Comparison of the Clinical Outcomes Between Early and Delayed Transplantation After SARS-CoV-2 Infection.

Our study analyzed 95 solid organ transplant (SOT) and 78 hematopoietic stem cell transplant (HSCT) recipients with prior coronavirus disease 2019 (COVID-19). Patients who underwent transplantation within 30 days of COVID-19 infection comprised the early group, and those who underwent transplantation post-30 days of COVID-19 infection comprised the delayed group. In the early transplantation group, no patient, whether undergoing SOT and HSCT, experienced COVID-19-associated complications. In the delayed transplantation group, one patient each from SOT and HSCT experienced COVID-19-associated complications. Additionally, among early SOT and HSCT recipients, two and six patients underwent transplantation within seven days of COVID-19 diagnosis, respectively. However, no significant differences were observed in the clinical outcomes of these patients compared to those in other patients. Early transplantation following severe acute respiratory syndrome coronavirus 2 infection can be performed without increased risk of COVID-19-associated complications. Therefore, transplantation needs not be delayed by COVID-19 infection.

Flexible hydrogels connecting adhesion and wetting.

Raindrops falling on window-panes spread upon contact, whereas hail can cause dents or scratches on the same glass window upon contact. While the former phenomenon resembles classical wetting, the latter is dictated by contact and adhesion theories. The classical Young-Dupre law applies to the wetting of pure liquids on rigid solids, whereas conventional contact mechanics theories account for rigid-on-soft or soft-on-rigid contacts with small deformations in the elastic limit. However, the crossover between adhesion and wetting is yet to be fully resolved. The key lies in the study of soft-on-soft interactions with material properties intermediate between liquids and solids. In this work, we translate adhesion to wetting by experimentally probing the static signature of hydrogels in contact with soft PDMS of varying elasticity of both the components. Consequently, we probe this transition across six orders of magnitude in terms of the characteristic elasto-adhesive parameter of the system. In doing so, we reveal previously unknown phenomenology and a theoretical model which smoothly bridges adhesion of glass spheres with total wetting of pure liquids on any given substrate.

Density Functional Theory Approach to Interpret Elastowetting of Hydrogels.

Sessile hydrogel drops on rigid surfaces exhibit a wetting/contact morphology intermediate between liquid drops and glass spheres. Using density functional theory, we reveal the contact forces acting between a hydrogel and a rigid glass surface. We show that while transitioning from liquid-like to solid-like hydrogels, there exists a critical hydrogel elasticity that enables a switch from attractive-to-repulsive interaction with the underlying rigid glass surface. Our theoretical model is validated by experimental observations of sessile polyacrylamide hydrogels of varying elasticity on glass surfaces. Further, the proposed model successfully approaches Young's law in the pure liquid limit and work of adhesion in the glassy limit. Lastly, we show a modified contact angle relation, taking into account the hydrogel elasticity to explain the features of a distinct hydrogel foot.

Outbreak investigation of Serratia marcescens bloodstream infection in an obstetric ward for high-risk pregnant women.

BACKGROUND: Serratia marcescens is a gram-negative bacterium that is widespread in the environment. S. marcescens bacteremia can be fatal during pregnancy and cause persistent chorioamnionitis. This study reports an outbreak of Serratia marcescens bloodstream infection (BSI) among high-risk pregnant women in an obstetric ward. The purpose of this study is to report our experience with the usefulness of the ATP test in hospital environmental management and to confirm that bloodstream infections of patients with the same strain were correlated by WGS testing. METHODS: This retrospective study collected the data of inpatients with S. marcescens bacteremia in obstetric ward for high-risk pregnant women from August 22, 2021, to October 14, 2021. We performed: an adenosine triphosphate (ATP) bioluminescence test in the environment with a high-contact area; environmental culture; on-site monitoring and staff education; and whole-genome sequencing (WGS) to evaluate genetic relationships among S. marcescens isolates. RESULTS: S. marcescens BSI occurred in four consecutive patients. None of the patients had central venous catheters. An ATP bioluminescence test revealed that high-contact areas and areas for injection preparation were not clean (≥ 1000 relative light units). However, S. marcescens was not identified in the environmental cultures, likely due to intensive environmental cleaning and discarding of potentially contaminated specimens before the culture test. On-site monitoring and education were conducted for 1 month. There were no further reports of BSI until 6 months after the last patient was discharged. WGS performed on three isolates from three patients indicated that the isolated S. marcescens was likely from the same strain. CONCLUSIONS: We controlled an S. marcescens outbreak by improving environmental cleaning as well as education of and behavior changes in healthcare workers. Using the ATP bioluminescence test can provide feedback on environmental cleaning and education. WGS played a role in determining the spread of BSI caused by the same strain.

Clinical safety of remdesivir therapy in COVID-19 patients with renal insufficiency.

Though remdesivir benefits COVID-19 patients, its use in those with renal dysfunction is currently limited due to concerns about possible toxic effects of accumulated sulfobutylether-ß-cyclodextrin (SBECD) on liver and kidney. We examined renal and hepatic function for a month in renally-impaired COVID-19 patients who were treated or not treated with remdesivir to assess the safety of the drug. A retrospective study was performed in adult COVID-19 patients with glomerular filtration rates of <30 ml/min/1.73 m2 at admission to a tertiary care hospital between November 2020 and March 2022. Data on serum creatinine and liver chemistry were collected serially. A total of 101 patients with impaired renal function were analyzed, comprising 64 remdesivir-treated patients and 37 who did not receive any antiviral agent. Although remdesivir-treated patients were more likely to be infected with the Omicron variant (79.7% vs. 48.6%), baseline characteristics did not differ significantly between the two groups. Among patients who initially did not require dialysis, 18.4% (7/38) of remdesivir-treated patients developed acute kidney injury (AKI) at days 4-6, compared with 51.7% (15/29) of non-remdesivir-treated patients. Liver injury severity worsened in 3.1% (2/64) of remdesivir-treated patients and 5.4% (2/37) of non-remdesivir-treated patients at days 4-6. In addition, there was no significant increase in AKI and liver injury over time in remdesivir-treated patients, and there were no cases of discontinuation of remdesivir due to adverse reactions. Concerns regarding the safety of SBECD should not lead to hasty withholding of remdesivir treatment in renally-impaired COVID-19 patients.

Clinical Characteristics of Nocardiosis: a Multicenter Retrospective Study in Korea.

BACKGROUND: Nocardiosis is a rare, but potentially life-threatening condition. It is difficult to diagnose, and bacterial culture identification can be time consuming. We investigated the characteristics of nocardiosis and the suitability of the treatment approach in Korea. MATERIALS AND METHODS: This retrospective study was conducted at 5 medical institutions between 2011 and 2021. We reviewed the medical records of patients with microbiologically confirmed nocardiosis. Appropriate antibiotic selection was defined as follows: (1) selecting antibiotics according to the species, (2) if the species of Nocardia was unknown, trimethoprim-sulfamethoxazole-based therapy or linezolid-based therapy was administered, and (3) selection of antibiotics using the antibiotic susceptibility test. The appropriate treatment periods for antibiotics were defined as treatment maintained from 3 to 12 months, depending on involvement of the organs. Descriptive analysis and Fisher exact test were used. Statistical significance was set at P-values of <0.05. RESULTS: Thirty patients were enrolled. Of these patients, 18 (60.0%) were male. The median age was 70.5 years. Among the diagnosed patients, 12 (40.0%) had an immunocompromised status. Eight (30.0%) patients received optimal treatment for the appropriate treatment period. Appropriate dosing duration was observed in 3 of the 12 (25.0%) immunocompromised patients. There was no significant difference between the presence or absence of immunosuppression and the adequacy of treatment for nocardiosis (P = 1.000). Skin and soft tissue (14 patients) were most frequently involved in this study. Nocardia species (spp.) were isolated from culture at a median of 6.0 days. There were 7 cases with N. farcinica (23.3%). CONCLUSION: We found that 60.0% of the patients with nocardiosis did not have an immunocompromised status. Further, 26.7% of the total patients received adequate treatment for nocardiosis. The reasons for suboptimal management of nocardiosis in Korea are presumed to be diagnostic difficulties, lack of awareness about nocardiosis, and difficulties in selecting antibiotics for Nocardia spp. among clinicians. The lack of antibiotic susceptibility tests for Nocardia spp. could be the source of these problems. Nocardiosis should be suspected in cases of recurrent infections with skin and soft tissue, musculoskeletal, or respiratory system involvement with or without an immunocompromised status. Clinical microbiological support is required for the diagnosis and selection of antibiotics in Korea. High clinical index of suspicion and clinical microbiological support are required for the accurate diagnosis of nocardiosis in Korea.

Organohydrogels with cellulose nanofibers enhanced supramolecular interactions toward high performance self-adhesive sensing pads.

Gel materials with tailored functions and tissue-like properties have gained significant interest in emerging applications, including tissue engineering scaffolds, flexible electronics, and soft robotics. In this work, we developed a stretchable, flexible, adhesive, and conductive organohydrogel through physical cross-linking of the poly (N-[tris (hydroxymethyl) methyl] acrylamide-co-acrylamide) (denoted as P(THMA-AM)) network in the presence of cellulose nanofiber (CNF), sodium chloride, and glycerol. The gel matrix is rich in intermolecular interactions, including hydrogen bonding and ionic interactions, which contribute to a highly compact and cohesive structure without the requirement of any chemical crosslinkers. Moreover, the plasticizing effect of glycerol can mitigate the self-entanglement of CNFs, enhancing their mobility and ultimately conferring the organohydrogel with exceptional stretchability and flexibility. The resulting organohydrogel exhibited superior mechanical properties, self-adhesion, and ionic conductivity, making it an excellent candidate for strain-sensing applications, particularly in distinguishing and monitoring human movements.

Clinical Characteristics of and Risk Factors for Subsequent Carbapenemase-producing Enterobacterales (CPE) Bacteraemia in Rectal CPE Carriers.

BACKGROUND: Due to high mortality and limited treatment options, the rise in carbapenemase-producing Enterobacterales (CPE) has become a major concern. This study aimed to evaluate the incidence and characteristics of subsequent CPE bacteraemia in rectal CPE carriers and investigate the risk factors for CPE bacteraemia compared with non-carbapenemase-producing (non-CP) Enterobacterales bacteraemia. METHODS: A retrospective analysis was conducted on adult patients who were confirmed to have CPE colonisation by stool surveillance culture at a tertiary hospital from January 2018 to February 2022. All episodes of Enterobacterales bacteraemia up to 6 months after CPE colonisation were identified. RESULTS: Of 1174 patients identified as rectal CPE carriers, 69 (5.8%; 95% CI 4.6-7.3%) experienced subsequent CPE bacteraemia during the 6 months after the diagnosis of CPE colonisation. Colonisation by a Klebsiella pneumoniae carbapenemase (KPC) producer (or CP-K. pneumoniae), colonisation by multiple CPE species, chronic kidney disease and haematological malignancy were independently associated with CPE bacteraemia in CPE carriers. When CPE carriers developed Enterobacterales bacteraemia, the causative agent was more frequently non-CP Enterobacterales than CPE (63.6% vs. 36.4%). Among these patients, colonisation with a KPC producer, CPE colonisation at multiple sites, shorter duration from colonisation to bacteraemia (< 30 days) and recent intraabdominal surgery were independent risk factors for CPE bacteraemia rather than non-CP Enterobacterales bacteraemia. CONCLUSIONS: In CPE carriers, non-CP Enterobacterales were more often responsible for bacteraemia than CPE. Empirical antibiotic therapy for CPE should be considered when sepsis is suspected in a CPE carrier with risk factors for CPE bacteraemia.

A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity.

Virtual memory T (TVM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although TVM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a TVM cell-originated CD44super-high(s-hi)CD49dlo CD8+ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8+ TVM cells and can cause alopecia areata. Mechanistically, CD44s-hiCD49dlo CD8+ T cells could be induced from conventional TVM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.

Protracted course of SARS-CoV-2 pneumonia in moderately to severely immunocompromised patients.

There have been few studies comparing the clinical characteristics and outcomes of SARS-CoV-2 pneumonia in individuals with and without moderately to severely immunocompromised conditions. We reviewed adult patients with SARS-CoV-2 infection who had radiologic evidence of pneumonia at a tertiary hospital in Seoul, South Korea, from February 2020 to April 2022. Moderately to severely immunocompromised status was defined as medical conditions or treatments that resulted in increased risk of severe COVID-19 and weakened immune response to COVID-19 vaccine as recommended by Centers for Disease Control and Prevention. The time to pneumonia development was defined as the time from symptom onset to the time when radiologic evidence of pneumonia was obtained. Viral clearance was defined as a Ct value > 30. COVID-19-related death was defined as 90-day death following imaging-confirmed pneumonia without any other plausible cause of death. A total of 467 patients with SARS-CoV-2 pneumonia were analyzed. Of these, 102 (22%) were moderately to severely immunocompromised. The median (IQR) time to pneumonia development was significantly longer in moderately to severely immunocompromised patients (9.5 [6-14] days) than the comparator (6 [3-8] days), p < 0.001), as was the median time to viral clearance (21 versus 12 days, p < 0.001). Moderately to severely immunocompromised status (aOR, 18.39; 95% CI, 5.80-58.30; p < 0.001) was independently associated with COVID-19-related death. Patients with moderately to severely immunocompromised conditions are likely to experience a more protracted course of SARS-CoV-2 pneumonia and a worse outcome than those without these conditions.

CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy.

PURPOSE: Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies. EXPERIMENTAL DESIGN: From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity. RESULTS: We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1- subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1-mediated reinvigoration of exhausted CD8+ T cells. CONCLUSIONS: CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.

Propionate Attenuates Growth of Oral Streptococci through Enhancing Methionine Biosynthesis.

Oral streptococci are considered as an opportunistic pathogen associated with initiation and progression of various oral diseases. However, since the currently-available treatments often accompany adverse effects, alternative strategy is demanded to control streptococci. In the current study, we investigated whether short-chain fatty acids (SCFAs), including sodium acetate (NaA), sodium propionate (NaP), and sodium butyrate (NaB), can inhibit the growth of oral streptococci. Among the tested SCFAs, NaP most potently inhibited the growth of laboratory and clinically isolated strains of Streptococcus gordonii under anaerobic culture conditions. However, the growth inhibitory effect of NaP on six different species of other oral streptococci was different depending on their culture conditions. Metabolic changes such as alteration of methionine biosynthesis can affect bacterial growth. Indeed, NaP enhanced intracellular methionine levels of oral streptococci as well as the mRNA expression level of methionine biosynthesis-related genes. Collectively, these results suggest that NaP has an inhibitory effect on the growth of oral streptococci, which might be due to alteration of methionine biosynthesis. Thus, NaP can be used an effective bacteriostatic agent for the prevention of oral infectious diseases caused by oral streptococci.

Capillary pressure mediated long-term dynamics of thin soft films.

HYPOTHESIS: The conventional solid-solid contact is well studied in the literature. However, a number of practical applications, such as adhesive patches and biomimetic surfaces, require a much deeper understanding of soft contact where there is a distinct time-dependent adhesion behavior due to the dual-phase structure (solids and liquids). To understand this, currently existing solid-solid contact behavior is extrapolated to soft contact, wherein the size-effect of the gel film and the preload are typically neglected. When introducing the finite-size effect and preload, gels could experience distinctive long-term contact dynamics in contact with another material. EXPERIMENTS: We reconstruct the evolving surface profile of the gel films intercalated between a glass sphere and glass slide using dual wavelength-reflection interference contrast microscopy. The macro-sized glass sphere compresses the gel. The indentation depth is comparable to the gel film thickness, wherein the conventional contact theories are inapplicable. FINDINGS: The gel surface experiences two deformation stages. The natural preload and elastic force develop the contact area in the early state. In the later state, the viscous free molecules of the gel develop the ridge. We discover that the residual surface stress relaxes over 85 hr. Our findings on the long-term gel deformation provide a new perspective on soft adhesion, from developing soft adhesives to understanding biological tissues.

Succession of the Abandoned Rice Fields Restores the Riparian Forest.

The vegetation changes in the abandoned rice fields with different abandonment histories were analyzed across the country of South Korea. The successional process was confirmed by changes in vegetation profiles and species composition. The vegetation profile showed the process of starting with grassland, passing through the shrub stage, and turning into a tree-dominated forest. DCA ordination based on vegetation data showed that the process began with grasslands consisting of Persicaria thunbergii, Juncus effusus var. decipiens, Phalaris arundinacea, etc., then partially went through shrubland stages consisting of Salix gracilistyla, S. integra, young Salix koreensis, etc., and ultimately changed to a Salix koreensis dominated forest. In order to study the relationship between the succession process of the abandoned rice paddies and riparian vegetation, information on riparian vegetation was collected in the same watershed as the abandoned rice paddies investigated. Riparian vegetation tended to be distributed in the order of grasslands consisting of Phragmites japonica, Miscanthus sacchariflorus, P. arundinacea, etc., shrubland dominated by Salix gracilistyla, S. integra, etc., and a S. koreensis community dominated forest by reflecting the flooding regime as far away from the waterway. The result of stand ordination based on the riparian vegetation data also reflected the trend. From this result, we confirmed that the temporal sequence of the vegetation change that occurred in the abandoned rice fields resembled the spatial distribution of the riparian vegetation. Consequently, succession of the abandoned rice fields restored the riparian forest, which has almost disappeared in Korea and other Asian countries that use rice as their staple food.

Spatial immune heterogeneity of hypoxia-induced exhausted features in high-grade glioma.

The tumor immune microenvironment (TIME) in high-grade glioma (HGG) exhibits high spatial heterogeneity. Though the tumor core and peripheral regions have different biological features, the cause of this spatial heterogeneity has not been clearly elucidated. Here, we examined the spatial heterogeneity of HGG using core and peripheral regions obtained separately from the patients with HGG. We analyzed infiltrating immune cells by flow cytometry from 34 patients with HGG and the transcriptomes by RNA-seq analysis from 18 patients with HGG. Peripheral region-infiltrating immune cells were in vitro cultured in hypoxic conditions and their immunophenotypes analyzed. We analyzed whether the frequencies of exhausted CD8+ T cells and immunosuppressive cells in the core or peripheral regions are associated with the survival of patients with HGG. We found that terminally exhausted CD8+ T cells and immunosuppressive cells, including regulatory T (TREG) cells and M2 tumor-associated macrophages (TAMs), are more enriched in the core regions than the peripheral regions. Terminally exhausted and immunosuppressive profiles in the core region significantly correlated with the hypoxia signature, which was enriched in the core region. Importantly, in vitro culture of peripheral region-infiltrating immune cells in hypoxic conditions resulted in an increase in terminally exhausted CD8+ T cells, CTLA-4+ TREG cells, and M2 TAMs. Finally, we found that a high frequency of PD-1+CTLA-4+CD8+ T cells in the core regions was significantly associated with decreased progression-free survival of patients with HGG. The hypoxic condition in the core region of HGG directly induces an immunosuppressive TIME, which is associated with patient survival.

Short-chain fatty acids inhibit the biofilm formation of Streptococcus gordonii through negative regulation of competence-stimulating peptide signaling pathway.

Streptococcus gordonii, a Gram-positive commensal bacterium, is an opportunistic pathogen closely related to initiation and progression of various oral diseases, such as periodontitis and dental caries. Its biofilm formation is linked with the development of such diseases by enhanced resistance against antimicrobial treatment or host immunity. In the present study, we investigated the effect of short-chain fatty acids (SCFAs) on the biofilm formation of S. gordonii. SCFAs, including sodium acetate (NaA), sodium propionate (NaP), and sodium butyrate (NaB), showed an effective inhibitory activity on the biofilm formation of S. gordonii without reduction in bacterial growth. SCFAs suppressed S. gordonii biofilm formation at early time points whereas SCFAs did not affect its preformed biofilm. A quorum-sensing system mediated by competence-stimulating peptide (CSP) is known to regulate biofilm formation of streptococci. Interestingly, SCFAs substantially decreased mRNA expression of comD and comE, which are CSP-sensor and its response regulator responsible for CSP pathway, respectively. Although S. gordonii biofilm formation was enhanced by exogenous synthetic CSP treatment, such effect was not observed in the presence of SCFAs. Collectively, these results suggest that SCFAs have an anti-biofilm activity on S. gordonii through inhibiting comD and comE expression which results in negative regulation of CSP quorum-sensing system. SCFAs could be an effective anti-biofilm agent against S. gordonii for the prevention of oral diseases.

Reduced Pressure Drop in Viscoelastic Polydimethylsiloxane Wall Channels.

Polydimethylsiloxane (PDMS) is an important viscoelastic material that finds applications in a large number of engineering systems, particularly lab-on-chip microfluidic devices built with a flexible substrate. Channels made of PDMS, used for transporting analytes, are integral to these applications. The PDMS viscoelastic nature can induce additional hydrodynamic contributions at the soft wall/fluid interface compared to rigid walls. In this research, we investigated the pressure drop within PDMS channels bounded by rigid tubes (cellulose tubes). The bulging effect of the PDMS was limited by the rigid tubes under flowing fluids. The PDMS viscoelasticity was modulated by changing the ratio of the base to the cross-linker from 10:1 to 35:1. We observed that the pressure drop of the flowing fluids within the channel decreased with the increased loss tangent of the PDMS in the examined laminar regime [Reynolds number (Re) ∼ 23-58.6 for water and Re ∼ 0.69-8.69 for glycerol solution]. The elastic PDMS 10:1 wall channels followed the classical Hagen Poiseuille's equation, but the PDMS walls with lower cross-linker concentrations and thicker walls decreased pressure drops. The friction factor (f) for the PDMS channels with the two working fluids could be approximated as f = 47/Re. We provide a correlation between the pressure drop and PDMS viscoelasticity based on experimental findings. In the correlation, the loss tangent predominates; the larger the loss tangent, the smaller is the pressure drop. The research findings appear to be unexpected if only considering the energy dissipation of viscoelastic PDMS walls. We attributed the reduction in the pressure drop to a lubricating effect of the viscoelastic PDMS walls in the presence of the working fluids. Our results reveal the importance of the subtle diffusion of the residual oligomers and water from the bulk to the soft wall/fluid interface for the observed pressure drop in soft wall channels.

Induction of Apoptotic Cell Death by Oral Streptococci in Human Periodontal Ligament Cells.

Initiation and progression of oral infectious diseases are associated with streptococcal species. Bacterial infection induces inflammatory responses together with reactive oxygen species (ROS), often causing cell death and tissue damage in the host. In the present study, we investigated the effects of oral streptococci on cytotoxicity and ROS production in human periodontal ligament (PDL) cells. Streptococcus gordonii showed cell cytotoxicity in a dose- and time-dependent manner. The cytotoxicity might be due to apoptosis since S. gordonii increased annexin V-positive cells, and the cytotoxicity was reduced by an apoptosis inhibitor, Z-VAD-FMK. Other oral streptococci such as Streptococcus mitis, Streptococcus sanguinis, and Streptococcus sobrinus also induced apoptosis, whereas Streptococcus mutans did not. All streptococci tested except S. mutans triggered ROS production in human PDL cells. Interestingly, however, streptococci-induced apoptosis appears to be ROS-independent, as the cell death induced by S. gordonii was not recovered by the ROS inhibitor, resveratrol or n-acetylcysteine. Instead, hydrogen peroxide (H2O2) appears to be important for the cytotoxic effects of streptococci since most oral streptococci except S. mutans generated H2O2, and the cytotoxicity was dramatically reduced by catalase. Furthermore, streptococcal lipoproteins are involved in cytotoxicity, as we observed that cytotoxicity induced by the lipoprotein-deficient S. gordonii mutant was less potent than that by the wild-type and was attenuated by anti-TLR2-neutralizing antibody. Indeed, lipoproteins purified from S. gordonii alone were sufficient to induce cytotoxicity. Notably, S. gordonii lipoproteins did not induce H2O2 or ROS but cooperatively induced cell death when co-treated with H2O2. Taken together, these results suggest that most oral streptococci except S. mutans efficiently induce damage to human PDL cells by inducing apoptotic cell death with bacterial H2O2 and lipoproteins, which might contribute to the progression of oral infectious diseases such as apical periodontitis.