抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Microglia are critical nervous system-specific immune cells serving as tissue-resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN-γ to an M1 phenotype for expression of pro-inflammatory cytokines or by IL-4/IL-13 to an M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL-13 (M2) polarization.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13139

Microglial M1/M2 polarization and metabolic states.

The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection Microglia use a defined armamentarium of genes to perform these tasks In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons Injury to neurons in Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy

Microglia in neurodegeneration.

Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

Application of NALP3-ASC inflammation complex and activator inhibitor thereof in terms of preparation of medicines for treating prion diseases

The invention provides an early diagnostic marker for chronic neurodegenerative diseases. The early diagnostic marker is beta-type soluble NSF attachment proteins (beta-SNAPs), wherein an amino acid sequence is shown in Seq ID No.1, or the sequence is an amino acid sequence with equal functions, which is formed by replacing, missing or adding one or more amino acids. By adopting the early diagnostic marker, the condition that early development of the chronic neurodegenerative diseases can be indicated by expression of beta-SNAPs and content change is found out for the first time, a proteomic approach for detecting the protein change is developed, a new thought is opened up for early diagnosis and early discovery of the chronic neurodegenerative diseases, and loss of the chronic neurodegenerative diseases is reduced to the minimal extent by deep mechanism research and building of a loss-time curve.

Early diagnostic marker for chronic neurodegenerative diseases and application of marker

The present invention provides a mycobacterium bovis Mce4E protein, and has an amino acid sequence which is shown in a sequence table SEQID NO.2, or an amino acid sequence which has the same function and is formed by replacement, deletion or addition of one or a plurality of amino acids of the sequence. The present invention also provides a preparation method of Mce4E, including the steps of construction of genetic engineering bacteria, in vitro induced expression, separation and purification, renaturation and other steps. The present invention further provides the genetic engineering bacteria PET30/Mce4E CGMCC No.1865 for the in vitro preparation of Mce4E. The Mce4E protein and mycobacterium bovis positive serum of the present invention can generate a specific serological reaction, so the Mce4E protein can be further used as an antigen for the development and detection of the test kits; the yield of the Mce4E protein can achieve 20mg/L in each culture media by using the preparation method of the present invention.

Cattle mycobacterium Mce4E protein, preparation method and uses thereof

The invention provides a recombinant human prion protein (hPrP), and a preparation method and application thereof. The amino acid sequence of the recombinant hPrP is shown as SEQ ID NO.2. The preparation method comprises the following steps: obtain an hPrP DNA (deoxyribonucleic acid) sequence having enzyme cutting sites through a PCR (polymerase chain reaction) method by taking a human whole blood gene as the template and using primers of which the nucleotide sequences are shown as SEQ ID NO.3 and SEQ ID NO.4; connecting the hPrP DNA sequence to a pPROEX-htb plasmid; removing unwanted enzyme cutting sites in front of a target gene in an expression carrier through a site-directed mutagenesis technology to obtain an hPrP fully true expression carrier; and performing expression, overhigh-affinity chromatographic column purification and renaturation on the carrier in Escherichia coli to obtain the recombinant hPrP. The recombinant hPrP obtained by the invention has good biological activity, and can be used for developing hPrP polyclonal antibodies, monoclonal antibodies and diagnosis kits for human prion diseases.

Recombinant human prion protein (hPrP), and preparation method and application thereof

Global quantitative phosphoproteome reveals phosphorylation network of bovine lung tissue altered by Mycobacterium bovis.

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