Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis.

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019.

Toe Grip Strength Is Associated with Improving Gait Function in Patients with Subacute Stroke.

Toe grip strength has recently been suggested to play an essential role in maintaining balance and postural stability for ambulatory function in older populations. This study aimed to investigate its association with improving gait function three months after onset in patients with subacute stroke. This longitudinal cohort study included 98 first-ever stroke patients (67 ± 9 years, 56% female) within one month from the onset who could not ambulate independently. Functional outcome indicators, including toe grip strength, hand grip strength, knee extensor strength, Fugl-Meyer Assessment of Lower Extremity (FMA_LE), and the Postural Assessment Scale for Stroke (PASS), were assessed before and three months after the intervention. We analyzed the correlation between participants' gait function using a 10-meter walk test time and various functional indicators. Then, multiple linear regression analysis was used to investigate whether toe grip strength was related to the improvement of gait function. Correlation analysis revealed a significant positive correlation between the 10MWT time and toe grip strength ratio (affected/unaffected side), with a moderate effect size (r = -0.61, p <0.001). Multiple regression analysis with covariates showed a significant relationship between 10MWT time and toe grip strength ratio (ß = -0.113, p < 0.001), FMA_LE (ß = -1.315, p = 0.004), PASS (ß = -3.275, p <0.001), and age (ß = -0.159, p = 0.004). In conclusion, toe grip strength was an essential factor associated with ambulatory function improvement in subacute stroke patients three months after onset. Additional toe grip muscle strengthening rehabilitation treatment can be expected to help improve the ambulatory function of subacute stroke patients in the future.

Use of Bioelectrical Impedance Analysis to Explore the Effectiveness of Stellate Ganglion Block in Patients with Post-Stroke Complex Regional Pain Syndrome: A Retrospective Pilot Study.

Post-stroke complex regional pain syndrome (CRPS) poses challenges in pain assessment for survivors. Stellate ganglion block (SGB) is a treatment, but evaluating its effectiveness is difficult for patients with communication limitations. Edema, a prominent symptom, can serve as an evaluation marker. Bioelectrical impedance analysis (BIA), assessing body composition and fluid status, is used independently of patient cooperation. This retrospective, observational pilot study aims to explore BIA's utility as an assessment tool post-SGB, revealing the effects and time courses of a single SGB on the bodily composition of post-stroke CRPS patients. Seven patients received ultrasound-guided SGB with a 5 mL solution containing 4 mL of 0.25% bupivacaine hydrochloride and 40 mg of triamcinolone into the prevertebral muscle space. BIA compared measures between affected and unaffected arms. The affected arm had higher segmental body water (SBW) and extracellular water ratios before SGB (p = 0.028 and p = 0.018, respectively). The SBW of the affected side, the SBW ratio, and the 1 and 5 kHz SFBIA ratios improved over time (p = 0.025, 0.008, 0.001, and 0.005, respectively). Rapid improvement occurred around 3 days post-injection, with maximum effects within approximately 1 week, persisting up to 3 weeks. SGB successfully reduced edema in post-stroke CRPS patients, with BIA serving as a useful tool for follow-up, facilitating the development of efficient treatment plans.

Three-Dimensional Magnetic Rehabilitation, Robot-Enhanced Hand-Motor Recovery after Subacute Stroke: A Randomized Controlled Trial.

We developed an end-effector-type rehabilitation robot that can uses electro- and permanent magnets to generate a three-way magnetic field to assist hand movements and perform rehabilitation therapy. This study aimed to investigate the therapeutic effect of a rehabilitation program using a three-dimensional (3D) magnetic force-based hand rehabilitation robot on the motor function recovery of the paralyzed hands of patients with stroke. This was a double-blind randomized controlled trial in which 36 patients with subacute stroke were assigned to intervention and control groups of 18 patients each. The intervention group received 30 min of rehabilitation therapy per day for a month using a 3D magnetic force-driven hand rehabilitation robot, whereas the control group received 30 min of conventional occupational therapy to restore upper-limb function. The patients underwent three behavioral assessments at three time points: before starting treatment (T0), after 1 month of treatment (T1), and at the follow-up 1-month after treatment completion (T2). The primary outcome measure was the Wolf Motor Function Test (WMFT), and secondary outcome measures included the Fugl-Meyer Assessment of the Upper Limb (FMA_U), Modified Barthel Index (MBI), and European Quality of Life Five Dimensions (EQ-5D) questionnaire. No participant safety issues were reported during the intervention. Analysis using repeated measures analysis of variance showed significant interaction effects between time and group for both the WMFT score (p = 0.012) and time (p = 0.010). In post hoc analysis, the WMFT scores and time improved significantly more in the patients who received robotic rehabilitation at T1 than in the controls (p = 0.018 and p = 0.012). At T2, we also consistently found improvements in both the WMFT scores and times for the intervention group that were superior to those in the control group (p = 0.024 and p = 0.018, respectively). Similar results were observed for FMA_U, MBI, and EQ-5D. Rehabilitation using the 3D hand-rehabilitation robot effectively restored hand function in the patients with subacute stroke, contributing to improvement in daily independence and quality of life.

Toward Practical Multivalent Ion Batteries with Quinone-Based Organic Cathodes.

Multivalent ion batteries have emerged as promising solutions to meet the future demands of energy storage applications, offering not only high energy density but also diverse socio-economic advantages. Among the various options for cathodes, quinone-based organic compounds have gained attention as suitable active materials for multivalent ion batteries due to their well-aligned ion channels, flexible structures, and competitive electrochemical performance. However, the charge carriers associated with anions that are often exploited in multivalent ion battery systems operate by way of a "non-rocking-chair" mechanism, which requires the use of an excess amount of electrolyte and results in a significant decrease in the energy density. In this review, by categorizing the various charge carriers exploited in previous studies on multivalent ion batteries, we summarize recently reported quinone-based organic cathodes for multivalent ion batteries and emphasize the importance of accurately identifying the charge carriers for calculating the energy density. We also propose potential future directions toward the practical realization of multivalent ion batteries, in link with their efficient energy storage applications.

Carrageenan as a Sacrificial Binder for 5 V LiNi0.5 Mn1.5 O4 Cathodes in Lithium-Ion Batteries.

5 V-class LiNi0.5 Mn1.5 O4 (LNMO) with its spinel symmetry is a promising cathode material for lithium-ion batteries. However, the high-voltage operation of LNMO renders it vulnerable to interfacial degradation involving electrolyte decomposition, which hinders long-term and high-rate cycling. Herein, this longstanding challenge presented by LNMO is overcome by incorporating a sacrificial binder, namely, λ-carrageenan (CRN), a sulfated polysaccharide. This binder not only uniformly covers the LNMO surface via hydrogen bonding and ion-dipole interaction but also offers an ionically conductive cathode-electrolyte interphase layer containing LiSOx F, a product of the electrochemical decomposition of the sulfate group. Taking advantage of these two auspicious properties, the CRN-based electrode exhibits cycling and rate performance far superior to that of its counterparts based on the conventional poly(vinylidene difluoride) and sodium alginate binders. This study introduces a new concept, namely "sacrificial" binder, for battery electrodes known to deliver superior electrochemical performance but be adversely affected by interfacial instability.

Loss of Neutralizing Activity of Tixagevimab/Cilgavimab (Evusheld™) Against Omicron BN.1, a Dominant Circulating Strain Following BA.5 During the Seventh Domestic Outbreak in Korea in Early 2023.

Tixagevimab/cilgavimab is a monoclonal antibody used to prevent coronavirus disease 2019 among immunocompromised hosts and maintained neutralizing activity against early omicron variants. Omicron BN.1 became a dominant circulating strain in Korea early 2023, but its susceptibility to tixagevimab/cilgavimab is unclear. We conducted plaque reduction neutralization test (PRNT) against BN.1 in a prospective cohort (14 patients and 30 specimens). BN.1 PRNT was conducted for one- and three-months after tixagevimab/cilgavimab administration and the average PRNT ND50 of each point was lower than the positive cut-off value of 20 (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825). In the paired analyses, tixagevimab/cilgavimab-administered sera could not actively neutralize BN.1 (PRNT ND50 11.5 ± 2.9, P = 0.001), compared with the reserved activity against BA.5 (ND50 310.5 ± 180.4). Unlike virus-like particle assay, tixagevimab/cilgavimab was not active against BN.1 in neutralizing assay, and would not be effective in the present predominance of BA.2.75 sublineages.

Rationally Designed Solution-Processible Conductive Carbon Additive Coating for Sulfide-based All-Solid-State Batteries.

Sulfide-based all-solid-state batteries (ASSBs) have emerged as promising candidates for next-generation energy storage systems owing to their superior safety and energy density. A conductive agent is necessarily added in the cathode composite of ASSBs to facilitate electron transport therein, but it causes the decomposition of the solid electrolyte and ultimately the shortening of lifetime. To resolve this dilemmatic situation, herein, we report a rationally designed solution-processible coating of zinc oxide (ZnO) onto vapor-grown carbon fiber as a conductive agent to reduce the contact between the carbon additive and the solid electrolyte and still maintain electron pathways to the active material. ASSBs with the carbon additive with an optimal coating of ZnO have markedly improved cycling performance and rate capability compared to those with the bare conductive agent, which can be attributed to hindering the decomposition of the solid electrolytes. The results highlight the usefulness of controlling the interparticle contacts in the composite cathodes in addressing the challenging interfacial degradation of sulfide-based ASSBs and improving their key electrochemical properties.

Radiologic changes of long term foot insole use in symptomatic pediatric flatfoot.

Clinically, flatfoot, known as pes planus, is quite prevalent. It is classified into 2 types: flexible and rigid, both of which may or may not have symptoms. If a flexible flatfoot is symptomatic, it must be treated to prevent subsequent complications. In principle, most physicians initially use conservative methods, such as foot insoles. This study aimed to demonstrate the effect of long term use of a foot insole using plain radiography as an objective measurement in children with symptomatic flexible flatfoot (SFFF) in large samples. This study analyzed the medical records of 292 children aged < 18 years who were diagnosed with SFFF. Of these, 200 children (62 boys and 138 girls, mean age: 6.49 ± 2.96 years) were selected and conservatively treated with foot insoles. They were periodically followed up within 3 to 4 months to modify the foot insole and perform radiologic evaluations, such as foot radiography. The calcaneal pitch angle (CPA) and talo first metatarsal angle were measured and compared individually using foot lateral radiographs, which were pictured in a bilateral barefoot state. The treatment was terminated by repeating the same procedure until the symptoms disappeared. A significant improvement (P < .001) was observed in the radiological indicators, both CPA and talo first metatarsal angle, regardless of age, after the application of soft foot insoles. However, the right foot CPA in the group with valgus deformity was an exception (P = .078). This study showed that in children diagnosed with SFFF under 18 years of age, wearing a periodically revised foot insole as conservative treatment could not only decrease the symptoms, but also improve the radiologic indices.

Utility of ultrasound as a promising diagnostic tool for stroke-related sarcopenia: A retrospective pilot study.

Stroke patients undergo extensive changes in muscle mass which lead to stroke-related sarcopenia. Stroke-related sarcopenia has a significant impact on the functional outcome of stroke survivors. So, it is important to measure muscle mass in stroke patients. This study aimed to examine the correlation between ultrasonographic quadriceps muscle thickness (QMT) and dual-energy X-ray absorptiometry (DXA) derived appendicular lean mass (ALM) in patients with acute hemiplegic stroke. Twenty five participants were included (13 men and 12 women) in this study, who were diagnosed with stroke within 1 month. For both paretic and non-paretic legs, QMT was measured by an ultrasound and ALM was obtained by performing DXA scan. We analyzed the difference and the correlation between ultrasonographic QMT and DXA-derived lean body mass of both paretic and non-paretic legs. Stroke patients were divided into 2 groups according to the paretic knee extensor power. Ultrasonographic QMT, DXA scan findings, and functional parameters were compared. There was a significant correlation between QMT and ALM index, and between QMT and site-specific lean mass (SSLM) of both the legs for both the sexes (P < .05). In multivariate linear regression model, we made adjustments for the confounding factors of age, sex, body mass index (BMI) and paretic knee extensor power. We observed a positive relationship between QMT and ALM index (P < .05), and between QMT and SSLM of both the legs (P < .05). The % QMT showed higher difference than % SSLM between paretic and non-paretic legs (10.25% vs 4.58%). The QMT measurements of ultrasound show a great relationship with DXA scan findings. Ultrasound better reflects the change of muscle mass between paretic and non-paretic legs than DXA scan at an acute phase of stroke. Ultrasound could be a useful tool to evaluate stroke-related sarcopenia.

SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death.

Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in patients with coronavirus disease 2019 (COVID-19). The most dominant immune cells in the brain are microglia. Yet, the relationship between neurological manifestations, neuroinflammation, and host immune response of microglia to SARS-CoV-2 has not been well characterized. Here, we reported that SARS-CoV-2 can directly infect human microglia, eliciting M1-like proinflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA sequencing (RNA-seq) analysis also revealed that endoplasmic reticulum (ER) stress and immune responses were induced in the early, and apoptotic processes in the late phases of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced proinflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor α (TNF-α), but not the anti-inflammatory cytokine IL-10. After this proinflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of proinflammatory microglial IL-6 and TNF-α and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in patients with COVID-19. IMPORTANCE Recent studies reported neurological and cognitive sequelae in patients with COVID-19 months after the viral infection with several symptoms, including ageusia, anosmia, asthenia, headache, and brain fog. Our conclusions raise awareness of COVID-19-related microglia-mediated neurological disorders to develop treatment strategies for the affected patients. We also indicated that HMC3 was a novel human cell line susceptible to SARS-CoV-2 infection that exhibited cytopathic effects, which could be further used to investigate cellular and molecular mechanisms of neurological manifestations of patients with COVID-19.

Computational design of a neutralizing antibody with picomolar binding affinity for all concerning SARS-CoV-2 variants.

Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.

Lithium-Conducting Self-Assembled Organic Nanotubes.

Supramolecular polymers are compelling platforms for the design of stimuli-responsive materials with emergent functions. Here, we report the assembly of an amphiphilic nanotube for Li-ion conduction that exhibits high ionic conductivity, mechanical integrity, electrochemical stability, and solution processability. Imine condensation of a pyridine-containing diamine with a triethylene glycol functionalized isophthalaldehyde yields pore-functionalized macrocycles. Atomic force microscopy, scanning electron microscopy, and in solvo X-ray diffraction reveal that macrocycle protonation during their mild synthesis drives assembly into high-aspect ratio (>103) nanotubes with three interior triethylene glycol groups. Electrochemical impedance spectroscopy demonstrates that lithiated nanotubes are efficient Li+ conductors, with an activation energy of 0.42 eV and a peak room temperature conductivity of 3.91 ± 0.38 × 10-5 S cm-1. 7Li NMR and Raman spectroscopy show that lithiation occurs exclusively within the nanotube interior and implicates the glycol groups in facilitating efficient Li+ transduction. Linear sweep voltammetry and galvanostatic lithium plating-stripping tests reveal that this nanotube-based electrolyte is stable over a wide potential range and supports long-term cyclability. These findings demonstrate how the coupling of synthetic design and supramolecular structural control can yield high-performance ionic transporters that are amenable to device-relevant fabrication, as well as the technological potential of chemically designed self-assembled nanotubes.

Receptor-binding domain of SARS-CoV-2 spike protein efficiently inhibits SARS-CoV-2 infection and attachment to mouse lung.

COVID-19, caused by a novel coronavirus, SARS-CoV-2, poses a serious global threat. It was first reported in 2019 in China and has now dramatically spread across the world. It is crucial to develop therapeutics to mitigate severe disease and viral spread. The receptor-binding domains (RBDs) in the spike protein of SARS-CoV and MERS-CoV have shown anti-viral activity in previous reports suggesting that this domain has high potential for development as therapeutics. To evaluate the potential antiviral activity of recombinant SARS-CoV-2 RBD proteins, we determined the RBD residues of SARS-CoV-2 using a homology search with RBD of SARS-CoV. For efficient expression and purification, the signal peptide of spike protein was identified and used to generate constructs expressing recombinant RBD proteins. Highly purified RBD protein fused with the Fc domain of human IgG showed potent anti-viral efficacy, which was better than that of a protein fused with a histidine tag. Intranasally pre-administrated RBD protein also inhibited the attachment of SARS-COV-2 to mouse lungs. These findings indicate that RBD protein could be used for the prevention and treatment of SARS-CoV-2 infection.

Computational Design of Potent D-Peptide Inhibitors of SARS-CoV-2.

Blocking the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) is an attractive therapeutic approach to prevent the virus from entering human cells. While antibodies and other modalities have been developed to this end, d-amino acid peptides offer unique advantages, including serum stability, low immunogenicity, and low cost of production. Here, we designed potent novel D-peptide inhibitors that mimic the ACE2 α1-binding helix by searching a mirror-image version of the PDB. The two best designs bound the RBD with affinities of 29 and 31 nM and blocked the infection of Vero cells by SARS-CoV-2 with IC50 values of 5.76 and 6.56 µM, respectively. Notably, both D-peptides neutralized with a similar potency the infection of two variants of concern: B.1.1.7 and B.1.351 in vitro. These potent D-peptide inhibitors are promising lead candidates for developing SARS-CoV-2 prophylactic or therapeutic treatments.

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses.

Zika virus (ZIKV), which is associated with severe diseases in humans, has spread rapidly and globally since its emergence. ZIKV and dengue virus (DENV) are closely related, and antibody-dependent enhancement (ADE) of infection between cocirculating ZIKV and DENV may exacerbate disease. Despite these serious threats, there are currently no approved antiviral drugs against ZIKV and DENV. The NS2B-NS3 viral protease is an attractive antiviral target because it plays a pivotal role in polyprotein cleavage, which is required for viral replication. Thus, we sought to identify novel inhibitors of the NS2B-NS3 protease. To that aim, we performed structure-based virtual screening using 467,000 structurally diverse chemical compounds. Then, a fluorescence-based protease inhibition assay was used to test whether the selected candidates inhibited ZIKV protease activity. Among the 123 candidate inhibitors selected from virtual screening, compound 1 significantly inhibited ZIKV NS2B-NS3 protease activity in vitro. In addition, compound 1 effectively inhibited ZIKV and DENV infection of human cells. Molecular docking analysis suggested that compound 1 binds to the NS2B-NS3 protease of ZIKV and DENV. Thus, compound 1 could be used as a new therapeutic option for the development of more potent antiviral drugs against both ZIKV and DENV, reducing the risks of ADE.

Comparison of Plaque Size, Thermal Stability, and Replication Rate among SARS-CoV-2 Variants of Concern.

SARS-CoV-2, like other RNA viruses, has a propensity for genetic evolution owing to the low fidelity of its viral polymerase. Several recent reports have described a series of novel SARS-CoV-2 variants. Some of these have been identified as variants of concern (VOCs), including alpha (B.1.1.7, Clade GRY), beta (B.1.351, Clade GH), gamma (P.1, Clade GR), and delta (B.1.617.2, Clade G). VOCs are likely to have some effect on transmissibility, antibody evasion, and changes in therapeutic or vaccine effectiveness. However, the physiological and virological understanding of these variants remains poor. We demonstrated that these four VOCs exhibited differences in plaque size, thermal stability at physiological temperature, and replication rates. The mean plaque size of beta was the largest, followed by those of gamma, delta, and alpha. Thermal stability, evaluated by measuring infectivity and half-life after prolonged incubation at physiological temperature, was correlated with plaque size in all variants except alpha. However, despite its relatively high thermal stability, alpha's small plaque size resulted in lower replication rates and fewer progeny viruses. Our findings may inform further virological studies of SARS-CoV-2 variant characteristics, VOCs, and variants of interest. These studies are important for the effective management of the COVID-19 pandemic.

Progress and Challenges in the Development of COVID-19 Vaccines and Current Understanding of SARS-CoV-2- Specific Immune Responses.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading globally, and the WHO has declared this outbreak a pandemic. Vaccines are an effective way to prevent the rapid spread of COVID-19. Furthermore, the immune response against SARS-CoV-2 infection needs to be understood for the development of an efficient and safe vaccine. Here, we review the current understanding of vaccine targets and the status of vaccine development for COVID-19. We also describe host immune responses to highly pathogenic human coronaviruses in terms of innate and adaptive immunities.

Collectin Kidney 1 Plays an Important Role in Innate Immunity against Streptococcus pneumoniae Infection.

Collectins are C-type lectins that are involved in innate immunity as pattern recognition molecules. Recently, collectin kidney 1 (CL-K1) has been discovered, and in vitro studies have shown that CL-K1 binds to microbes and activates the lectin complement pathway. However, in vivo functions of CL-K1 against microbes have not been elucidated. To investigate the biological functions of CL-K1, we generated CL-K1 knockout (CL-K1-/-) mice and then performed a Streptococcus pneumoniae infection analysis. First, we found that recombinant human CL-K1 bound to S. pneumoniae in a calcium-dependent manner, and induced complement activation. CL-K1-/- mice sera formed less C3 deposition on S. pneumoniae. Furthermore, immunofluorescence analysis in the wild-type (WT) mice demonstrated that CL-K1 and C3 were localized on S. pneumoniae in infected lungs. CL-K1-/- mice revealed decreased phagocytosis of S. pneumoniae. Consequently, less S. pneumoniae clearance was observed in their lungs. CL-K1-/- mice showed severe pulmonary inflammation and weight loss in comparison with WT mice. Finally, the decreased clearance and severe pulmonary inflammation caused by S. pneumoniae infection might cause higher CL-K1-/- mice lethality. Our results suggest that CL-K1 might play an important role in host protection against S. pneumoniae infection through the activation of the lectin complement pathway.

Three pentraxins C-reactive protein, serum amyloid p component and pentraxin 3 mediate complement activation using Collectin CL-P1.

BACKGROUND: Pentraxins (PTXs) are a superfamily of multifunctional conserved proteins involved in acute-phase responses. Recently, we have shown that collectin placenta 1 (CL-P1) and C-reactive protein (CRP) mediated complement activation and failed to form terminal complement complex (TCC) in normal serum conditions because of complement factor H inhibition. METHODS: We used CL-P1 expressing CHO/ldlA7 cells to study the interaction with PTXs. Soluble type CL-P1 was used in an ELISA assay for the binding, C3 and TCC deposition experiments. Furthermore, we used our previously established CL-P1 expressing HEK293 cells for the C3 fragment and TCC deposition assay. RESULTS: We demonstrated that CL-P1 also bound serum amyloid p component (SAP) and pentraxin 3 (PTX3) to activate the classical pathway and the alternative pathway using factor B. CRP and PTX3 further amplified complement deposition by properdin. We found that CRP and PTX3 recruit CFH, whereas SAP recruits C4 binding protein on CL-P1 expressing cell surfaces to prevent the formation of TCC in normal serum conditions. In addition, depletion of CFH, C4BP and complement factor I (CFI) failed to prevent TCC formation both in ELISA and cell experiments. Furthermore, soluble complement receptor 1, an inhibitor of all complement pathways prevents PTX induced TCC formation. CONCLUSION: Our current study hypothesizes that the interaction of pentraxins with CL-P1 is involved in complement activation. GENERAL SIGNIFICANCE: CL-P1 might generally inhibit PTX induced complement activation and host damage to protect self-tissues.