Are North American Bunyamwera serogroup viruses etiologic agents of human congenital defects of the central nervous system?

In 1941 Gregg provided the first evidence that rubella virus (family Togaviridae, genus Rubivirus) causes human congenital defects (1). Although rubella virus infection usually causes a mild disease comprising fever and rash, rubella epidemics have been associated with congenital defects in children of women who became infected during their first trimester of pregnancy (2). The risk of in utero rubella infection was reduced by the introduction of safe and effective vaccines for women of child-bearing age. Congenital abnormalities in fetal or neonatal ruminants also are related to exposure of pregnant dams to various viruses, including bovine viral diarrhea virus (family Togaviridae, genus Pestivirus), the arthropod-borne bluetongue viruses (family Reoviridae, genus Orbivirus), Wesselsbron virus (family Flaviviridae, genus Flavivirus), Rift Valley fever virus (family Bunyaviridae, genus Phlebovirus), Nairobi sheep disease virus (family Bunyaviridae, genus Nairovirus), and Akabane and Aino (family Bunyaviridae, genus Bunyavirus, Simbu serogroup) viruses (3-10). Infections of livestock with these viruses may produce low-titer viremia with no apparent clinical disease, or high-titer viremia and severe clinical illness in the dam. In utero infections may result in malformations of the developing fetus, fetal death with resorption, mummification, or miscarriage. Stillborn ruminants may show various musculoskeletal and central nervous system defects, including a syndrome of arthrogryposis with hydranencephaly (AGH). Bunyamwera serogroup viruses (family Bunyaviridae, genus Bunyavirus) have been isolated from humans, and some, including Cache Valley (CV) and Tensaw (TEN) viruses, have been isolated from symptomatic and asymptomatic large mammals (11). Antibodies to CV virus and other viruses of the Bunyamwera serogroup are prevalent in livestock and large wild mammals and in humans in the Western Hemisphere from Alaska to Argentina (11). Viruses of this serogroup are isolated primarily from mosquitoes of the genera Aedes and Anopheles. These viruses have focal geographic distributions, although some are found over great expanses. CV virus, a common North American bunyavirus, has been isolated principally from mosquitoes of the genera Culiseta, Aedes, and Anopheles. The geographic distribution of this virus includes all North America, except the extreme southeastern states and southern Mexico (11). In the southeastern United States, TEN virus, also isolated from mosquitoes of the genera Anopheles and Aedes, is the only known representative of the Bunyamwera serogroup, probably because of the range of the principal vectors and vertebrate hosts; mutual exclusion of these two viruses likely occurs because of cross-protectivity between them (12). Serologic and temporal associations of infection with CV virus and congenital malformations, including primarily AGH, were observed in sheep near San Angelo, Texas, between December 1986 and February 1987, suggesting that this virus causes AGH (13). Subsequent outbreaks of similar congenital defects occurred in sheep in Illinois in 1988 (J. Pearson, pers. comm.) and in North Dakota, Pennsylvania, Maryland, Michigan, and Nebraska in 1986 and 1987 (14). Antibody to CV virus (but not to other viruses) was found to correlate significantly with the occurrence of AGH and other congenital anomalies during the Texas outbreak (15, 16), and IgM antibody to CV virus was detected in colostrum-free neonates with AGH (C.H. Calisher, unpublished data). (Neither maternal IgM nor maternal IgG crosses the placenta in sheep; therefore, antibody in fetuses or in neonates before they received colostrum indicates fetal exposure to an infectious agent [17].) In 1976, antibody to CV virus was detected in serum from cattle that had delivered calves with AGH in Saskatchewan, Canada, in 1975; however, the prevalence of antibodies to CV virus in the bovine population of that area was not investigated (R.E. Shope, pers. comm.). In Texas, in 1981, CV virus was isolated from a sick sheep and from a healthy cow in a herd with reproductive problems (18). This virus also was isolated in Texas in 1988 from a sentinel sheep in pasture where an outbreak of congenital defects had occurred in 1986 to 1987. These historical data suggest that Dispatches