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

J. Appl. Cryst.の発刊に際して

Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

/pdf/antimicrobial-peptides-of-multicellular-organisms-24vvoqtunk.pdf

Antimicrobial peptides of multicellular organisms

Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

/pdf/protein-misfolding-functional-amyloid-and-human-disease-2w386pwb7k.pdf

Protein Misfolding, Functional Amyloid, and Human Disease

Few microorganisms are as versatile as Escherichia coli. An important member of the normal intestinal microflora of humans and other mammals, E. coli has also been widely exploited as a cloning host in recombinant DNA technology. But E. coli is more than just a laboratory workhorse or harmless intestinal inhabitant; it can also be a highly versatile, and frequently deadly, pathogen. Several different E. coli strains cause diverse intestinal and extraintestinal diseases by means of virulence factors that affect a wide range of cellular processes.

Pathogenic Escherichia coli

This chapter describes the virulence and regulation of chaperone-usher pathway (CUP) pili, focusing on type 1 and P pili in uropathogenic Escherichia coli (UPEC), the most common cause of urinary tract infections (UTIs). UPEC and E. coli in general heavily rely on CUP pili to mediate attachment to biotic and abiotic surfaces. The pathogenesis of community-acquired UPEC UTI is thought to begin with UPEC colonization of the periurethral area from the fecal flora. Depending on the specific niche UPEC inhabits, it encounters different elements of the immune response as well as different environmental pressures, necessitating precise gene regulation. The ability of UPEC to transcend the acute population bottleneck is described in detail. In addition to up-regulation of genes involved in general metabolism, several genes classified as being involved in removal of reactive oxygen species and hydrophobic compounds were also upregulated. Further, negative cross-regulatory interactions between pili may serve to divert resources to the conditions most effective for persistence or transit throughout hosts. Antivirulence compounds such as pilicides and mannosides represent novel strategies to translate basic knowledge from the investigation of pilus structure and function into new therapeutics that may have efficacy in treating UTIs by affecting CUP expression and function.

Uropathogenic Escherichia coli Virulence and Gene Regulation

Many Gram-negative pathogens assemble adhesive structures on their surfaces that allow them to colonize host tissues and cause disease. Novel compositions which inhibit or prevent the formation of a pilus chaperone-subunit complex are disclosed. Interfering with the function of the pili chaperone negatively affects the chaperone/usher pathway which is one molecular mechanism by which Gram-negative bacteria assemble adhesive pili structures and thus prevent or inhibit pilus assembly. Also provided are methods for the treatment or prevention of diseases caused by tissue-adhering pilus-forming bacteria by inhibiting the function of pilus chaperones. Also provided are pharmaceutical preparations capable of inhibiting or preventing the formation of a pilus chaperone-subunit complex. Also provided are methods of synthesizing the N-substituted amino acid compounds and compounds useful for the synthesis thereof. In particular, novel fluorinated linker compounds and methods of synthesis are provided. Methods for using the fluorinated linker compounds in methods of solid-phase synthesis of the N-substituted amino acid compounds are also disclosed.

Compounds directed against pilus biogenesis and activity in pathogenic bacteria; methods and compositions for synthesis thereof

Biofilms offer cover for many pathogenic bacteria. A recent paper in Nature reveals that lactoferrin is an innate tool that inhibits biofilm formation.

Innate defense evicts bacterial squatters

Novel amino methylated 2-pyridinones, precursors, intermediates, and derivatives; the methods for the preparation of the same; uses of the same for inhibiting pili formation in bacteria; and pharmaceutical compositions comprising these compounds are described in this application. The present compounds may be employed to inhibit biofilm formation and thereby inhibit adherence of bacteria to a host cell.

Amino Methylated 2-Pyridinones

1.INTRODUCTION Ur inary t r ac t i n f e c t i o n s are commonly caused by Escher ich ia c o l i . E. c o l i i so l a tes associated w i th upper u r i na ry t r ac t i n f e c t i o n s and acute p y e l o n e p h r i t i s d i f f e r from the normal fecal f l o r a in several aspects. Uropathogens belong to a r e s t r i c t e d number of serotypes; they express mannose res i s t an t adhesins in add i t i on to mannose s p e c i f i c Type 1 p i l i ; they f r equen t l y produce a capsule, and they of ten secrete hemolysins (17,18). The Gala(1-4)Gal s p e c i f i c adhesin associated w i th so ca l l ed P p i l l is the most commonly encountered v i ru lence associated adhesin in uropathogenic E. c o l i (7 -9 ) . This adhesin recognizes Gala( l -4 )Gal both in terminal and ex terna l pos i t i ons in the g loboser ies of g l y c o l i p i d s (3) . The i n t e r a c t i o n between the adhesin and receptor is of high a f f i n i t y based on the fact that so lub le receptor analogues can i n h i b i t bac te r i a l b ind ing (8) . P p i l i are encoded by the pap chromosomal gene c l us te r which is arranged as an operon (18). I nd i v i dua l E. c o l i i so la tes may conta in one, but f r equen t l y conta in two operons, each of which express a P -p i l us of a d i s t i n c t serotype. These operons are located far away from each other on the chromosome but are usua l l y g e n e t i c a l l y l inked to the h ly operon encoding hemolysin (4 ,13) .

Scott J. Hultgren

Papers

Uropathogenic Escherichia coli Virulence and Gene Regulation

Compounds directed against pilus biogenesis and activity in pathogenic bacteria; methods and compositions for synthesis thereof

Innate defense evicts bacterial squatters

Amino Methylated 2-Pyridinones

Biogenesis of pili adhesins associated with urinary tract infectious Escherichia coli