Spectroscopic Manifestations Of (Anti)Aromaticity In Oxidized And Reduced Porphyrin And Norcorrole.

Aromaticity and antiaromaticity are foundational principes in organic chemistry, regularly invoked to explain stability, structure, and magnetic and electronic properties. There are ongoing challenges in assigning molecules as aromatic or antiaromatic using optical spectroscopy. Here we report spectroelectrochemical and computational analyses of porphyrin (18π neutral, aromatic) and norcorrole (16π neutral, antiaromatic), and their oxidized (16π porphyrin dication) and reduced (norcorrole 18π dianion) forms. Our results show that while the visible spectra are characteristic of (anti)aromaticity consistent with Hückel's rules, the IR spectra are much less informative, owing to the relative rigidity of norcorrole. The results have implications for the assignment of (anti)aromaticity in both ground-state and time-resolved excited-state spectra.

Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece.

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.

Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection.

Most patients with COVID-19 in the intensive care unit develop an acute respiratory distress syndrome characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability. Activation of the complement system is a hallmark of moderate and severe COVID-19, with abundant deposition of complement proteins in inflamed tissue and on the endothelium during COVID-19. Using a transgenic mouse model of SARS-CoV-2 infection, we assessed the therapeutic utility of an inhibitory antibody (HG4) targeting MASP-2, a key enzyme in the lectin pathway. Treatment of infected mice with HG4 reduced the disease severity score and improved survival vs mice that received an isotype control antibody. Administration of HG4 significantly reduced the lung injury score, including alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage. The ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology is reflected by a significant reduction in the proinflammatory activation of brain microglia in HG4-treated mice.

Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of complement could reduce the pathology and improve the outcomes in a murine model of LPS-induced lung injury that closely mimics ARDS in human. In vitro, LPS binds to murine and human collectin 11, human MBL and murine MBL-A, but not to C1q, the recognition subcomponent of the classical pathway. This binding initiates deposition of the complement activation products C3b, C4b and C5b-9 on LPS via the lectin pathway. HG-4, a monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway, inhibited lectin pathway functional activity in vitro, with an IC50 of circa 10nM. Administration of HG4 (5mg/kg) in mice led to almost complete inhibition of the lectin pathway activation for 48hrs, and 50% inhibition at 60hrs post administration. Inhibition of the lectin pathway in mice prior to LPS-induced lung injury improved all pathological markers tested. HG4 reduces the protein concentration in bronchoalveolar lavage fluid (p<0.0001) and levels of myeloid peroxide (p<0.0001), LDH (p<0.0001), TNFα and IL6 (both p<0.0001). Lung injury was significantly reduced (p<0.001) and the survival time of the mice increased (p<0.01). From the previous findings we concluded that inhibition of the lectin pathway has the potential to prevent ARDS pathology.

Clear aligner therapy in the mixed dentition: Indications and practitioner perspectives.

INTRODUCTION: This study evaluated current trends and perspectives among orthodontists regarding clear aligner therapy in the mixed dentition (CAMD), including insights into perceived indications, compliance, oral hygiene, and other factors. METHODS: An original, 22-item survey was mailed to a randomized, nationally representative sample of practicing orthodontists (n = 800) and a specific, randomized subsample of high-aligner-prescribing orthodontists (n = 200). Questions assessed respondents' demographic information, experience with clear aligner therapy, and perceived advantages and disadvantages of CAMD compared with fixed appliances (FAs). Responses were compared using McNemar's chi-square and paired t tests to assess CAMD vs FAs. RESULTS: One thousand orthodontists were surveyed, and 181 (18.1%) responded over 12 weeks. CAMD use was less common than mixed dentition FAs, but most respondents predicted an increase in their future CAMD use (57.9%). Among respondents using CAMD, the number of patients with mixed dentition treated with clear aligners was significantly lower than the number of total patients with clear aligners (23.7% vs 43.8%; P <0.0001). Fewer respondents considered skeletal expansion, growth modification, sagittal correction, and habit cessation feasible indications for CAMD compared with FAs (P <0.0001). Perceived compliance was similar for CAMD and FAs (P = 0.5841), but perceived oral hygiene was significantly better with CAMD (P <0.0001). CONCLUSIONS: CAMD is an increasingly common treatment modality for children. Most surveyed orthodontists reported limited indications for CAMD compared with FAs but perceived noticeable benefits for oral hygiene with CAMD.

Camera-based radiotherapy dosimetry using dual-material 3D printed scintillator arrays.

PURPOSE AND OBJECTIVE: To describe a methodology for the dual-material fused deposition modeling (FDM) 3D printing of plastic scintillator arrays, to characterize their light output under irradiation using an sCMOS camera, and to establish a methodology for the dosimetric calibration of planar array geometries. MATERIALS AND METHODS: We have published an investigation into the fabrication and characterization of single element FDM printed scintillators intending to produce customizable dosimeters for radiation therapy applications. 1 This work builds on previous investigations by extending the concept to the production of a high-resolution (scintillating element size 3 × 3 × 3 mm3 ) planar scintillator array. The array was fabricated using a BCN3D Epsilon W27 3D printer and composed of polylactic acid (PLA) filament and BCF-10 plastic scintillator. The array's response was initially characterized using a 20 × 20 cm2 6 MV photon field with a source-to-surface (SSD) distance of 100 cm and the beam incident on the top of the array. The light signals emitted under irradiation were imaged using 200 ms exposures from a sCMOS camera positioned at the foot of the treatment couch (210 cm from the array). The collected images were then processed using a purpose-built software to correct known optical artefacts and determine the light output for each scintillating element. The light output was then corrected for element sensitivity and calibrated to dose using Monte Carlo simulations of the array and irradiation geometry based on the array's digital 3D print model. To assess the accuracy of the array calibration both a 3D beam and a clinical VMAT plan were delivered. Dose measurements using the calibrated array were then compared to EBT3 GAFChromic film and OSLD measurements, as well as Monte Carlo simulations and TPS calculations. RESULTS: Our results establish the feasibility of dual-material 3D printing for the fabrication of custom plastic scintillator arrays. Assessment of the 3D printed scintillators response across each row of the array demonstrated a nonuniform response with an average percentage deviation from the mean of 2.1% ± 2.8%. This remains consistent with our previous work on individual 3D printed scintillators which showed an average difference of 2.3% and a maximum of 4.0% between identically printed scintillators.1 Array dose measurements performed following calibration indicate difficulty in differentiating the scintillator response from ambient background light contamination at low doses (<20-25 cGy) and dose rates (≤100 MU/min). However, when analysis was restricted to exclude dose values less than 10% of the Monte Carlo simulated max dose the average absolute percentage dose difference between Monte Carlo simulation and array measurement was 5.3% ± 4.8% for the fixed beam delivery and 5.4% ± 5.2% for the VMAT delivery CONCLUSION: In this study, we developed and characterized a 3D printed array of plastic scintillators and demonstrated a methodology for the dosimetric calibration of a simple array geometry.

Unbuilding the city: Deconstruction and the circular economy in Vancouver.

Globally, the construction, renovation, and demolition sectors are increasingly responsible for growing resource demand and structural waste, even given progress in energy efficient technologies, 'green' building design, and local planning regulations. In response, the Circular Economy has become a popular agenda in the construction, renovation, and demolition sector as it offers a new model that not only maximizes materials reuse and recovery but also reframes urban systems and the built environment in a closed-loop (cradle-to-cradle) paradigm. In particular, popular visions of the Circular Economy promote, among other actions, 'optimizing' the end-of-the-life of buildings and their materials. Deconstruction (i.e. piece-by-piece demolition) is one key optimization strategy that has received increasing, yet limited, attention by researchers. This paper traces the development of an incipient deconstruction sector in Vancouver, focusing on the possibilities and challenges of deconstruction and material recovery practices as viable strategies for a transformative Circular Economy. I investigate two related aspects: first, the emerging policy landscape surrounding green demolition, and second, the development of 'unbuilding' practices and more formal 'Deconstruction Hubs'. Overall, the paper finds that while these developments represent fundamental steps towards a more sustainable built environment, there remain a number of significant social, political and economic limitations that must be confronted if we are to meet the growing demands for more radical sustainability and 'circularity' not only in Canadian construction, renovation, and demolition sectors, but across Canadian cities and beyond.

Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19.

A high incidence of secondary Klebsiella pneumoniae and Staphylococcus aureus infection were observed in patients with severe COVID-19. The cause of this predisposition to infection is unclear. Our data demonstrate consumption of complement in acute COVID-19 patients reflected by low levels of C3, C4, and loss of haemolytic activity. Given that the elimination of Gram-negative bacteria depends in part on complement-mediated lysis, we hypothesised that secondary hypocomplementaemia is rendering the antibody-dependent classical pathway activation inactive and compromises serum bactericidal activity (SBA). 217 patients with severe COVID-19 were studied. 142 patients suffered secondary bacterial infections. Klebsiella species were the most common Gram-negative organism, found in 58 patients, while S. aureus was the dominant Gram-positive organism found in 22 patients. Hypocomplementaemia was observed in patients with acute severe COVID-19 but not in convalescent survivors three months after discharge. Sera from patients with acute COVID-19 were unable to opsonise either K. pneumoniae or S. aureus and had impaired complement-mediated killing of Klebsiella. We conclude that hyperactivation of complement during acute COVID-19 leads to secondary hypocomplementaemia and predisposes to opportunistic infections.

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins.

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.

Characterization of novel 3D printed plastic scintillation dosimeters.

We propose a new methodology for the fabrication and evaluation of scintillating detector elements using a consumer grade fusion deposition modeling (FDM) 3D printer. In this study we performed a comprehensive investigation into both the effects of the 3D printing process on the scintillation light output of 3D printed plastic scintillation dosimeters (PSDs) and their associated dosimetric properties. Fabrication properties including print variability, layer thickness, anisotropy and extrusion temperature were assessed for 1 cm3 printed samples. We then examined the stability, dose linearity, dose rate proportionality, energy dependence and reproducibility of the 3D printed PSDs compared to benchmarks set by commercially available products. Experimental results indicate that the shape of the emission spectrum of the 3D printed PSDs do not show significant spectral differences when compared to the emission spectrum of the commercial sample. However, the magnitude of scintillation light output was found to be strongly dependent on the parameters of the fabrication process. Dosimetric testing indicates that the 3D printed PSDs share many desirable properties with current commercially available PSDs such as dose linearity, dose rate independence, energy independence in the MV range, repeatability, and stability. These results demonstrate that not only does 3D printing offer a new avenue for the production and manufacturing of PSDs but also allows for further investigation into the application of 3D printing in dosimetry. Such investigations could include options for 3D printed, patient-specific scintillating dosimeters that may be used as standalone dosimeters or incorporated into existing 3D printed patient devices (e.g. bolus or immobilization) used during the delivery of radiation therapy.

The Pneumococcal Surface Proteins PspA and PspC Sequester Host C4-Binding Protein To Inactivate Complement C4b on the Bacterial Surface.

Complement is a critical component of antimicrobial immunity. Various complement regulatory proteins prevent host cells from being attacked. Many pathogens have acquired the ability to sequester complement regulators from host plasma to evade complement attack. We describe here how Streptococcus pneumoniae adopts a strategy to prevent the formation of the C3 convertase C4bC2a by the rapid conversion of surface bound C4b and iC4b into C4dg, which remains bound to the bacterial surface but no longer forms a convertase complex. Noncapsular virulence factors on the pneumococcus are thought to facilitate this process by sequestering C4b-binding protein (C4BP) from host plasma. When S. pneumoniae D39 was opsonized with human serum, the larger C4 activation products C4b and iC4b were undetectable, but the bacteria were liberally decorated with C4dg and C4BP. With targeted deletions of either PspA or PspC, C4BP deposition was markedly reduced, and there was a corresponding reduction in C4dg and an increase in the deposition of C4b and iC4b. The effect was greatest when PspA and PspC were both knocked out. Infection experiments in mice indicated that the deletion of PspA and/or PspC resulted in the loss of bacterial pathogenicity. Recombinant PspA and PspC both bound serum C4BP, and both led to increased C4b and reduced C4dg deposition on S. pneumoniae D39. We conclude that PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b.

Endoscopically Assisted Modified Caldwell-Luc Approach to Enucleation of Dentigerous Cyst With Ectopic Tooth From the Maxillary Sinus.

Dentigerous cysts in the craniomaxillofacial complex are a benign pathology commonly associated with ectopically placed teeth. Owing to slow and asymptomatic growth, they often attain considerable size before diagnosis that may compromise adjacent anatomical structures. Various techniques for removal of dentigerous cysts from the maxillary sinus have been described. This case report demonstrates a hybrid endoscopically assisted modification of the Caldwell-Luc approach to provide the technical advantages of both techniques.

In vitro characterization of gamma oscillations in the hippocampal formation of the domestic chick.

Avian and mammalian brains have evolved independently from each other for about 300 million years. During that time, the hippocampal formation (HF) has diverged in morphology and cytoarchitecture, but seems to have conserved much of its function. It is therefore an open question how seemingly different neural organizations can generate the same function. A prominent feature of the mammalian hippocampus is that it generates different neural oscillations, including the gamma rhythm, which plays an important role in memory processing. In this study, we investigate whether the avian hippocampus also generates gamma oscillations, and whether similar pharmacological mechanisms are involved in this function. We investigated the existence of gamma oscillations in avian HF using in vitro electrophysiology in P0-P12 domestic chick (Gallus gallus domesticus) HF brain slices. Persistent gamma frequency oscillations were induced by the bath application of the cholinergic agonist carbachol, but not by kainate, a glutamate receptor agonist. Similar to other species, carbachol-evoked gamma oscillations were sensitive to GABAA , AMPA/kainate and muscarinic (M1) receptor antagonism. Therefore, similar to mammalian species, muscarinic receptor-activated avian HF gamma oscillations may arise via a pyramidal-interneuron gamma (PING)-based mechanism. Gamma oscillations are most prominent in the ventromedial area of the hippocampal slices, and gamma power is reduced more laterally and dorsally in the HF. We conclude that similar micro-circuitry may exist in the avian and mammalian hippocampal formation, and this is likely to relate to the shared function of the two structures.

Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.

All 3 activation pathways of complement-the classic pathway (CP), the alternative pathway, and the lectin pathway (LP)- converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation of C3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a, which is formed by both the CP and the LP. Whereas in the absence of C4, CP can no longer activate C3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding lectin-associated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.-Yaseen, S., Demopulos, G., Dudler, T., Yabuki, M., Wood, C. L., Cummings, W. J., Tjoelker, L. W., Fujita, T., Sacks, S., Garred, P., Andrew, P., Sim, R. B., Lachmann, P. J., Wallis, R., Lynch, N., Schwaeble, W. J. Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.

Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree.

The nucleolus serves as a principal site of ribosome biogenesis but is also implicated in various non-ribosomal functions, including negative regulation of the pro-apoptotic transcription factor p53. Although disruption of the nucleolus may trigger the p53-dependent neuronal death, neurotoxic consequences of a selective impairment of ribosome production are unclear. Here, we report that in rat forebrain neuronal maturation is associated with a remarkable expansion of ribosomes despite postnatal down-regulation of ribosomal biogenesis. In cultured rat hippocampal neurons, inhibition of the latter process by knockdowns of ribosomal proteins S6, S14, or L4 reduced ribosome content without disrupting nucleolar integrity, cell survival, and signaling responses to the neurotrophin brain-derived neurotrophic factor. Moreover, reduced general protein synthesis and/or formation of RNA stress granules suggested diminished ribosome recruitment to at least some mRNAs. Such a translational insufficiency was accompanied by impairment of brain-derived neurotrophic factor-mediated dendritic growth. Finally, RNA stress granules and smaller dendritic trees were also observed when ribosomal proteins were depleted from neurons with established dendrites. Thus, a robust ribosomal apparatus is required to carry out protein synthesis that supports dendritic growth and maintenance. Consequently, deficits of ribosomal biogenesis may disturb neurodevelopment by reducing neuronal connectivity. Finally, as stress granule formation and dendritic loss occur early in neurodegenerative diseases, disrupted homeostasis of ribosomes may initiate and/or amplify neurodegeneration-associated disconnection of neuronal circuitries.

Deficiency in mannose-binding lectin-associated serine protease-2 does not increase susceptibility to Trypanosoma cruzi infection.

Trypanosoma cruzi is the causative agent of Chagas' disease, a chronic illness affecting 10 million people around the world. The complement system plays an important role in fighting microbial infections. The recognition molecules of the lectin pathway of complement activation, mannose-binding lectin (MBL), ficolins, and CL-11, bind to specific carbohydrates on pathogens, triggering complement activation through MBL-associated serine protease-2 (MASP-2). Previous in vitro work showed that human MBL and ficolins contribute to T. cruzi lysis. However, MBL-deficient mice are only moderately compromised in their defense against the parasite, as they may still activate the lectin pathway through ficolins and CL-11. Here, we assessed MASP-2-deficient mice, the only presently available mouse line with total lectin pathway deficiency, for a phenotype in T. cruzi infection. Total absence of lectin pathway functional activity did not confer higher susceptibility to T. cruzi infection, suggesting that it plays a minor role in the immune response against this parasite.

Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4.

Mannan-binding lectin-associated serine protease 2 (MASP-2) has been described as the essential enzyme for the lectin pathway (LP) of complement activation. Since there is strong published evidence indicating that complement activation via the LP critically contributes to ischemia reperfusion (IR) injury, we assessed the effect of MASP-2 deficiency in an isogenic mouse model of renal transplantation. The experimental transplantation model used included nephrectomy of the remaining native kidney at d 5 post-transplantation. While wild-type (WT) kidneys grafted into WT recipients (n=7) developed acute renal failure (control group), WT grafts transplanted into MASP-2-deficient recipients (n=7) showed significantly better kidney function, less C3 deposition, and less IR injury. In the absence of donor or recipient complement C4 (n=7), the WT to WT phenotype was preserved, indicating that the MASP-2-mediated damage was independent of C4 activation. This C4-bypass MASP-2 activity was confirmed in mice deficient for both MASP-2 and C4 (n=7), where the protection from postoperative acute renal failure was no greater than in mice with MASP-2 deficiency alone. Our study highlights the role of LP activation in renal IR injury and indicates that injury occurs through MASP-2-dependent activation events independent of C4.

Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection.

Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (Pn), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of Pn (100 µg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the Pn treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of Pn treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of Pn at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the saline-treated control group (P < 0.0001). Our findings show a significant therapeutic benefit of Pn administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.

The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection.

The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.