Baculoviruses establish systemic infections within susceptible insect hosts, even though host tissues are surrounded by basal lamlnae, extracellular matrices that exclude particles smaller than these viruses. Using a recombinant Autgrapha californwca M nuclear polyhedrosis virus containing a lacZ reporter gene under the control of a constitutive promoter, we followed the progression of infection in Tichoplusia ni larvae. We discovered that infection of the larval insect tracheal system (and not hemocytes, as thought previously) provides the major conduit for this virus to pass through basal laminae and to spread throughout the host. Tracheal epidermal cells, the only known cellular components of the tracheal system, share a common lymph system. Locally these cells contact one another by interdigitating cytoplasmic extensions called epidermal feet. These two features of the tracheal system are likely to facilitate the rapid systemic spread of the virus. The findings reported here have major implications for the fields of insect pathology and biological control and usher in an important consideration regarding host-range factors.Nuclear polyhedrosis viruses (NPV) (family Baculoviridae) are enveloped double-stranded DNA viruses that infect only arthropod hosts, primarily lepidopteran insect larvae. NPVs are unusual among viruses because they produce two phenotypes, one that transmits infection between hosts and one that spreads infection within the host. The first phenotype consists of one or more enveloped virions, each containing one or more nucleocapsids sequestered within a crystalline matrix ofprotein. Such viral occlusions are called polyhedra. As with the spore stages of many bacteria and fungi, polyhedra resist desiccation and allow for temporal escape from inhospitable environments. After ingestion by susceptible larval insect hosts, polyhedra rapidly dissociate in the alkaline gut juices and release occlusion-derived virus (ODV). Even though ODV lack surface spikes or peplomers, they enter midgut columnar epithelial cells by membrane fusion (1-3). These infected epithelial cells produce the second phenotype, budded virus (BV), which buds through the basal cell membrane at sites containing gp64, a viral-encoded glycoprotein that forms spikes on the surface of BV. These gp64-containing structures mediate entry of BV into target cells by promoting fusion of the BV envelope and endocytic vesicular membranes (4-6).Early investigations of baculovirus infections focused on host pathology and the potential use of baculoviruses for biological control purposes. Accurate descriptions of the progression of pathogenesis in virus-infected insects, however, were hampered by the limits of the light and electron microscopy techniques commonly used, both with and without accompanying immunohistochemistry. Rare events are difficult to capture by using these techniques because they require meticulous serial sectioning and the three-dimensional reconstruction of hundreds, if not thousands, of sections for each insect....
Neurofibromatosis 1 (NF1) is a common genetic disorder characterized by abnormalities of tissues derived from the neural crest. To define germ-line mutations in the NF1 gene, we studied 20 patients with familial or sporadic cases of NF1 diagnosed clinically and one patient with only café-au-lait spots and no other diagnostic criteria. A protein truncation assay identified abnormal polypeptides synthesized in vitro from five RT-PCR products that represented the entire NF1 coding region. Truncated polypeptides were observed in 14 individuals. The mutations responsible for the generation of abnormal polypeptides were characterized by DNA sequencing. Thirteen previously unpublished mutations were characterized in the 14 individuals. The mutation 2027insC was observed in two unrelated individuals; the other 12 mutations were unique. The sequence changes included seven nonsense and four frameshift mutations that created premature translation termination signals, and two large in-frame deletions that led to the synthesis of truncated polypeptides. One of the mutations was found in the child with a single clinical diagnostic criterion, providing her with a presumptive diagnosis of NF1. Our results confirm that truncating mutations are frequent in both familial and sporadic NF1 cases. The identification of mutations in 14 of 21 individuals studied (67%) suggests that the use of protein truncation assays will rapidly accelerate the rate of identification of NF1 mutations. Because we scanned the entire NF1 coding region in each individual, the distribution of NF1 truncating mutations was discerned for the first time. The mutations were relatively evenly distributed throughout the coding region with no evidence for clustering.
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