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Active immunity and maternally transmitted passive immunity to respiratory syncytial virus (RSV) were studied in cotton rats. Animals infected with respiratory syncytial virus developed complete resistance to pulmonary reinfection, which lasted at least 18 months. Nasal resistance was of shorter duration and began to diminish in 8 months. Pulmonary resistance was transferred by parabiosis, but nasal resistance was not. Adoptive transfer studies with fractionated convalescent blood showed that serum antibody, but not circulating lymphocytes, conferred pulmonary resistance. Immune females conferred antibody to their young prenatally and postnatally, with most of the antibody being transferred via colostrum and milk. Maternally transmitted immunity was more effective in the lungs than in the nose and was transient in both organs. Foster nursing experiments showed colostrum and milk to be the most important routes of immune transfer. Although resistance in infants generally correlated with serum neutralizing antibody levels, several exceptions to this correlation suggested that immune factors other than neutralizing antibody may also play an important role in maternal passive immunity.

The cotton rat Sigmodon hispidus has provided an animal model of adenovirus pneumonia that permits investigation of the viral gene products required to produce the disease and the molecular mechanisms effecting the damage. This study was One utility of the modern techniques of virology and molecular biology should be to reveal the basic molecular mechanisms by which viruses such as adenoviruses produce disease. The discovery that intranasal inoculation of type 5 adenovirus (AdS) into cotton rats results in development of a pneumonia that pathologically simulates that produced in humans (1) provided the opportunity to determine the viral gene functions required to produce the pneumonia and the molecular mechanisms by which the virus induced the disease. Extensive studies have been carried out on the replication of adenovirus in the lungs of the Sigmodon hispidus species of cotton rats and on the relationship of viral multiplication to the development of pneumonia (2, 3). Productive viral replication was only detected in the epithelial cells of the bronchi and bronchioles of the lung and the nasal mucosa. Onset of viral multiplication, which reached maximum titers 2-4 days after infection (depending upon the size of the inoculum), was soon followed by progressively increasing peribronchial, perivascular, and alveolar septal infiltration of lymphocytes and monocyte/macrophages and finally by lymphocytic infiltration of the basal bronchiolar wall into the epithelium; scattered polymorphonuclear leukocytes (PMN) were also present (2, 3). The maximum pathology was attained 5-7 days after infection, which was also dependent upon the viral inoculum. The use of conditionally lethal, temperature-sensitive mutants [e.g., H5ts125 (4)] unable to replicate their DNA at the cotton rat's normal body temperature, about 39.2°C, led to unexpected results: the cellular inflammatory response was the same as in wild-type (Wt) virus-infected lungs, although quantitatively not as extensive. These data indicate that only early gene products appear necessary to induce the inflammatory response to viral infection. It was further demonstrated that the E1B 58-kDa protein, which is required to shut off host protein synthesis during adenovirus productive infection (5, 6), is also essential for producing maximum viral pneumonia (3).Early region 3 (E3) has been termed a "nonessential" region since naturally occurring mutants or hybrid viruses in which almost the entire region is deleted still replicate like Wt virus in cultured cells (7). It seemed unlikely that almost 10% of the genome would have survived in evolution if its encoded genes did not play a significant role in the virus's life cycle. Therefore, extensive studies were done to determine whether the E3 region might play a critical role in pathogenesis. It is the objective of this communication to report the results of that investigation. Data will be presented to show that gene products of the E3 region do in fact play a strategic role in viral pathogenesis. However, their ...

Cotton rats previously inoculated with Formalin-inactivated respiratory syncytial virus (RSV) were challenged intranasally with live RSV to induce an enhancement of RSV disease similar to that observed after the administration of Formalin-inactivated RSV vaccine to human infants 20 years ago. Within 24 h after infection with RSV, cotton rats developed pulmonary lesions that reached a maximum by day 4. Histologically, the lesions resembled an experimental pulmonary Arthus reaction. An action of Formalin on RSV appears to be responsible for this effect, because live virus or virus heated in the absence of Formalin did not induce enhanced immunopathology. Selected epitopes on the fusion (F) or attachment (G) or both RSV surface glycoproteins that are involved in inducing neutralizing antibodies were modified to reduce or ablate their antigenicity. However, other epitopes on the F or G or both glycoproteins were not ablated by Formalin, because cotton rats inoculated parenterally with a Formalin-inactivated virus developed a high level of F and G antibodies measurable by an enzyme-linked immunosorbent assay. At this time, the effect of Formalin on RSV cannot be localized to either the F or G glycoprotein of RSV.