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Fulltext Chronic Inflammatory Diseases at Secondary Sites Ensuing Urogenital or Pulmonary Chlamydia Infections

Cheok YY, Lee CYQ, Cheong HC, Looi CY, Wong WF

Microorganisms, 2020 Jan 17;8(1).
PMID: 31963395 DOI: 10.3390/microorganisms8010127

Chlamydia trachomatis and C. pneumoniae are members of the Chlamydiaceae family of obligate intracellular bacteria. The former causes diseases predominantly at the mucosal epithelial layer of the urogenital or eye, leading to pelvic inflammatory diseases or blindness; while the latter is a major causative agent for pulmonary infection. On top of these well-described diseases at the respective primary infection sites, Chlamydia are notoriously known to migrate and cause pathologies at remote sites of a host. One such example is the sexually acquired reactive arthritis that often occurs at few weeks after genital C. trachomatis infection. C. pneumoniae, on the other hand, has been implicated in an extensive list of chronic inflammatory diseases which include atherosclerosis, multiple sclerosis, Alzheimer's disease, asthma, and primary biliary cirrhosis. This review summarizes the Chlamydia infection associated diseases at the secondary sites of infection, and describes the potential mechanisms involved in the disease migration and pathogenesis.
Fulltext An Overview of Helicobacter pylori Survival Tactics in the Hostile Human Stomach Environment

Cheok YY, Lee CYQ, Cheong HC, Vadivelu J, Looi CY, Abdullah S, et al.

Microorganisms, 2021 Dec 03;9(12).
PMID: 34946105 DOI: 10.3390/microorganisms9122502

Helicobacter pylori is well established as a causative agent for gastritis, peptic ulcer, and gastric cancer. Armed with various inimitable virulence factors, this Gram-negative bacterium is one of few microorganisms that is capable of circumventing the harsh environment of the stomach. The unique spiral structure, flagella, and outer membrane proteins accelerate H. pylori movement within the viscous gastric mucosal layers while facilitating its attachment to the epithelial cells. Furthermore, secretion of urease from H. pylori eases the acidic pH within the stomach, thus creating a niche for bacteria survival and replication. Upon gaining a foothold in the gastric epithelial lining, bacterial protein CagA is injected into host cells through a type IV secretion system (T4SS), which together with VacA, damage the gastric epithelial cells. H. pylori does not only establishes colonization in the stomach, but also manipulates the host immune system to permit long-term persistence. Prolonged H. pylori infection causes chronic inflammation that precedes gastric cancer. The current review provides a brief outlook on H. pylori survival tactics, bacterial-host interaction and their importance in therapeutic intervention as well as vaccine development.
Fulltext T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, et al.

Front Immunol, 2018;9:2569.
PMID: 30473697 DOI: 10.3389/fimmu.2018.02569

T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
Fulltext Lung-infiltrating T helper 17 cells as the major source of interleukin-17A production during pulmonary Cryptococcus neoformans infection

Movahed E, Cheok YY, Tan GMY, Lee CYQ, Cheong HC, Velayuthan RD, et al.

BMC Immunol, 2018 Nov 08;19(1):32.
PMID: 30409128 DOI: 10.1186/s12865-018-0269-5

BACKGROUND: IL-17A has emerged as a key player in the pathologies of inflammation, autoimmune disease, and immunity to microbes since its discovery two decades ago. In this study, we aim to elucidate the activity of IL-17A in the protection against Cryptococcus neoformans, an opportunistic fungus that causes fatal meningoencephalitis among AIDS patients. For this purpose, we examined if C. neoformans infection triggers IL-17A secretion in vivo using wildtype C57BL/6 mice. In addition, an enhanced green fluorescence protein (EGFP) reporter and a knockout (KO) mouse models were used to track the source of IL-17A secretion and explore the protective function of IL-17A, respectively.
RESULTS: Our findings showed that in vivo model of C. neoformans infection demonstrated induction of abundant IL-17A secretion. By examining the lung bronchoalveolar lavage fluid (BALF), mediastinal lymph node (mLN) and spleen of the IL-17A-EGFP reporter mice, we showed that intranasal inoculation with C. neoformans promoted leukocytes lung infiltration. A large proportion (~ 50%) of the infiltrated CD4+ helper T cell population secreted EGFP, indicating vigorous TH17 activity in the C. neoformans-infected lung. The infection study in IL-17A-KO mice, on the other hand, revealed that absence of IL-17A marginally boosted fungal burden in the lung and accelerated the mouse death.
CONCLUSION: Therefore, our data suggest that IL-17A is released predominantly from TH17 cells in vivo, which plays a supporting role in the protective immunity against C. neoformans infection.
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.
CPAF, HSP60 and MOMP antigens elicit pro-inflammatory cytokines production in the peripheral blood mononuclear cells from genital Chlamydia trachomatis-infected patients

Cheong HC, Lee CYQ, Cheok YY, Shankar EM, Sabet NS, Tan GMY, et al.

Immunobiology, 2019 01;224(1):34-41.
PMID: 30477893 DOI: 10.1016/j.imbio.2018.10.010

BACKGROUND: Persistent inflammation caused by Chlamydia trachomatis in the female genital compartment represents one of the major causes of pelvic inflammatory disease (PID), ectopic pregnancy and infertility in females. Here, we examined the pro-inflammatory cytokine response following stimulation with three different types of C. trachomatis antigens, viz. chlamydial protease-like factor (CPAF), heat shock protein 60 (HSP60) and major outer membrane protein (MOMP).
METHODS: A total of 19 patients with genital C. trachomatis infection and 10 age-matched healthy controls were recruited for the study. Peripheral blood mononuclear cells (PBMCs) isolated from genital C. trachomatis-infected females were cultured in the presence of CPAF, HSP60 and MOMP antigens, and cytokines were measured by ELISA assay.
RESULTS: We reported that pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) were robustly secreted following antigenic exposure. Notably, CPAP and MOMP were more potent in triggering IL-1β, as compared to HSP60. Elevated levels of the proinflammatory cytokines were also noted in the samples infected with plasmid-bearing C. trachomatis as compared to those infected with plasmid-free strains.
CONCLUSIONS: Our study highlights distinct ability of chlamydial antigens in triggering pro-inflammatory response in the host immune cells.
Fulltext Diversity of endocervical microbiota associated with genital Chlamydia trachomatis infection and infertility among women visiting obstetrics and gynecology clinics in Malaysia

Cheong HC, Yap PSX, Chong CW, Cheok YY, Lee CYQ, Tan GMY, et al.

PLoS One, 2019;14(11):e0224658.
PMID: 31738795 DOI: 10.1371/journal.pone.0224658

The cervical microbiota constitutes an important protective barrier against the invasion of pathogenic microorganisms. A disruption of microbiota within the cervical milieu has been suggested to be a driving factor of sexually transmitted infections. These include Chlamydia trachomatis which frequently causes serious reproductive sequelae such as infertility in women. In this study, we profiled the cervical microbial composition of a population of 70 reproductive-age Malaysian women; among which 40 (57.1%) were diagnosed with genital C. trachomatis infection, and 30 (42.8%) without C. trachomatis infection. Our findings showed a distinct compositional difference between the cervical microbiota of C. trachomatis-infected subjects and subjects without C. trachomatis infection. Specifically, significant elevations of mostly strict and facultative anaerobes such as Streptococcus, Megasphaera, Prevotella, and Veillonella in the cervical microbiota of C. trachomatis-positive women were detected. The results from the current study highlights an interaction of C. trachomatis with the environmental microbiome in the endocervical region.