Reviews 31 Whittermore, S.R. and Seiger, A. (1987) The expression, local- 42 Brewster, W.J. et al. (1994) Diabetic neuropathy, nerve growth ization and functional significance of ␤-nerve growth factor in factor and other neurotrophic factors. Trends Neurosci. 17, the central nervous system. Brain Res. 12, 439–464 321–323 32 Bogen, S.A. et al. (1995) In situ analysis of cytokine responses 43 Abe, T., Morgan, D.A. and Gutterman, D.D. (1997) Protective in experimental murine schistosomiasis. Lab. Invest. 73, role of nerve growth factor against postischemic dysfunction 253–258 of sympathetic coronary innervation. Circulation 95, 213–220 33 Breder, C.D. et al. (1993) Distribution and characterization of 44 Levi-Montalcini, R. et al. (1975) Nerve growth factor induces tumor necrosis factor-␣-like immunoreactivity in the murine volume increase and enhances tyrosine hydroxylase synthesis central nervous system. J. Comp. Neurol. 337, 543–567 in chemically axotomized sympathetic ganglia of newborn 34 Tchelingerian, J.L., Vignais, L. and Jacque, C. (1994) TNF-␣ rats. Proc. Natl. Acad. Sci. U. S. A. 72, 595–599 gene expression is induced in neurons after hippocampal 45 Aloe, L. and Levi-Montalcini, R. (1979) Nerve growth factor lesion. NeuroReport 5, 585–588 induced overgrowth of axotomized superior cervical ganglia 35 Fiore, M. et al. (1996) Schistosoma mansoni: influence of infec- in neonatal rats. Similarities and differences with NGF effects tion on mouse behavior. Exp. Parasitol. 83, 46–54 in chemically axotomized sympathetic ganglia. Arch. Ital. Biol. 36 Fiore, M., Moroni, R. and Aloe, L. (1997) Removal of the sub- 117, 287–307 maxillary salivary glands and infection with the trematode 46 Rylett, R.J. and Williams, L.R. (1994) Role of neurotrophins in Schistosoma mansoni alters exploratory behavior and pain cholinergic-neurone function in the adult and aged CNS. thresholds in female mice. Physiol. Behav. 62, 399–406 Trends Neurosci. 17, 486–488 37 Isseroff, H. et al. (1989) Schistosomiasis: role of endogenous 47 Siliprandi, R., Canella, R. and Carmignoto, G. (1993) Nerve opioids in suppression of gonadal steroid secretion. Comp. growth factor promotes functional recovery of retinal ganglion Biochem. Physiol. 94A, 41–45 cells after ischemia. Invest. Ophthalmol. Vis. Sci. 34, 3232–3236 38 Alleva, E., Aloe, L. and Bigi, S. (1993) An updated role for 48 Fisher, W. et al. (1987) Amelioration of cholinergic neuron nerve growth factor in neurobehavioural regulation of adult atrophy and spatial memory impairment in aged rats by nerve vertebrates. Rev. Neurosci. 4, 41–62 growth factor. Nature 329, 65–68 39 Olton, D.S. and Markowska, A.L. (1994) Memory and hip- 49 Phelps, C.H. et al. (1989) Potential use of nerve growth factor to pocampal function as targets for neurotoxic substances. treat Alzheimer’s disease. Neurobiol. Aging 10, 205–207 Neurotoxicology 15, 439–444 50 Holtzman, D.M. et al. (1993) Nerve growth factor reverses 40 Anand, P. (1995) Nerve growth factor regulates nociception in neuronal atrophy in a Down syndrome model of age-related human health and disease. Br. J. Anaesth. 75, 201–208 neurodegeneration. Neurology 43, 2668–2673 41 Owen, D.J., Logan, A. and Robinson, P.P. (1989) A role for 51 Aloe, L. (1987) Intracerebral pretreatment with nerve growth nerve growth factor in collateral reinnervation from sensory factor prevents irreversible brain lesions in neonatal rats nerves in the guinea pig. Brain Res. 476, 248–255 injected with ibotenic acid. BioTechniques 5, 1085–1086 How Does Trichinella spiralis Make Itself at Home? D.D. Despommier The nurse cell–parasite complex of Trichinella spiralis Trachipleistophora hominis, Sarcocystis sp. and Hepatazoa is unlike anything else in Nature. It is derived from a sp.) have succeeded. A smaller number of helminth normal portion of striated skeletal muscle cell and develops species, mostly larval stages of cestodes, and even in a matter of 15 to 20 days after the larva invades that fewer species of larval nematodes, have found a cell type. What are the molecular mechanisms at work home there. that result in this unique relationship? Here, Dickson Nematodes in the genus Trichinella are the re- Despommier presents a hypothesis to account for its markable exception, with five recognized species formation, in which secreted tyvelosylated proteins of the (Trichinella spiralis, T. nativa, T. britovi, T. nelsoni and larva play a central role. These proteins are always present T. pseudospiralis)3, and more likely to achieve species in the intracellular niche of the larva from Day 7 after status, that not only live and thrive there, but have in infection and may be responsible for redirecting host all likelihood evolved complex strategies for remodel- genomic expression, leading to nurse cell formation. ing that niche4 into one that they can occupy for many months to years. Unlike the majority of intra- The list of parasites infecting humans is long and rich cellular parasites, Trichinella occupies the host cell in species diversity. Within each of us, numerous fun- without killing it, and thus it is considered one of the damental niches tempt the uninvited. While striated most successful of all parasitic symbionts, because it skeletal muscle tissue ranks as one of the most abun- is this strategy that enables it to travel world-wide dant1, only a handful of protozoans and helminths and extend its range into all parts of the earth in have been successful in colonizing this niche2. For which the scavenging of carrion occurs. example, among the numerous species of protozoa, By what mechanism(s) does this nematode accom- only a few (eg. Trypanosoma cruzi, Toxoplasma gondii, plish its goal of long-term survival? As alluded to, one plausible hypothesis4 states that the parasite is Dickson D. Despommier is at the Division of Environmental responsible for remodeling the muscle cell, and does Health Sciences and Department of Microbiology, Columbia so by secreting a variety of proteins into its intra- University, 630 West 168th St, New York City, NY 10032, USA. cellular niche, resulting in a reprogramming of host Tel: +1 212 305 5014, Fax: +1 212 305 4496, genomic expression. There are several lines of indi- e-mail: [email protected] rect evidence in support of this view, in addition to 318 Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(98)01287-3 Parasitology Today, vol. 14, no. 8, 1998 Reviews the fact that no other skeletal muscle cell myopathy methods, and was demonstrable within the nurse cell remotely resembles the complexity of permanent from that point on. Thus, the VEGF gene remains changes associated with those encountered during upregulated throughout the infection period, while nurse cell formation. the mRNA signal appears to be strongest at Day 15. A The hypothesis predicts that after the larva enters constant, low level of production of VEGF peptide the muscle cell it assumes the role of both architect (also known as vascular permeability factor) after cir- and construction foreman, informing the host via its culatory rete formation is complete implies a perma- peptides how to go about changing its new surround- nently heightened state of vascular permeability, and ings. The result is the nurse cell4, a dramatically would present obvious advantages to the parasite for altered portion of infected myocyte devoid of muscle- maintaining itself within the host for long periods of specific proteins (Fig. 1a) that is multinucleated (Fig. time. 1b), and whose presumed function is to support the The vessels of the circulatory rete are now known growth, development and maintenance of the para- to be derived from adjacent venules, not arterioles as site throughout its life in that essential niche. Figures was thought previously4, and they have the diameter 1 and 2 summarize some of the modifications that the of sinusoids, thus facilitating the rapid flow of formed host cell undergoes over the 15–20 day period during elements through them. The large diameter of the which the nurse cell developmental program is up- vessels, compared with capillaries, also favors rapid regulated. Each graphic represents a summary of data exchange of nutrients and wastes, but offers less than gathered from a variety of laboratories. optimal conditions for the efficient exchange of gasses between the nurse cell and the red blood cells that Capsule collagen synthesis circulate past it. These observations are consistent The nurse cell–parasite complex is surrounded by with data collected from a variety of experimental ap- a collagen capsule5 and consists predominantly of proaches indicating that larval and nurse cell (Fig. 1c) two collagen types, IV and VI (Fig. 1d and e), both of energy metabolism are anaerobic15. This metabolic which are synthesized by the nurse cell6. Parasite strategy explains how the parasite remains infectious secretion of proteins within the matrix of the infected for another host (ie. scavengers) from days up to host cell begins on Day 7 after infection7 (Fig. 1h). The weeks after the death of the infected host (depending onset of host collagen type IV and type VI mRNA upon the ambient temperature) in its decaying muscle synthesis is between Days 7 and 8. By Day 8, parasite tissue – the ultimate in anaerobic environments. This peptides localize to the nucleoplasm of all enlarged phenomenon is also seen under laboratory conditions16. nurse cell nuclei7,8. Hence, upregulation of these two host genes is temporally coincident with peptide Information exchange secretion. Throughout the period of collagen synthe- The comparison between building a house and sis, all enlarged nuclei remain transcriptionally active, constructing a nurse cell is an especially attractive resulting in the overexpression of these two collagen one, because at the heart of the relationships between proteins. Collagen type IV synthesis then ceases on the host and the parasite and a new home buyer and about Day 26, while synthesis of type VI collagen their contractor is the requirement that they commu- continues throughout the infection at a low level6.