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

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Pattern Recognition Receptors and Inflammation

https://www.cell.com/immunity/pdf/S1074-7613(11)00190-7.pdf

Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity

The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

/pdf/inflammatory-mechanisms-in-obesity-4zcumnwrzk.pdf

Inflammatory Mechanisms in Obesity

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.

/pdf/the-ectodomain-of-toll-like-receptor-9-is-cleaved-to-13oclfn0ay.pdf

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Receptors of the innate immune system recognize conserved microbial features and provide key signals that initiate immune responses. Multiple transmembrane and cytosolic receptors have evolved to recognize RNA and DNA, including members of the Toll-like receptor and RIG-I-like receptor families and several DNA sensors. This strategy enables recognition of a broad range of pathogens; however, in some cases, this benefit is weighed against the cost of potential self recognition. Recognition of self nucleic acids by the innate immune system contributes to the pathology associated with several autoimmune or autoinflammatory diseases. In this review, we highlight our current understanding of nucleic acid sensing by innate immune receptors and discuss the regulatory mechanisms that normally prevent inappropriate responses to self.

Nucleic acid recognition by the innate immune system.

Toll-like receptor (TLR) 9 requires proteolytic processing in the endolysosome to initiate signaling in response to DNA. However, recent studies conflict as to which proteases are required for receptor cleavage. We show that TLR9 proteolysis is a multistep process. The first step removes the majority of the ectodomain and can be performed by asparagine endopeptidase (AEP) or cathepsin family members. This initial cleavage event is followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. This dual requirement for AEP and cathepsins is observed in all cell types that we have analyzed, including mouse macrophages and dendritic cells. In addition, we show that TLR7 and TLR3 are processed in an analogous manner. These results define the core proteolytic steps required for TLR9 function and suggest that receptor proteolysis may represent a general regulatory strategy for all TLRs involved in nucleic acid recognition.

/pdf/nucleic-acid-recognition-by-toll-like-receptors-is-coupled-1ba91qhnh0.pdf

Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase.

The obligate intracellular parasite Toxoplasma gondii is able to infect nearly all nucleated cell types of warm-blooded animals. This is achieved through the injection of hundreds of parasite effectors into the host cell cytosol, allowing the parasite to establish a vacuolar niche for growth, replication, and persistence. Here we show that Toxoplasma infection actives an inflammasome response in mice and rats, an innate immune sensing system designed to survey the host cytosol for foreign components leading to inflammation and cell death. Oral infection with Toxoplasma triggers an inflammasome response that is protective to the host, limiting parasite load and dissemination. Toxoplasma infection is sufficient to generate an inflammasome response in germfree animals. Interleukin 1β (IL-1β) secretion by macrophage requires the effector caspases 1 and 11, the adapter ASC, and NLRP1, the sensor previously described to initiate the inflammasome response to Bacillus anthracis lethal factor. The allele of NLRP1b derived from 129 mice is sufficient to enhance the B6 bone marrow-derived macrophage (BMDM) inflammasome response to Toxoplasma independent of the lethal factor proteolysis site. Moreover, N-terminal processing of NLRP1b, the only mechanism of activation known to date, is not observed in response to Toxoplasma infection. Cumulatively, these data indicate that NLRP1 is an innate immune sensor for Toxoplasma infection, activated via a novel mechanism that corresponds to a host-protective innate immune response to the parasite.

https://iai.asm.org/content/iai/82/1/460.full.pdf

NLRP1 Is an Inflammasome Sensor for Toxoplasma gondii

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA−) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA− strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria.

/pdf/toxoplasma-effector-maf1-mediates-recruitment-of-host-27ba63sdg6.pdf

Sarah E. Ewald

Papers

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Nucleic acid recognition by the innate immune system.

Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase.

NLRP1 Is an Inflammasome Sensor for Toxoplasma gondii

Toxoplasma effector MAF1 mediates recruitment of host mitochondria and impacts the host response.