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The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a virus called “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).” In the majority of patients, infection with COVID-19 may be asymptomatic or may cause only mild symptoms. However, in some patients, there can also be immunological problems, such as macrophage activation syndrome (CSS) that results in cytokine storm syndrome (CSS) and acute respiratory distress syndrome (ARDS). Comprehension of host-microbe communications is the critical aspect in the advancement of new therapeutics against infectious illnesses. Endogenous animal lectins, a class of proteins, may perceive non-self glycans found on microorganisms. Serum mannose-binding lectin (sMBL), as a part of the innate immune framework, recognizes a wide range of microbial microorganisms and activates complement cascade via an antibody-independent pathway. Although the molecular basis for the intensity of SARS-CoV-2 infection is not generally understood, scientific literature indicates that COVID-19 is correlated with unregulated activation of the complement in terms of disease severity. Disseminated intravascular coagulation (DIC), inflammation, and immune paralysis contribute to unregulated complement activation. Pre-existing genetic defects in MBL and their association with complement play a major role in immune response dysregulation caused by SARS-CoV-2. In order to generate anti-complement-based therapies in Covid-19, an understanding of sMBL in immune response to SARS-CoV-2 and complement is therefore essential. This review highlights the role of endogenous sMBL and complement activation during SARS-CoV-2 infection and their therapeutic management by various agents, mainly plant lectins, since antiviral mannose-binding plant lectins (pMBLs) offer potential applications in the prevention and control of viral infections.

Abstract Mannose-capped lipoarabinomannan (ManLAM), present in all members of the Mycobacterium tuberculosis complex and in other pathogenic Mycobacterium spp, is a high molecular mass amphipathic lipoglycan with a defined critical role in mycobacterial survival during infection. In particular, ManLAM is well-characterized for its importance in providing M. tuberculosis a safe portal of entry to phagocytes, regulating the intracellular trafficking network, as well as immune responses of infected host cells. These ManLAM immunological characteristics are thought to be linked to the subtle but unique and well-defined structural characteristics of this molecule, including but not limited to the degree of acylation, the length of the D-mannan and D-arabinan cores, the length of the mannose caps, as well as the presence of other acidic constituents such as succinates, lactates and/or malates, and also the presence of 5-methylthioxylosyl. The impact of all these structural features on ManLAM spatial conformation and biological functions during M. tuberculosis infection is still uncertain. In this review, we dissect the relationship between ManLAM structure and biological function addressing how this relationship determines M. tuberculosis interactions with host cells, and how it aids this exceptional pathogen during the course of infection. Mycobacterium tuberculosis mannose-capped lipoarabinomannan: relationship between structure and biological function.

The complement system is a first-line innate host immune defence against invading pathogens. It is activated via three pathways, termed Classical, Lectin and Alternative, which are mediated by antibodies, carbohydrate arrays or microbial liposaccharides, respectively. The three complement pathways converge in the formation of C3-convertase followed by the assembly of a lethal pore-like structure, the membrane attack complex (MAC), on the pathogen surface. We found that the infectious stage of the helminth parasite Fasciola hepatica , the newly excysted juvenile (NEJ), is resistant to the damaging effects of complement. Despite being coated with mannosylated proteins, the main initiator of the Lectin pathway, the mannose binding lectin (MBL), does not bind to the surface of live NEJ. In addition, we found that recombinantly expressed serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively prevent activation of the complement via the Lectin pathway. Our experiments demonstrate that rFhSrp1 and rFhSrp2 inhibit native and recombinant MBL-associated serine proteases (MASPs), impairing the primary step that mediates C3b and C4b deposition on the NEJ surface. Indeed, immunofluorescence studies show that MBL, C3b, C4b or MAC are not deposited on the surface of NEJ incubated in normal human serum. Taken together, our findings uncover new means by which a helminth parasite prevents the activation of the Lectin complement pathway to become refractory to killing via this host response, in spite of presenting an assortment of glycans on their surface.

It is now well established that tumours undergo changes in cellular metabolism 1 . As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake 2 , we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose 3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types. Mannose reduces the growth of tumour cells by impairing the metabolism of glucose, and enhances cell death when used in combination with conventional chemotherapy.

Purpose To test whether d -mannose powder is effective for recurrent urinary tract infection (UTI) prevention. Materials and methods After initial antibiotic treatment of acute cystitis, 308 women with history of recurrent UTI and no other significant comorbidities were randomly allocated to three groups. The first group ( n  = 103) received prophylaxis with 2 g of d -mannose powder in 200 ml of water daily for 6 months, the second ( n  = 103) received 50 mg Nitrofurantoin daily, and the third ( n  = 102) did not receive prophylaxis. Results Overall 98 patients (31.8 %) had recurrent UTI: 15 (14.6) in the d -mannose group, 21 (20.4) in Nitrofurantoin group, and 62 (60.8) in no prophylaxis group, with the rate significantly higher in no prophylaxis group compared to active groups ( P  < 0.001). Patients in d -mannose group and Nitrofurantoin group had a significantly lower risk of recurrent UTI episode during prophylactic therapy compared to patients in no prophylaxis group (RR 0.239 and 0.335, P  < 0.0001). In active groups, 17.9 % of patients reported side effects but they were mild and did not require stopping the prophylaxis. Patients in d -mannose group had a significantly lower risk of side effects compared to patients in Nitrofurantoin group (RR 0.276, P  < 0.0001), but the clinical importance of this finding is low because Nitrofurantoin was well tolerated. Conclusions In our study, d -mannose powder had significantly reduced the risk of recurrent UTI which was no different than in Nitrofurantoin group. More studies will be needed to validate the results of this study, but initial findings show that d -mannose may be useful for UTI prevention.

The lectin pathway of complement aids in removing apoptotic cells and maintenance of tissue homeostasis. However, its role in SLE pathogenesis remains unknown. This study aimed to assess the association of ficolins, mannose-binding lectin (MBL), and other pathogen recognition molecules (PRMs) of the lectin pathway and their corresponding autoantibodies with various clinical manifestations and disease activity in SLE patients from Western India. In this cross-sectional study, 282 clinically diagnosed SLE patients were included. Serum levels of ficolins, antigenic MBL, MBL-associated serine proteases (MASPs), MBL-associated protein 44 (MAp44), Collectin liver-1 (CL-L1), and their corresponding autoantibodies were quantified using ELISA. Group differences were analyzed using Mann-Whitney U tests, while associations/relationships were evaluated using chi-square tests and Spearman’s correlations. Serum levels of ficolin-2 ( p < 0.001 ), MASP-3 ( p = 0.030 ), and MAp44 ( p < 0.001 ) were significantly elevated, while antigenic MBL ( p < 0.001 ) and MASP-1 ( p < 0.001 ) were significantly reduced in SLE patients compared to healthy controls (HCs). Renal involvement was associated with elevated ficolin-1 ( p = 0.009 ), while hematological manifestations were linked to reduced MASP-1 ( p = 0.018 ), MASP-3 ( p = 0.002 ), and MAp44 ( p = 0.002 ) levels. Mucocutaneous manifestations were associated with elevated MAp44 ( p < 0.001 ) and anti-ficolin-1 ( p = 0.038 ) autoantibodies. Anti-ficolin-1 ( p = 0.001 ), anti-ficolin-2 ( p = 0.001 ), and anti-ficolin-3 ( p < 0.001 ) autoantibodies were significantly elevated in SLE patients compared to HCs. Anti-ficolin-2 autoantibodies were negatively correlated with ficolin-2 ( r =-0.153, p  = 0.015). Anti-MBL antibodies were correlated with SLEDAI ( r  = 0.169, p  = 0.007) and anti-dsDNA antibodies ( r  = 0.178, p  = 0.005). These findings indicate altered levels of lectin pathway-associated PRMs and their corresponding autoantibodies in SLE. Their association with clinical manifestations, disease activity, and complement-related parameters, suggest their potential as novel biomarkers in SLE.

The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated gene knockout lupus-prone MRL/ mice ( MRL/ mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from MRL/ mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the MRL/ mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and MRL/ mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/ mice, most likely activation of the LP and/or AP.