborne microplastics: An indoor air contaminant of emerging concern

Kek HY, Tan H, Othman MHD, Nyakuma BB, Ho WS, Sheng DDCV, et al.

Environ Res, 2024 Mar 15;245:118055.
PMID: 38154562 DOI: 10.1016/j.envres.2023.118055

Airborne Microplastics (MPs), an emerging environmental issue, have gained recent attention due to their newfound presence in indoor environments. Utilizing the Web of Science database for literature collection, the paper presents a comprehensive review of airborne MPs including emission sources, assessment methods, exposure risks, and mitigation strategies. This review delves into the diverse sources and mechanisms influencing indoor airborne MP pollution, underscoring the complex interplay between human activities, ventilation systems, and the characteristics of indoor environments. Major sources include the abrasion of synthetic textiles and the deterioration of flooring materials, with factors like carpeting, airflow, and ventilation significantly impacting MP levels. Human activities, such as increased movement in indoor spaces and the intensive use of plastic-based personal protective equipment (PPE) post-pandemic, notably elevate indoor MP concentrations. The potential health impacts of airborne MPs are increasingly concerning, with evidence suggesting their role in respiratory, immune, and nervous system diseases. Despite this, there is a scarcity of information on MPs in diverse indoor environments and the inhalation risks associated with the frequent use of PPE. This review also stresses the importance of developing effective strategies to reduce MP emissions, such as employing HEPA-filtered vacuums, minimizing the use of synthetic textiles, and enhancing indoor ventilation. Several future research directions were proposed, including detailed temporal analyses of indoor MP levels, interactions of MP with other atmospheric pollutants, the transport dynamics of inhalable MPs (≤10 μm), and comprehensive human exposure risk assessments.