By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-related research:
Armies historically have fielded three main fighting forces: infantry, cavalry and artillery. In addition, they raised a small, secret, elect unit that fought mainly with knives and piano wire, to infiltrate the enemy's ranks and kill up-close and personally.
The human immune system has a similar order of battle, based largely on three white-blood-cell fighting forces: antibodies, cytotoxic T lymphocytes (CTLs) and macrophages. CTLs and antibodies are programmed to find the pathogenic enemy, memorize the shape of its antigenic target molecules, engage it, and kill it. Macrophages knock off dangerous intruders by engulfing and digesting them.
And, like traditional armies, the immune defenses deploy a small, little-known fighting formation, the natural killer T (NKT) cells.
Until 1976, no one suspected the existence of NKTs. Immunologists discovered them accidentally while testing tumor-specific CTL action in tumor-bearing mice. Much to their surprise and dismay, they found that in normal un-immunized animals, without benefit of CTL, something was punching lethal holes in other, unrelated tumors.
They traced this effect to large, unusual, variant T lymphocytes, which soon got named natural killer cells. They make up anywhere from 5 to 10 percent of the blood's recirculating lymphocyte population. These maverick NKT enforcer cells turned out to be death for many human tumors and infectious viruses.
There was one historic exception: A young woman who completely lacked NKT cells in her immune system. Although her antibody and T cell counts were normal, she came down with repeated infection by varicella virus, which causes chickenpox, and life-threatening cytomegalovirus.
Just how NKTs get in their deadly anti-tumor and antiviral licks has remained largely an immunological mystery. Now, it appears that the main reason for NKT's existence is to fight off parasitic diseases, such as malaria, African sleeping sickness and leishmania.
An article in the Jan. 8, 1999, issue of Science tells that story in these terms: "CD1d-restricted immunoglobulin G formation to GPI-anchored antigens mediated by NKT cells." Its senior author is immunologist Louis Schofield, at Australia's Royal Melbourne Hospital.
In this research paper's title, the telltale words are "GPI-anchored antigens." GPI stands for "glycosylphosphatidylinositol," which is a widespread surface protein in the membrane of certain parasites. The co-authors report that, in their experiments, NKT cells latched onto this antigenic fragment of the molecule that anchors the parasite protein to its target cell's membrane. Then, partnered with another protein, CD1d, NKTs orchestrated a series of events that unleashed a death-dealing antibody attack against the three species of invasive parasite.
They speculate that this result may describe "a general mechanism for rapid ... antibody responses to diverse pathogens." In particular, they suggest, their findings may help efforts to develop a malaria vaccine. Previous attempts have been unable to induce an antibody response to malarial surface antigens.
Crystal Structure of E. coli's Protein Pores For Pumping Iron Hints At Antibiotic Resistance Ploys
Do you remember this ecological verse?
So, naturalists observe, a flea
Hath smaller fleas that on him prey;
And these have smaller still to bite 'em;
And so proceed, ad infinitum.
That food chain runs both ways, from the biggest flea through successive predators, all the way up to Homo sapiens. And in the opposite direction, all the way from the smallest flea down to bacteria, notably Escherichia coli. And every last mouth, from top to bottom, is open wide for a ration of elemental iron.
E. coli, the last consumer on the bottom of the iron totem pole, has the hardest time ingesting the iron it needs to stay alive. The bacterium expends a lot of energy opening and closing channels on its surface to admit the metal. So, biochemists have tethered a molecule of antibiotic onto the chelated-iron transporter protein, to force entry into the bacterial cell. (See BioWorld Today, May 23, 1997, p. 1.)
So far, so good - but not far enough. Even when the penicillin, for instance, smuggles its way inside the microorganism, bacterial drug resistance limits its germ-killing effect.
Enter the X-ray crystallographers. A paper in the January issue of Nature Structural Biotechnology carries the title: "Crystal structure of the outer membrane active transporter FepA from Escherichia coli." Its senior author is Johann Deisenhofer, at the University of Texas Southwest Medical Center, in Dallas.
That transporter receptor ferries an iron-laden protein across the organism's outer membrane pores into the periplasmic space. There, another protein ushers it through the inner membrane into the cytoplasm, where an enzyme releases the metal for E. coli's metabolic needs.
An editorial accompanying the article observed that "The importance of the [transporter] crystal structures to the field cannot be overstated. Outer membrane receptors ... enable not only the acquisition of iron from the environment, but also allow pathogens to obtain iron from their human hosts and allow antibiotics with structural similarities to siderophores to gain entry into bacteria."
In Wake Of Mad Cow Disease, Creutzfeldt-Jakob Cases Jumped From 10 In 1996 To 34 More Today
Bovine spongiform encephalitis (mad cow disease) broke out in Britain 11 years ago. Eight years later, in 1996, a variant form of Creutzfeldt-Jakob disease (CJD) had infected 10 people in Britain and France with a prion disease similar to that afflicting the British cattle. There is no treatment for man or beast, and after a long incubation period, the outcome is invariably fatal. Prion diseases feature accumulation of an abnormal prion protein in the tonsils and other lymphoreticular tissues of the body, on their way to invading the central nervous system.
Today, the number of CJD cases has risen by another 33 in the UK, and one in France.
This week's issue of The Lancet, dated Jan. 23, 1999, carries a paper titled: "Investigation of variant CJD and other human prion diseases with tonsil biopsy samples." The researchers tested 68 tonsil necropsy specimens from patients with prion disease, other neurological disorders, and normal controls.
They found that "all lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD ... were positive for [abnormal prions]." The co-authors made the point that in an appropriate clinical setting, a simple tonsil biopsy, if it contained abnormal prions, could diagnose CJD in living patients, rather than their postmortem tissue samples. n