ScienceWeek

MEDICAL BIOLOGY: ON CHEMOKINES AND INFLAMMATION

The following points are made by I.F. Charo and R.M. Ransohoff (New Engl. J. Med. 2006 354:610):

1) Chemokines (chemotactic cytokines) are small heparin-binding proteins that direct the movement of circulating leukocytes to sites of inflammation or injury[1]. During the past decade, a vast expansion in the understanding of chemokine biology has occurred. Originally studied because of their role in inflammation, chemokines and their receptors are now known to play a crucial part in directing the movement of mononuclear cells throughout the body, engendering the adaptive immune response and contributing to the pathogenesis of a variety of diseases. Chemokine receptors are some of the most tractable drug targets in the huge battery of molecules that regulate inflammation and immunity. For this reason, clinical trials involving chemokine-receptor antagonists for the treatment of inflammatory conditions have recently begun.

2) The approximately 50 human chemokines that are knon segregate into four families on the basis of differences in structure and function.[1-5] A systematic nomenclature has been adopted in the past several years. The largest family consists of CC chemokines, so named because the first two of the four cysteine residues in these molecules are adjacent to each other. CC chemokines attract mononuclear cells to sites of chronic inflammation. The most thoroughly characterized CC chemokine is monocyte chemoattractant protein 1 (MCP-1), termed "chemokine ligand CCL2" in the systematic nomenclature. It is a potent agonist for monocytes, dendritic cells, memory T cells, and basophils. Other CC chemokines include macrophage inflammatory protein (MIP)-1{alpha} (CCL3), MIP-1-beta (CCL4), and RANTES (CCL5). It is likely that dimers or even tetramers are the active form of many CC chemokines.

3) A second family of chemokines consists of CXC chemokines, which have a single amino acid residue interposed between the first two canonical cysteines. Some CXC chemokines, of which interleukin-8 (CXCL8) is the prototype, attract polymorphonuclear leukocytes to sites of acute inflammation. CXCL8 also activates monocytes and may direct the recruitment of these cells to vascular lesions. The third family is the CX3C family, of which fractalkine (CX3CL1) is the only member. The chemokine domain of CX3CL1 is fused to a mucin-like stalk and transmembrane and cytoplasmic regions, thereby forming a cell-adhesion receptor capable of arresting cells under physiologic flow conditions. An enzyme, tumor necrosis factor (TNF)-{alpha} converting enzyme, can cleave CX3CL1 from the cell membrane, freeing the cytokine to function as a soluble chemoattractant. CXCL16, the other chemokine with a chemokine domain linked to a mucin stalk, also mediates cell adhesion and can be released as a soluble chemoattractant. CXCL16, present on macrophages and dendritic cells, mediates interactions between antigen-presenting cells and T cells. CXCL16 also has scavenger-receptor activity for oxidized lipids containing phosphatidylserine and may participate in atherogenesis. Lymphotactin (XCL1), the sole member of the fourth family, has a single cysteine residue.

4) Chemokines affect cells by activating surface receptors that are seven-transmembrane domain G-protein coupled receptors; leukocyte responses to particular chemokines are determined by their complement of chemokine receptors. The binding of the chemokine to the receptor activates signaling cascades that culminate in the rearrangement, change of shape, and cell movement of actin. Unlike other chemokine receptors, CXCR4 is expressed in many tissues, including those of the central nervous system. In mice, the targeted deletion of CXCR4 or its ligand, CXCL12, causes perinatal death, indicating that this ligand and its receptor have a vital developmental function.

References (abridged):

1. Luster AD. Chemokines -- chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436-445

2. Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 2004;22:891-928

3. Handel TM, Domaille PJ. Heteronuclear (1 H, 13 C, 15 N) NMR assignments and solution structure of the monocyte chemoattractant protein-1 (MCP-1) dimer. Biochemistry 1996;35:6569-6584

4. Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005;23:127-159

5. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2:108-115

New Engl. J. Med. http://www.nejm.org

MEDICAL BIOLOGY: ON MICROBIAL ANTIBIOTIC RESISTANCE

The following points are made by Martin Leeb (Nature 2004 431:892):

1) In the late 1960s, the battle against bacterial infections was considered won, in the developed world at least. By the time of Woodstock, antibiotics were curing previously lethal infections in a matter of days. Infected cuts and food poisoning were no longer life-threatening, diseases such as syphilis and gonorrhoea seemed to be on the way to eradication, and ancient scourges such as plague and cholera could now be controlled.

2) Now antimicrobial resistance threatens to turn back the clock. Resistance is spreading rapidly, particularly in hospitals, where many different bacterial strains can come into contact with each other and where antibiotics are heavily used. The more an antibiotic is used, the more resistance to it spreads, forcing physicians to try other antibiotics. Even drugs that once served as a last resort are losing their potency. Some believe that the cycle of resistance is inevitable, and that with every new drug we use, we select for resistant microbes that survive and multiply unhampered by treatment with the same antibiotic.

3) The only apparent solution is to continue to develop new drugs. But just as we need them most, the antimicrobial drug pipeline is running dry. Until ten years ago, all major drug companies ran antibacterial research programs. Today, these programs have been drastically pruned, and many have been cut altogether as pharmaceutical companies pursue more lucrative areas, such as chronic illnesses and mood disorders. The desperate nature of the situation led the Infectious Diseases Society of America (IDSA) to issue a white paper in July 2004 calling for a variety of measures to get antibiotic research back on track, starting in the US. The report followed a year-long investigation into the economics of drug development. In the absence of independent action by the pharmaceutical industry, the report says, the US Congress and federal regulatory agencies must step in with financial incentives for pharmaceutical companies to get back into the antimicrobial business.

4) This all makes for a potential healthcare calamity. Although the number of hospital-acquired infections has been gradually declining in the US, a greater proportion of these infections --now about 70% -- are resistant to at least one antibiotic. This results in a delay in effective treatment, prolonging illness and increasing the risk of death. Two million people will pick up an infection in a US hospital this year, for example, and 90,000 of them will die of it, according to estimates by the US Centers for Disease Control and Prevention.(1-3)

References:

1. Wegener, H. C. Curr. Opin. Microbiol. 6, 439-445 (2003)

2. DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. J. Health Econ. 22, 151-185 (2003)

3. Spellberg, B., Powers, J. H., Brass, E. P., Miller, L. G. & Edwards, J. E. Jr Clin. Infect. Dis. 38, 1279-1286 (2004)

Nature http://www.nature.com/nature

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Related Material:

MEDICAL BIOLOGY: ON BACTERIAL ANTIBIOTIC RESISTANCE

The following points are made by Carlos F. Amabile-Cuevas (American Scientist 2003 91:138):

1) Antibiotics are compounds that kill or at least inhibit the growth of bacterial cells without harming the patient. No single antibiotic can kill or inhibit all bacteria. Natural penicillin and macrolides such as erythromycin, for instance, cannot penetrate into the gut bacterium Escherichia coli and its relatives; only a handful of drugs work against the almost impermeable Mycobacterium tuberculosis, which causes tuberculosis. The intrinsic resistance of bacteria defines the "spectrum" of each antibiotic; wide-spectrum antibiotics are effective against a variety of germs, whereas narrow-spectrum antibiotics only control a few species. But the antibiotic resistance we normally speak about refers to cases in which organisms that were originally killed by a certain drug suddenly keep growing in its presence. When a concentration of antibiotic safely attainable in the blood and tissues of a patient no longer affects an organism, we say the strain has become resistant.

2) The first explanation for resistance was that mutations, small changes in the genetic information, of a bacterial cell somehow prevented an antibiotic from acting on it. Certainly, many resistant organisms arose through the acquisition of spontaneous mutations; this is particularly true for germs causing tuberculosis. But, unexpectedly, genes conferring resistance rapidly emerged and accumulated, quickly yielding multi-resistant bacteria -- i.e., strains resistant to three or more antibiotics. Also, some bacteria were found to have the same resistance genes as those found in species that naturally produce antibiotics. (Most antibiotics are obtained from various species of soil bacteria, which have been producing these compounds for millions of years.)

3) It became clear that bacteria can exchange genes, a process known as "horizontal gene transfer". In this way, a mutation conferring antibiotic resistance can be acquired by neighboring bacteria, even if they are very distantly related species. The resistance genes can spread from mutants or even directly from antibiotic-producing species. Furthermore, such genes can accumulate in a single cell, resulting in multi-resistant germs.

4) Bacteria often carry the resistance genes in small DNA molecules called "plasmids", which act as genetic "supplements" to the core genome. Exchanging these supplements is easier than mobilizing genes in the genome. Genes conferring other dangerous traits, such as virulence, are also often found in plasmids.

American Scientist http://www.americanscientist.org

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Notes by ScienceWeek:

Biologists recognize two types of gene transfer from one organism to another: vertical and horizontal. Vertical gene transfer occurs between parents and offspring, and horizontal gene transfer is the transfer that may occur between organisms otherwise.

It is in bacteria that horizontal gene transfer has been studied most extensively, particularly in the last decade. Three types of horizontal gene transfer are known: conjugation, transduction, and transformation.

Conjugation is a type of sexual reproduction exhibited by some bacteria, the process involving the exchange of genetic material by means of a tube or bridge, the transfer of DNA occurring either in one direction or in both directions.

Transduction involves the transfer of genetic material from one bacterium to another with the intermediation of a virus. Essentially, when the virus infects one bacterium, it often carries away pieces of that bacterium's genome, and those pieces, upon the infection of a new bacterium, become incorporated into the second bacterial genome.

Finally, transformation is the process involving the uptake or incorporation of DNA fragments (plasmids) by a bacterium, first observed in 1944 by Oswald Avery.

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