Xiaoxing You

Integrating physicochemical environmental cues with pathogen detection is essential for an effective and balanced host defense. While Toll-like receptors (TLRs) detect pathogen-associated molecular patterns (PAMPs), transient receptor potential (TRP) ion channels detect specific physicochemical shifts characteristic of inflamed tissues, including extracellular acidosis, hyperosmolarity, oxidative stress, and mechanical perturbations of the lipid bilayer. Emerging evidence indicates that these two sensory systems interact via a bidirectional signaling axis. This review summarizes recent advances in the molecular mechanisms of TRP-TLR crosstalk, focusing on the three principal modes: direct physical coupling, indirect functional coupling via second messengers, and spatial co-organization within membrane microdomains. We examine how TLR signaling regulates TRP channel expression and post-translational modification. Reciprocally, we detail how TRP-mediated ionic fluxes modulate TLR ligand recognition, signal amplification, and effector functions, including phagocytosis and cytokine secretion. Crucially, we illustrate how the dysregulation of this subcellular crosstalk scales up to drive tissue pathologies, including neuropathic pain sensitization, central neuroinflammation, and barrier organ dysfunction. The TRP-TLR axis represents a convergence of immune and sensory signaling. Understanding this interaction provides a basis for identifying novel therapeutic targets for infectious and inflammatory diseases.

Mycoplasma pneumoniae is a primary cause of community-acquired pneumonia, characterized by an excessive host inflammatory response that often drives lung pathology. While Toll-like receptor 2 (TLR2) is the principal sensor for this pathogen, the regulatory mechanisms that calibrate its signaling intensity remain incompletely understood. In this study, we delineate a novel disinhibition-amplification network controlling the macrophage response to M. pneumoniae. We demonstrate that TLR2 engagement triggers the secretion of Matrix metalloproteinase-9 (MMP-9), which subsequently activates the host sialidase Neu1. Activated Neu1 translocates to the cell surface and disrupts the constitutive inhibitory interaction between Siglec-5 and TLR2, effectively releasing a molecular brake. Concurrently, infection induces the specific upregulation of the activating receptor Siglec-14. We reveal that Siglec-14 physically interacts with TLR2 and recruits the Spleen Tyrosine Kinase (Syk) to the plasma membrane. Crucially, this Siglec-14/Syk axis functions as a necessary molecular scaffold that amplifies and sustains MAPK and NF-κB signaling. Disruption of this network, either by silencing Neu1 or Siglec-14, significantly attenuates the inflammatory response. These findings identify the Siglec-5/Siglec-14 receptor pair as a critical checkpoint in mycoplasma pathogenesis and suggest that targeting the MMP9-Neu1-Siglec-14 axis offers a new therapeutic strategy to mitigate inflammation-mediated lung damage.

Bartonella henselae establishes persistent infections by manipulating host cell survival, but mechanisms beyond the known type IV secretion system (T4SS)-cAMP pathway are poorly understood. Here, we delineate a novel anti-apoptotic axis in human endothelial cells hijacked by B. henselae. We found that infection upregulates the pro-survival factor amphiregulin (AREG). This induction is initiated by the intracellular sensor NOD2, which triggers a PI3K/AKT/CREB signaling cascade, culminating in CREB-dependent transcription of AREG. Functional studies confirmed that secreted AREG acts via its receptor, EGFR, to suppress apoptosis, establishing a complete NOD2-AREG-EGFR autocrine loop. Collectively, our findings characterize a sophisticated survival strategy where B. henselae links intracellular innate immune sensing to the activation of an autocrine growth factor loop. The delineation of this novel NOD2-AREG-EGFR axis reveals a parallel mechanism of host cell manipulation, adding a new layer of complexity to our understanding of Bartonella–host interactions.

Airway epithelial cells play a pivotal role in the early host response to Mycoplasma pneumoniae colonization. Our previous study has revealed that M. pneumoniae infection induces metabolic reprogramming in bronchial epithelial cells. However, the mechanisms underlying these metabolic shifts and their contribution to the pathogenesis of pneumonia remain unclear. Herein, we demonstrate that M. pneumoniae infection activates signal transducer and activator of transcription 3 (STAT3), which drives citrate accumulation in airway epithelial cells. Citrate is metabolized by adenosine triphosphate-citrate lyase (ACLY) into acetyl coenzyme A, which is further converted to malonyl coenzyme A, promoting post-translational modifications such as histone acetylation and glyceraldehyde-3-phosphate dehydrogenase malonylation (GAPDH). In vivo, pharmacological inhibition of STAT3 or ACLY attenuated pulmonary inflammation and pro-inflammatory cytokine expression yet paradoxically delayed pathogen clearance, as evidenced by increased colonyforming units in bronchoalveolar lavage fluid and lung tissue. These findings demonstrate that targeting the STAT3/ACLY axis exerts antiinflammatory potential without direct antibacterial activity. Our work highlights the dual regulatory roles of citrate metabolism in inflammation and pathogen control and suggests that combined use of STAT3/ACLY inhibitors with conventional antibiotics may be necessary to achieve both immunomodulation and effective bacterial eradication.

Nucleases are critical metabolic enzymes expressed by mycoplasmas to acquire nucleic acid precursors from the host for their parasitic existence. Certain nucleases, either membrane-bound or secreted, not only contribute to the growth of mycoplasmas but also serve as key virulence factors due to their unique spatial structures and physiological activity. The pathogenesis includes, but is not limited to, degradation of host DNA and RNA, leading to disruptions of nucleic acid metabolism and the induction of host cell apoptosis; degradation of neutrophil extracellular traps (NETs), allowing escape from neutrophil-mediated killing; and upregulation of inflammatory molecules to modulate the immune response of the host. Understanding the biological functions of nucleases is essential for gaining deeper insights into the virulence and immune evasion strategies of mycoplasmas, which can inform the development of novel approaches for the prevention, diagnosis, and treatment of mycoplasma infections.

Mycoplasma pneumoniae is a prevalent respiratory microbe that causes acute inflammation in the respiratory system. Surfactant proteins (SP), particularly SP-A and SP-D, are essential for the immunological protection against M. pneumoniae infection. Variant SP-A2 may lead to immune reactions, which could account for the variability in clinical manifestations among individuals. Mechanistically, these surfactant proteins may act as candidate receptors, facilitating both the adhesion of M. pneumoniae and internalization of community-acquired respiratory distress syndrome toxin. They also exhibit a high affinity for lipid ligands on the surface of M. pneumoniae membranes via their carbohydrate recognition domains, which aid in the direct clearing of the bacteria. In addition, SP-A and SP-D demonstrated synergistic effects in augmenting the intake and elimination of M. pneumoniae by alveolar macrophages. Furthermore, these surfactant proteins negatively regulate pulmonary inflammation by influencing lymphocyte and dendritic cell activities, reducing airway eosinophilic infiltration, and managing asthma-related inflammatory responses. A thorough understanding of the immunomodulatory roles of surfactant proteins in M. pneumoniae infection will shed light on how homeostasis is preserved during mycoplasma pneumonia and may guide the development of novel therapeutic strategies against this organism.

Gram-negative Bartonella species are facultative intracellular bacteria that can survive in the harsh intracellular milieu of host cells. They have evolved strategies to evade detection and degradation by the host immune system, which ensures their proliferation in the host. Following infection, Bartonella alters the initial immunogenic surface-exposed proteins to evade immune recognition via antigen or phase variation. The diverse lipopolysaccharide structures of certain Bartonella species allow them to escape recognition by the host pattern recognition receptors. Additionally, the survival of mature erythrocytes and their resistance to lysosomal fusion further complicate the immune clearance of this species. Certain Bartonella species also evade immune attacks by producing biofilms and anti-inflammatory cytokines and decreasing endothelial cell apoptosis. Overall, these factors create a challenging landscape for the host immune system to rapidly and effectively eradicate the Bartonella species, thereby facilitating the persistence of Bartonella infections and creating a substantial obstacle for therapeutic interventions. This review focuses on the effects of three human-specific Bartonella species, particularly their mechanisms of host invasion and immune escape, to gain new perspectives in the development of effective diagnostic tools, prophylactic measures, and treatment options for Bartonella infections.

The immune response to Mycoplasma pneumoniae infection plays a key role in clinical symptoms. Previous investigations focused on the pro-inflammatory effects of leukocytes and the pivotal role of epithelial cell metabolic status in finely modulating the inflammatory response have been neglected. Herein, we examined how glycolysis in airway epithelial cells is affected by M. pneumoniae infection in an in vitro model. Additionally, we investigated the contribution of ATP to pulmonary inflammation. Metabolic analysis revealed a marked metabolic shift in bronchial epithelial cells during M. pneumoniae infection, characterized by increased glucose uptake, enhanced aerobic glycolysis, and augmented ATP synthesis. Notably, these metabolic alterations are orchestrated by adaptor proteins, MyD88 and TRAM. The resulting synthesized ATP is released into the extracellular milieu via vesicular exocytosis and pannexin protein channels, leading to a substantial increase in extracellular ATP levels. The conditioned medium supernatant from M. pneumoniae -infected epithelial cells enhances the secretion of both interleukin (IL)-1β and IL-18 by peripheral blood mononuclear cells, partially mediated by the P2X7 purine receptor (P2X7R). In vivo experiments confirm that addition of a conditioned medium exacerbates pulmonary inflammation, which can be attenuated by pre-treatment with a P2X7R inhibitor. Collectively, these findings highlight the significance of airway epithelial aerobic glycolysis in enhancing the pulmonary inflammatory response and aiding pathogen clearance.

Mycoplasma belong to the genus Mollicutes and are notable for their small genome sizes (500–1300 kb) and limited biosynthetic capabilities. They exhibit pathogenicity by invading various cell types to survive as intracellular pathogens. Adhesion is a crucial prerequisite for successful invasion and is orchestrated by the interplay between mycoplasma surface adhesins and specific receptors on the host cell membrane. Invasion relies heavily on clathrin‐ and caveolae‐mediated internalization, accompanied by multiple activated kinases, cytoskeletal rearrangement, and a myriad of morphological alterations, such as membrane invagination, nuclear hypertrophy and aggregation, cytoplasmic edema, and vacuolization. Once mycoplasma successfully invade host cells, they establish resilient sanctuaries in vesicles, cytoplasm, perinuclear regions, and the nucleus, wherein specific environmental conditions favor long‐term survival. Although lysosomal degradation and autophagy can eliminate most invading mycoplasmas, some viable bacteria can be released into the extracellular environment via exocytosis, a crucial factor in the prolonging infection persistence. This review explores the intricate mechanisms by which mycoplasma invades host cells and perpetuates their elusive survival, with the aim of highlighting the challenge of eradicating this enigmatic bacterium.