Canakinumab in the treatment of systemic juvenile idiopathic arthritis: a retrospective single center study in China.

Objective: Systemic juvenile idiopathic arthritis (sJIA) is characterized by excessive production of proinflammatory cytokines. As an anti-IL-1 agent, canakinumab has been approved in the USA and Europe for the treatment of sJIA patients aged ≥2 years. However, the use of canakinumab has never been reported in China. In this study, we aimed to assess the efficacy and safety of canakinumab in Chinese patients with sJIA. Methods: A total of 11 patients with sJIA who were treated with canakinumab were included in this study. Clinical data were collected retrospectively from medical records. Efficacy was evaluated by the systemic juvenile arthritis disease activity score (sJADAS). The follow-up was performed at canakinumab initiation, at months 1, 3, 6, 9 and 12, or at the last follow-up. Results: Of the 11 patients enrolled, 91.0% (10/11) had previously received treatment with tocilizumab. The mean duration of canakinumab was 9 (3-18) months. 45.5% (5/11) of patients showed complete response, 45.5% (5/11) showed partial response, and 9.0% (1/11) showed no response. 18.2% (2/11) experienced disease flare during the treatment with canakinumab. 81.8% (9/11) of patients successfully reduced the dose of corticosteroids, with six discontinuing corticosteroids. 45.6% (5/11) of patients experienced infection. No serious adverse events occurred during the treatment with canakinumab. Conclusions: Canakinumab may be effective and tolerable for Chinese sJIA patients, helping to reduce the dosage of corticosteroids. However, additional researches on large samples are required to evaluate its efficacy and safety.

Data of the subatomic resolution structure of glucose isomerase complexed with xylitol inhibitor.

Glucose isomerase (GI) is a crucial enzyme in industrial processes, including the production of high-fructose corn syrup, biofuels, and other renewable chemicals. Understanding the mechanisms of GI inhibition by GI inhibitors can offer valuable insights into enhancing production efficiency. We previously reported the subatomic resolution structure of Streptomyces rubiginosus GI (SruGI) complexed with a xylitol inhibitor, determined at 0.99 Å resolution, was reported. Structural analysis showed that the xylitol inhibitor is partially bound to the M1 binding site at the SruGI active site, enabling it to distinguish the xylitol-bound and -free state of SruGI. This structural information demonstrates that xylitol binding to the M1 site causes a conformational change in the metal binding site and the substrate binding channel of SruGI. Herein, detailed information on data collection and processing procedures of the subatomic resolution structure of the SruGI complexed with xylitol was reported.

Applications of the Yariv reagent in polysaccharide analysis and plant physiology from theory to practice.

Arabinogalactan (AG), a biologically active substance found abundantly in plants, is of significant interest in plant physiology due to its unique physicochemical properties. Yariv reagent, widely utilized in AG-II related applications, forms insoluble precipitates when bound to AG-II. This paper provides a comprehensive overview of the synthesis methods, physicochemical properties, and various dissociation methods of the Yariv reagent to enhance its utility in AG-II studies. Furthermore, the review explores the binding mechanisms and applications of the Yariv reagent, highlighting the advancements in studying the Yariv-AG complex in plant physiology. The aim of this review is to inspire new research ideas and foster novel applications of the Yariv reagent from synthesis to implementation.

Structural characterization of an inulin neoseries-type fructan from Ophiopogonis Radix and the therapeutic effect on liver fibrosis in vivo.

Ophiopogonis Radix is a well-known Traditional Chinese Medicine and functional food that is rich in polysaccharides and has fructan as a characteristic component. In this study, an inulin neoseries-type fructan designated as OJP-W2 was obtained and characterized from Ophiopogonis Radix, and its potential therapeutic effect on liver fibrosis in vivo were investigated. Structural studies revealed that OJP-W2 had a molecular weight of 5.76 kDa and was composed of glucose and fructose with a molar ratio of 1.00:30.87. Further analysis revealed OJP-W2 has a predominantly lineal (1-2)-linked ß-D-fructosyl units linked to the glucose moiety of the sucrose molecule with (2-6)-linked ß-D-fructosyl side chains. Pharmacological studies revealed that OJP-W2 exerted a marked hepatoprotective effect against liver fibrosis, the mechanism of action was involved in regulating collagen deposition (α-SMA, COL1A1 and liver Hyp contents) and TGF-ß/Smads signaling pathway, alleviating liver inflammation (IL-1ß, IL-6, CCL5 and F4/80) and MAPK signaling pathway, and inhibiting hepatic apoptosis (Bax, Bcl-2, ATF4 and Caspase 3). These data provide evidence for expanding Ophiopogonis Radix-acquired fructan types and advancing our understanding of the specific role of inulin neoseries-type fructan in liver fibrosis therapy.

Structural and Functional Analyses of the Flavoprotein Disulfide Reductase FN0820 of Fusobacterium nucleatum.

Escherichia coli RclA and Staphylococcus aureus MerA are part of the Group I flavoprotein disulfide reductase (FDR) family and have been implicated in the contribution to bacterial pathogenesis by defending against the host immune response. Fusobacterium nucleatum is a pathogenic, anaerobic Gram-negative bacterial species commonly found in the human oral cavity and gastrointestinal tract. In this study, we discovered that the F. nucleatum protein FN0820, belonging to the Group I FDR family, exhibited a higher activity of a Cu2+-dependent NADH oxidase than E. coli RclA. Moreover, FN0820 decreased the dissolved oxygen level in the solution with higher NADH oxidase activity. We found that L-tryptophan and its analog 5-hydroxytryptophan inhibit the FN0820 activities of NADH oxidase and the concomitant reduction of oxygen. Our results have implications for developing new treatment strategies against pathogens that defend the host immune response with Group I FDRs.

Structural insight into the role of thiolase from Fusobacterium nucleatum.

Fusobacterium nucleatum (F. nucleatum) is an anaerobic gram-negative bacterium that was previously thought to be related to the progression of colorectal cancer. In F. nucleatum, thiolase participates in fatty acid metabolism, and it can catalyse the transfer of an acetyl group from acetyl-CoA to another molecule, typically a fatty acid or another molecule in the synthesis of lipids. To gain deeper insight into the molecular mechanism governing the function of thiolase in F. nucleatum (Fn0495), we herein report the structure of Fn0495. The monomer of Fn0495 consists of three subdomains, namely, the N-terminal domain (residues 1-117 and 252-270), the C-terminal domain (residues 273-393), and the loop domain (residues 118-251). Fn0495 shows a unique difference in the charge and structure of the substrate binding pocket compared with homologous proteins. This research found three conserved residues (Cys88, His357, and Cys387) in Fn0495 arranged near a potential substrate binding pocket. In this study, the conformational changes between the covering loop, catalytic cysteine loop, regulatory determinant region, and homologous protein were compared. These results will enhance our understanding of the molecular characteristics and roles of the thiolase family.

Xylitol binding to the M1 site of glucose isomerase induces a conformational change in the substrate binding channel.

Glucose isomerase (GI) is extensively used in the food industry for production of high-fructose corn syrup and for the production of biofuels and other renewable chemicals. Structure-based studies on GI inhibitors are important for improving its efficiency in industrial applications. Here, we report the subatomic crystal structure of Streptomyces rubiginosus GI (SruGI) complexed with its inhibitor, xylitol, at 0.99 Å resolution. Electron density map and temperature factor analysis showed partial binding of xylitol to the M1 metal binding site of SruGI, providing two different conformations of the metal binding site and the substrate binding channel. The xylitol molecule induced a conformational change in the M2 metal ion-interacting Asp255 residue, which subsequently led to a conformational change in the side chain of Asp181 residue. This led to the positional shift of Pro25 by 1.71 Å and side chain rotation of Phe26 by 21°, where located on the neighboring protomer in tetrameric SruGI. The conformation change of these two residues affect the size of the substrate-binding channel of GI. Therefore, xylitol binding to M1 site of SruGI induces not only a conformational changes of the metal-binding site, but also conformational change of substrate-binding channel of the tetrameric SruGI. These results expand our knowledge about the mechanism underlying the inhibitory effect of xylitol on GI.

Genomic and metabolomic insights into the antimicrobial compounds and plant growth-promoting potential of Bacillus velezensis Q-426.

BACKGROUND: The Q-426 strain isolated from compost samples has excellent antifungal activities against a variety of plant pathogens. However, the complete genome of Q-426 is still unclear, which limits the potential application of Q-426. RESULTS: Genome sequencing revealed that Q-426 contains a single circular chromosome 4,086,827 bp in length, with 4691 coding sequences and an average GC content of 46.3%. The Q-426 strain has a high degree of collinearity with B. velezensis FZB42, B. velezensis SQR9, and B. amyloliquefaciens DSM7, and the strain was reidentified as B. velezensis Q-426 based on the homology analysis results. Many genes in the Q-426 genome have plant growth-promoting activity, including the secondary metabolites of lipopeptides. Genome mining revealed 14 clusters and 732 genes encoding secondary metabolites with predicted functions, including the surfactin, iturin, and fengycin families. In addition, twelve lipopeptides (surfactin, iturin and fengycin) were successfully detected from the fermentation broth of B. velezensis Q-426 by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS), which is consistent with the genome analysis results. We found that Q-426 produced indole-3-acetic acid (IAA) at 1.56 mg/l on the third day of incubation, which might promote the growth of plants. Moreover, we identified eighteen volatile compounds (VOCs, including 2-heptanone, 6-methylheptan-2-one, 5-methylheptan-2-one, 2-nonanone, 2-decanone, 2-undecanone, 2-dodecanone, 2-tridecanone, 2-tetradecanone, 2-nonadecanone, pentadecanoic acid, oleic acid, dethyl phthalate, dibutyl phthalate, methyl (9E,12E)-octadeca-9,12-dienoate), pentadecane, (6E,10E)-1,2,3,4,4a,5,8,9,12,12a-decahydro-1,4-methanobenzo[10]annulene, and nonanal) based on gas chromatograph-mass spectrometer (GC/MS) results. CONCLUSIONS: We mined secondary metabolite-related genes from the genome based on whole-genome sequence results. Our study laid the theoretical foundation for the development of secondary metabolites and the application of B. velezensis Q-426. Our findings provide insights into the genetic characteristics responsible for the bioactivities and potential application of B. velezensis Q-426 as a plant growth-promoting strain in ecological agriculture.

An arabinogalactan isolated from Pollen Typhae induces the apoptosis of RKO cells by promoting macrophage polarization.

An arabinogalactan (PTPS-1-2) was isolated and characterized from Pollen Typhae, and its potential antitumor effects on activating macrophages to produce immunomodulatory factors and promoting apoptosis in colorectal cancer cells were investigated. Structural characterization showed that PTPS-1-2 had a molecular weight of 59 kDa and was composed of rhamnose, arabinose, glucuronic acid, galactose, and galacturonic acid with a molar ratio of 7.6: 17.1: 6.5: 61.4: 7.4. Its backbone was predominantly composed of T-ß-D-Galp, 1,3-ß-D-Galp, 1,6-ß-D-Galp, 1,3,6-ß-D-Galp, 1,4-α-D-GalpA, 1,2-α-L-Rhap, additionally, branches contained 1,5-α-L-Araf, T-α-L-Araf, T-ß-D-4-OMe-GlcpA, T-ß-D-GlcpA and T-α-L-Rhap. PTPS-1-2 activated RAW264.7 cell by triggering the NF-kB signaling pathway and M1 macrophage polarization. Furthermore, the conditioned medium (CM) of Mφ pretreated with PTPS-1-2 exerted marked antitumor effects by inhibiting RKO cell proliferation and suppressing cell colony formation. Collectively, our findings suggested that PTPS-1-2 might be a therapeutic option for the prevention and treatment of tumors.

Structural and Biochemical Analyses of the Butanol Dehydrogenase from Fusobacterium nucleatum.

Butanol dehydrogenase (BDH) plays a significant role in the biosynthesis of butanol in bacteria by catalyzing butanal conversion to butanol at the expense of the NAD(P)H cofactor. BDH is an attractive enzyme for industrial application in butanol production; however, its molecular function remains largely uncharacterized. In this study, we found that Fusobacterium nucleatum YqdH (FnYqdH) converts aldehyde into alcohol by utilizing NAD(P)H, with broad substrate specificity toward aldehydes but not alcohols. An in vitro metal ion substitution experiment showed that FnYqdH has higher enzyme activity in the presence of Co2+. Crystal structures of FnYqdH, in its apo and complexed forms (with NAD and Co2+), were determined at 1.98 and 2.72 Å resolution, respectively. The crystal structure of apo- and cofactor-binding states of FnYqdH showed an open conformation between the nucleotide binding and catalytic domain. Key residues involved in the catalytic and cofactor-binding sites of FnYqdH were identified by mutagenesis and microscale thermophoresis assays. The structural conformation and preferred optimal metal ion of FnYqdH differed from that of TmBDH (homolog protein of FnYqdH). Overall, we proposed an alternative model for putative proton relay in FnYqdH, thereby providing better insight into the molecular function of BDH.

Versatile functionalization of pectic conjugate: From design to biomedical applications.

Pectin exists extensively in nature and has attracted much attention in biological applications for its unique chemical and physical characteristics. Functionalized pectin, especially pectic conjugates, has given many possibilities for pectin to improve its properties and bioactivity as well as to deliver active molecules. To better exploit this strategy of pectic functionalization, this review presents in detail the structural modifications of pectin, different synthetic methods, and design strategies of pectic conjugates involving both traditional chemical and "green" approaches. Here, the research ideas and applications of pectic prodrugs as well as the development of preparation based on pectic conjugates are reviewed, with emphasis on crosslinking systems of functionalized pectin and nanosystems based on self-assembly techniques. We hope this review will provide comprehensive and valuable information for the functionalization and systematization of the pectic conjugate from synthesis to application.

Engineering a Ligase Binding DNA Aptamer into a Templating DNA Scaffold to Guide the Selective Synthesis of Circular DNAzymes and DNA Aptamers.

Functional nucleic acids (FNAs), such as DNAzymes and DNA aptamers, can be engineered into circular forms for improved performance. Circular FNAs are promising candidates for bioanalytical and biomedical applications due to their intriguing properties of enhanced biological stability and compatibility with rolling circle amplification. They are typically made from linear single-stranded (ss) DNA molecules via ligase-mediated ligation. However, it remains a great challenge to synthesize circular ssDNA molecules in high yield due to inherent side reactions where two or more of the same ssDNA molecules are ligated. Herein, we present a strategy to overcome this issue by first using in vitro selection to search from a random-sequence DNA library a ligatable DNA aptamer that binds a DNA ligase and then by engineering this aptamer into a general-purpose templating DNA scaffold to guide the ligase to execute selective intramolecular circularization. We demonstrate the broad utility of this approach via the creation of several species of circular DNA molecules, including a circular DNAzyme sensor for a bacterium and a circular DNA aptamer sensor for a protein target with excellent detection sensitivity and specificity.

Structure characterization of pectin from the pollen of Typha angustifolia L. and the inhibition activity of lipid accumulation in oleic acid induced L02 cells.

The pollen of Typha angustifolia L. decoction was clinically used to treat hyperlipidemia in China. A pectin polysaccharide (PTPS-2-2) was obtained from T. angustifolia pollen through water extraction, ion-exchange chromatography, and gel chromatography. Structural characterization showed that PTPS-2-2 had a molecular weight of 54 kDa and was composed of rhamnose, arabinose, xylose, galactose, and galacturonic acid with a molar ratio of 11.5: 36.5: 4.1: 36.7: 11.2. PTPS-2-2 consisted of rhamnogalacturonan I (RG-I) and arabinogalactan II (AG-II) domains. Its backbone was predominantly composed of →4-α-D-GalpA-(1 â†’ 2)-α-L-Rhap-(1→, with branches of 1,3-Galp, 1,6-Galp, 1,3,6-Galp, T-Araf, 1.5-Araf and T-Xylp, connected to the 4-position of 1,2-Rhap and the 3-position of 1,4-GalpA. The inhibitory effect of PTPS-2-2 on lipid accumulation was studied in vitro, using L02 cells induced by oleic acid. This experiment shows that PTPS-2-2 treatment at 100-400 µg/mL dose-dependently reduce cellular triglycerides (TG), cholesterol (TC), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, while elevated superoxide dismutase (SOD) levels. This indicated that PTPS-2-2 potentially ameliorated oleic acid-induced hepatic steatosis by inhibiting lipid accumulation and oxidative stress.

Review on the genus Polygonatum polysaccharides: Extraction, purification, structural characteristics and bioactivities.

The genus Polygonatum is gaining increasing attention from nutrition experts as well as health-conscious consumers because of its excellent performance in providing nutrients. Among these plants, Polygonatum sibiricum and Polygonatum odoratum have been selected for inclusion in China's Medicinal Food Directory due to their high safety profile. Polysaccharides are considered the main functional component and one of the main active ingredients of the plant. In addition, polysaccharides from genus Polygonatum have a variety of nutritional, biological and health-promoting properties, such as immunomodulatory, anti-inflammatory, cardiovascular protective, neuroprotective, antitumor, antidiabetic, antiosteoporosis, and hepatoprotective properties. This paper reviews the origin, extraction, purification, structural characteristics, biological activity, safety, toxicological evaluation, and structure-activity relationship of polysaccharides from the genus Polygonatum. Ultimately, we hope that this work can provide a more useful reference for understanding the polysaccharide structure and developing of new functional foods from polysaccharides of the genus Polygonatum.

Extraction, characterization, and anti-nonalcoholic steatohepatitis activity of a (1,3) (1,6)-ß-D-glucan from the Polyporus umbellatus (Pers.) Fries.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by inflammation and hepatic steatosis that may coincide with fibrotic activity. To date, no pharmacological agents have been approved for NASH treatment. Here, a homogeneous (1,3),(1,6)-ß-D-glucan (PUP-W-1, Mw: 41.07 kDa) was successfully purified from Polyporus umbellatus (Pers.) Fries sclerotia and characterized. The analysis showed that the PUP-W-1 backbone consisted of a repeating chain of eight →3)-ß-D-Glcp-(1 â†’ units, with branched chains of four ß-D-Glcp residues, joined by repeating 1,6-linkage units at the O-6 position of the backbone. The pharmacological effects of PUP-W-1 treatment in the context of NASH pathogenesis were explored using a methionine choline-deficient (MCD) diet-induced murine steatohepatitis model. The MCD model mice exhibited pronounced steatohepatitis, inflammatory activity, steatosis, stellate cell activation, and mild fibrotic activity. Treatment of the mice for three weeks with PUP-W-1 prevented the development of NASH due to the suppression of inflammation, lipid accumulation, and fibrosis. As suggested by these findings, PUP-W-1 may hold promise as a natural drug candidate or precursor for the treatment of NASH.

Structural Basis of the Inhibition of L-Methionine γ-Lyase from Fusobacterium nucleatum.

Fusobacterium nucleatum is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (FN0625, FN1055, FN1220, and FN1419) of F. nucleatum are involved in producing hydrogen sulfide (H2S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 Å, showing the unique conformation of the PLP-binding site when compared with L-methionine γ-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H2S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5'-phosphate-binding site. Gallic acid has little effect on the other H2S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from F. nucleatum and found a new lead compound for inhibitor development.

Heterologous expression of quorum sensing transcriptional regulator LitR and its function in virulence-related gene regulation in foodborne pathogen Aeromonas hydrophila.

BACKGROUND: Aeromonas hydrophila is an important foodborne and zoonotic pathogen causing serious diseases. Hence, revealing the pathogenic mechanism of A. hydrophila will be of importance in the development of novel therapies. Aeromonas hydrophila litR was reported to be regulated by two quorum sensing (QS) pathways, indicating that it is involved in QS network regulation correlated with bacterial virulence. However, the function of LitR is currently not understood. Therefore, we aimed to reveal the potential regulatory mechanisms of LitR on virulence-related genes. METHODS AND RESULTS: In this study, amino acid sequences analysis of LitR was conducted, providing bioinformatics evidence for its function as a potential transcriptional regulator. LitR protein was heterologous expressed, purified and its in-vitro multimeric forms were observed with gel filtration chromatography. The correlation between intracellular LitR expression level and cell density was analyzed with immunoblots. Regulation mechanisms of LitR on several important virulence-related factors were investigated with qRT-PCR, EMSA, DNase I footprinting and microscale thermophoresis binding assays, etc. Results showed that recombinant LitR protein aggregated mainly as dimer and hexamer in vitro. Intracellular expression level of LitR was positively correlated with cell density of A. hydrophila. Furthermore, LitR exhibited complicated regulation modes on virulence-related genes; it could directly bind to promoter regions of the hemolysin, serine protease and T6SS effector protein VgrG encoded genes. The promoter region of the hemolysin gene showed high binding affinity and mainly two binding sites for LitR. Different dissociation constants were obtained for LitR interaction with the hemolysin gene binding motifs I and II. Assays focusing on physiological characteristics of A. hydrophila prove that LitR positively regulated hemolytic and total extracellular protease activities. CONCLUSIONS: This study investigated the function of LitR as a quorum sensing transcriptional regulator in regulation of virulence-related genes, which will help reveal the mechanisms of A. hydrophila pathogenicity. LitR could serve as a potential target for development of new antimicrobial agents from the perspective of QS regulation.

Gelatin/alginate-based microspheres with sphere-in-capsule structure for spatiotemporal manipulative drug release in gastrointestinal tract.

Microsphere with sphere-in-capsule structure is a multi-drugs delivery system to achieve the purpose of combination therapy. In this paper, we have prepared gelatin/alginate-based microspheres with sphere-in-capsule structure by a relatively fast, simple, and easily large-scale industrialized emulsification method for spatiotemporal manipulative drug release in gastrointestinal tract. Calcium alginate microspheres encapsulated with bovine serum albumin (BSA) were first prepared as inner microspheres, and then inner microspheres and ranitidine hydrochloride (RH) were co-encapsulated by gelatin microspheres to form double-layer microspheres with sphere-in-capsule structure. The size and distribution of microspheres can be easily controlled by emulsifying conditions. The microspheres with sphere-in-capsule structure displayed desirable encapsulation efficiency of BSA (61.52 %) and RH (56.07 %). The in vitro simulated drug release showed the spatiotemporal release feature of microspheres with sphere-in-capsule structure. In the specific simulated fluid, the release behavior and cumulative release of RH (sustainedly released 95 % in simulated gastric fluid) and BSA (rapidly released 73 % in simulated intestinal fluid) were different. The drug release mechanisms were analyzed to determine RH and BSA's release behavior. Overall, the microspheres with sphere-in-capsule structure have the potential application of spatiotemporal manipulative drug delivery in the gastrointestinal tract.

Pediatric isoniazid-resistant tuberculosis of the bone marrow manifesting as hemophagocytic syndrome: A case report.

Hemophagocytic syndrome (HPS) is a critical syndrome of ineffective hyperinflammatory immune response resulting in infiltration of lymphocytes and histiocytes in various organs. Causes can be hereditary or due to malignancy, autoimmune disease, or infection. HPS due to Mycobacterium tuberculosis is rare as only a handful of cases are reported, and they are mostly associated with severe disseminated tuberculosis (TB). We reported a 9-year-old boy with tuberculosis of the bone marrow accompanied with hemophagocytic syndrome. The patient presented with manifestation of HPS and had no respiratory symptoms or risk factors for TB but was later diagnosed of isoniazid-resistant TB in the bone marrow. He had a good outcome after receiving anti-TB drugs and corticosteroids on time. This case highlights that bone marrow might be a shelter for Mycobacterium tuberculosis. Concurrent testing for drug susceptibility in TB cases with an uncommon manifestation is recommended even for first episodes. Early diagnosis and etiological confirmation of the infection origin and appropriate treatment are essential to improve survival in this otherwise life-threatening condition.

Talaromyces marneffei Infections in 8 Chinese Children with Inborn Errors of Immunity.

PURPOSE: Talaromyces marneffei (TM) is an opportunistic fungus leading to multi-organ damages and poor prognosis in immunocompromised individuals. TM infections in children are rare and our knowledge to TM infection is insufficient. To investigate the clinical characteristics of TM-infected children and to explore the underlying mechanisms for host against TM, we analysed TM-infected patients diagnosed in our hospital. METHODS: Eight patients with TM infections have been identified in Shenzhen Children's Hospital during 2017-2021. Clinical data were collected from medical records. Immunological features were evaluated by flow cytometry. Literatures were also reviewed to summarize the reported inborn errors of immunity (IEIs) with TM infections. RESULTS: All 8 children were HIV-negative. The most common symptom of TM infections was fever (8/8), followed by weight loss (7/8), pneumonia (7/8), hepatomegaly (7/8), splenomegaly (6/8), anemia (6/8), lymphadenopathy (5/8), thrombocytopenia (3/8), diarrhea (3/8), rashes or skin lesions (3/8), and osteolytic lesions (1/8). Five children died during the follow-ups. CD3+ T cells were decreased in 6 patients. Eight patients had reduced natural killer cells. All patients went gene sequencing and were finally diagnosed as IEIs, including STAT1 gain-of-function, IL-2 receptor common gamma chain deficiency, adenosine deaminase deficiency, CD40 ligand deficiency, and STAT3 deficiency. Another 4 types of IEIs (CARD9, IFN-γ receptor 1, RelB, and NFKB2 deficiency), have been reported with TM infections based on literature review. CONCLUSION: TM infections resulted in systemic injuries and high mortality. The spectrum of IEIs underlying TM infections indicated that T cell-mediated immunity, IFN-γ, IL-17 signalings and NF-κB pathways were important for host responses against TM infection. In reverse, for HIV-negative children without other secondary immunodeficiencies, IEIs should be considered in TM-infected children.