Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency:Two case reports

BACKGROUND Mannosyl-oligosaccharide glucosidase(MOGS)deficiency is an extremely rare type of congenital disorder of glycosylation(CDG),with only 12 reported cases.Its clinical,genetic,and glycomic features are still expanding.Our aim is to update the novel clinical and glycosylation features of 2 previously reported patients with MOGS-CDG.CASE SUMMARY We collected comprehensive clinical information,and conducted the immunoglobulin G1 glycosylation assay using nano-electrospray ionization source quadruple time-of-flight mass spectrometry.Novel dysmorphic features included an enlarged tongue,forwardly rotated earlobes,a birth mark,overlapped toes,and abnormal fat distribution.Novel imaging findings included pericardial effusion,a deep interarytenoid groove,mild congenital subglottic stenosis,and laryngomalacia.Novel laboratory findings included peripheral leukocytosis with neutrophil predominance,elevated C-reactive protein and creatine kinase,dyslipidemia,coagulopathy,complement 3 and complement 4 deficiencies,decreased proportions of T lymphocytes and natural killer cells,and increased serum interleukin 6.Glycosylation studies showed a significant increase of hypermannosylated glycopeptides(Glc3Man7GlcNAc2/N2H10 and Man5GlcNAc2/N2H5)and hypersialylated glycopeptides.A compensatory glycosylation pathway leading to an increase in Man5GlcNAc2/N2H5 was indicated with the glycosylation profile.CONCLUSION We confirmed abnormal glycomics in 1 patient,expanding the clinical and glycomic spectrum of MOGS-CDG.We also postulated a compensatory glycosylation pathway,leading to a possible serum biomarker for future diagnosis.

Interaction of viruses with host immune system and immunomodulation in chronic viral infections

The WHO estimates that almost500 million people world-wide are chronically infected with hepatitis B and C viruses(HBV and HCV)and human immune deficiency virus(HIV).During the recent years,significant progress was made in treatment of chronic infection with HBV,HCV,and HIV,mainly based on directly antiviral agents.However,

Antiviral Activity of Dual-acting Hydrocarbon-stapled Peptides against HIV-1 Predominantly Circulating in China

Objective New rationally designed i,i＋7-hydrocarbon-stapled peptides that target both HIV-1 assembly and entry have been shown to have antiviral activity against HIV-1 subtypes circulating in Europe and North America. Here, we aimed to evaluate the antiviral activity of these peptides against HIV-1 subtypes predominantly circulating in China. Methods The antiviral activity of three i,i＋7-hydrocarbon-stapled peptides, NYAD-36, NYAD-67, and NYAD-66, against primary HIV-1 CRF07_BC and CRFOI_AE isolates was evaluated in peripheral blood mononuclear cells （PI3MCs）. The activity against the CRF07_BC and CRF01_AE Env-pseudotyped viruses was analyzed in TZM-bl cells. Results We found that all the stapled peptides were effective in inhibiting infection by all the primary HIV-1 isolates tested, with 50% inhibitory concentration toward viral replication （ICso） in the low micromolar range. NYAD-36 and NYAD-67 showed better antiviral activity than NYAD-66 did. We further evaluated the sensitivity of CRF01_AE and CRF07_BC Env-pseudotyped viruses to these stapled peptides in a single-cycle virus infectivity assay. As observed with the primary isolates, the ICs0s were in the low micromolar range, and NYAD-66 was less effective than NYAD-36 and NYAD-67. Conclusion Hydrocarbon-stapled peptides appear to have broad antiviral activity against the predominant HIV-1 viruses in China. This finding may provide the impetus to the rational design of peptides for future antiviral therapy.

Recent transmission of Mycobacterium tuberculosis in China： the implication of molecular epidemiology for tuberculosis control

Tuberculosis （TB） has remained an ongoing concern in China. The national scale-up of the Directly Observed Treatment, Short Course （DOTS） program has accelerated the fight against TB in China. Nevertheless, many challenges still remain, including the spread of drug-resistant strains, high disease burden in rural areas, and enormous rural-to-urban migrations. Whether incident active TB represents recent transmission or endogenous reactivation has helped to prioritize the strategies for TB control. Evidence from molecular epidemiology studies has delineated the recent transmission of Mycobacterium tuberculosis （M. tuberculosis） strains in many settings. However, the transmission patterns of TB in most areas of China are still not clear. Studies carried out to date could not capture the real burden of recent transmission of the disease in China because of the retrospective study design, incomplete sampling, and use of low-resolution genotyping methods. We reviewed the implementations of molecular epidemiology of TB in China, the estimated disease burden due to recent transmission of M. tuberculosis strains, the primary transmission of drug-resistant TB, and the evaluation of a feasible genotyping method of M. tuberculosis strains in circulation.

Filamentation initiated by Cas2 and its association with the acquisition process in cells

Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity.The process is critical for the ecology of the oral microflora and oral health.Although molecular mechanisms for spacer acquisition are known,it has never been established if this process is associated with the morphological changes of bacteria.In this study,we demonstrated a novel Cas2-induced filamentation phenotype in E.coli that was regulated by co-expression of the Cas1 protein.A 30 amino acid motif at the carboxyl terminus of Cas2 is necessary for this function.By imaging analysis,we provided evidence to argue that Cas-induced filamentation is a step coupled with new spacer acquisition during which filaments are characterised by polyploidy with asymmetric cell division.This work may open new opportunities to investigate the adaptive immune response and microbial balance for oral health.

Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus

Middle East respiratory syndrome （MERS）, an emerging infectious disease caused by MERS coronavirus （MERS-CoV）, has garnered worldwide attention as a consequence of its continuous spread and pandemic potential, making the development of effective vaccines a high priority. We previously demonstrated that residues 377-588 of MERS-CoV spike （S） protein receptor-binding domain （RBD） is a very promising MERS subunit vaccine candidate, capable of inducing potent neutralization antibody responses. In this study, we sought to identify an adjuvant that optimally enhanced the immunogenicity of S377-588 protein fused with Fc of human IgG （S377-588-Fc）. Specifically, we compared several commercially available adjuvants, including Freund＇s adjuvant, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59 with regard to their capacity to enhance the immunogenicity of this subunit vaccine. In the absence of adjuvant, S377-588-Fc alone induced readily detectable neutralizing antibody and T-cell responses in immunized mice. However, incorporating an adjuvant improved its immunogenicity. Particularly, among the aforementioned adjuvants evaluated, MF59 is the most potent as judged by its superior ability to induce the highest titers of IgG, IgG1 and IgG2a subtypes, and neutralizing antibodies. The addition of MF59 significantly augmented the immunogenicity of S377-588-Fcto induce strong IgG and neutralizing antibody responses as well as protection against MERS-CoV infection in mice, suggesting that MF59 is an optimal adjuvant for MERS-CoV RBD-based subunit vaccines.

Enhancement of endocytic uptake of H IV-1 virions into CD4-negative epithelial cells by HIV-1 gp41 via its interaction with POB1

We previously used recombinant soluble gp41 （rsgp41） as a targetto screen a ntnnan oone marrow cul,~n library by the yeast two-hybrid assay, and we identified an HW-1 gp41-binding protein, human POB1 （the partner of RalBP1）. We found that the gp41- binding site was located at the C-term- inal region （aa462-521） of POB1 and the POBl-binding site was on the N-term- inal heptad repeat （NHR） region of HIV-1 gp41.

Various brain-eating amoebae: the protozoa, the pathogenesis, and the disease

Among various genera of free-living amoebae prevalent in nature,some members are identified as causative agents of human encephalitis,in which Naegleria fowleri followed by Acanthamoeba spp.and Balamuthia mandrillaris have been successively discovered.As the three dominant genera responsible for infections,Acanthamoeba and Balamuthia work as opportunistic pathogens of granulomatous amoebic encephalitis in immunocompetent and immunocompromised individuals,whereas Naegleria induces primary amoebic meningoencephalitis mostly in healthy children and young adults as a more violent and deadly disease.Due to the lack of typical symptoms and laboratory findings,all these amoebic encephalitic diseases are difficult to diagnose.Considering that subsequent therapies are also affected,all these brain infections cause significant mortality worldwide,with more than 90%of the cases being fatal.Along with global warming and population explosion,expanding areas of human and amoebae activity in some regions lead to increased contact,resulting in more serious infections and drawing increased public attention.In this review,we summarize the present information of these pathogenic free-living amoebae,including their phylogeny,classification,biology,and ecology.The mechanisms of pathogenesis,immunology,pathophysiology,clinical manifestations,epidemiology,diagnosis,and therapies are also discussed.

Tactics used by HIV-1 to evade host innate, adaptive, and intrinsic immunities

Objective To review the mechanisms by which HIV evades different components of the host immune system.Data sources This review is based on data obtained from published articles from 1991 to 2012.To perform the PubMed literature search,the following key words were input：HIV and immune evasion.Study selection Articles containing information related to HIV immune evasion were selected.Results Although HIV is able to induce vigorous antiviral immune responses,viral replication cannot be fully controlled,and neither pre-existing infected cells nor latent HIV infection can be completely eradicated.Like many other enveloped viruses,HIV can escape recognition by the innate and adaptive immune systems.Recent findings have demonstrated that HIV can also successfully evade host restriction factors,the components of intrinsic immune system,such as APOBEC3G （apolipoprotein B mRNA-editing enzyme,catalytic polypeptide-like 3G）,TRIM5α （tripartite motif 5-α）,tetherin,and SAMHD1 （SAM-domain HD-domain containing protein）.Conclusions HIV immune evasion plays an important role in HIV pathcgenesis.Fully understanding the tactics deployed by HIV to evade various components of the host immune systems will allow for the development of novel strategies aimed toward the prevention and cure of HIV/AIDS.

Plasmacytoid dendritic cells promote acute kidney injury by producing interferon-α

Acute kidney injury(AKI)is a common clinical complication associated with high mortality in patients.Immune cells and cytokines have recently been described to play essential roles in AKI pathogenesis.Plasmacytoid dendritic cells(pDCs)are a unique DC subset that specializes in type Ⅰ interferon(IFN)production.Here,we showed that pDCs rapidly infiltrated the kidney in response to AKI and contributed to kidney damage by producing IFN-α.Deletion of pDCs using DTR^(BDCA2) transgenic(Tg)mice suppressed cisplatin-induced AKI,accompanied by marked reductions in proinflammatory cytokine production,immune cell infiltration and apoptosis in the kidney.In contrast,adoptive transfer of pDCs during AKI exacerbated kidney damage.We further identified IFN-α as the key factor that mediated the functions of pDCs during AKI,as IFN-α neutralization significantly attenuated kidney injury.Furthermore,IFN-α produced by pDCs directly induced the apoptosis of renal tubular epithelial cells(TECs)in vitro.In addition,our data demonstrated that apoptotic TECs induced the activation of pDCs,which was inhibited in the presence of an apoptosis inhibitor.Furthermore,similar deleterious effects of pDCs were observed in an ischemia reperfusion(IR)-induced AKI model.Clinically,increased expression of IFN-α in kidney biopsies was observed in kidney transplants with AKI.Taken together,the results of our study reveal that pDCs play a detrimental role in AKI via IFN-α.