Multiple viruses, bacteria, and parasites can infect the developing human fetus, resulting in a range of outcomes that include fetal demise, developmental anomalies, and disease of the newborn [1
]. Disease may also be clinically silent at birth and not become evident until after the first few months or years of life. Factors important in determining outcome include pathogen identity, gestational timing of infection, pathogen load, tissue tropism, inflammatory response, and immune status of the mother and fetus.
For example, human infection with the rubella virus during the first 11 weeks of gestation results in teratogenic changes in most fetuses that survive the acute infection, with abnormalities commonly detected in the heart, eye, and central nervous system [2
]. At later times in gestation (11–16 weeks), infection is less likely to result in congenital anomalies, but may still result in hearing loss, mental retardation, and growth deficits [3
]. Sequelae from congenital rubella may become manifest at even later times of postnatal life, with insulin-dependent diabetes apparent in up to 20% of infected humans by adulthood [4
]. Although congenital infections caused by rubella virus have been greatly decreased as a consequence of vaccination, effective vaccines are not available for infections caused by other pathogens, such as cytomegalovirus, which are also important causes of congenital infection.
Perinatal infection by less common or emerging pathogens may become increasingly prevalent. One such emerging viral pathogen is lymphocytic choriomeningitis virus (LCMV), an arenavirus that has been increasingly recognized as a teratogen in recent years [5
LCMV was initially isolated by Armstrong and Lillie in 1933 [12
] from the cerebrospinal fluid of a woman who was thought to have St. Louis encephalitis. This patient had presented with general malaise, but her condition worsened, and she died. The virus isolated from her cerebrospinal fluid was passaged five times through monkeys and, with each passage, produced a disease resembling St. Louis encephalitis. On the sixth passage, the virus was inoculated into a monkey that was immune to St. Louis encephalitis. However, the virus still produced the disease, indicating that the virus was not St. Louis encephalitis virus. This new infectious agent was named “lymphocytic choriomeningitis virus” for the pathologic changes that it induced in the choroid plexus and meninges of infected mice and monkeys [12
The virus was subsequently isolated from cerebrospinal fluid of multiple patients with aseptic meningitis. Thus, it was established that LCMV was an important etiologic agent of aseptic meningitis in humans. Subsequent clinical and etiologic studies identified LCMV as one of the most frequent infectious causes of aseptic meningitis in humans [13
The first recognized case of congenital infection with LCMV was reported in England in 1955 [14
]. In the decades that followed, multiple cases of congenital LCMV infection were reported throughout Europe [15
]. Although LCMV has been recognized as an important cause of aseptic meningitis in the United States for decades, the first cases of congenital LCMV infection were not reported in the United States until 1993 [17
Like all arenaviruses, LCMV utilizes rodents as its principal reservoir [19
]. Mus musculus
, the common house mouse, is both the natural host and reservoir for the virus, which is transferred vertically from one generation to the next within the mouse population by intrauterine infection. Although heavily infected with LCMV, mice that acquire the virus prenatally often remain asymptomatic because the virus is not cytolytic and because congenital infection provides the mice with immunological tolerance for the virus [22
]. Throughout their lives, mice prenatally infected with LCMV shed the virus in large quantities in nasal secretions, saliva, milk, semen, urine, and feces.
Postnatal humans acquire LCMV by inhalation of aerosolized virus or by direct contact with fomites contaminated with infectious virus. LCMV infection during postnatal life (childhood or adulthood) typically consists of a brief febrile illness from which the patient fully recovers. Symptoms include headache, fever, myalgia, photophobia, and vomiting. In as many as one-third of postnatal infections, the disease is asymptomatic.
Human-to-human horizontal infection has not been documented, except for the unusual circumstances in which the virus was acquired through transplantation of infected tissues [24
]. In contrast, human-to-human vertical transmission does occur and is the basis for congenital LCMV infection.
Because LCMV is prevalent in the environment and has a great geographic range, the virus infects large numbers of humans. An epidemiologic study has demonstrated that 9% of house mice in urban Baltimore are infected with LCMV, and that substantial clustering occurs where the prevalence is higher [25
]. Serological studies have demonstrated that 5.1% of healthy black women in Birmingham and 4.7% of adults in Baltimore possess antibodies to LCMV, indicating prior exposure and infection [25
The prevalence and incidence of congenital LCMV infection are unknown. While case reports of infection during pregnancy demonstrate that LCMV can induce severe defects in brain structure and function [6
], it is not known whether the profoundly affected infants described in the case reports represent the typical outcome of gestational LCMV infection, or whether they represent only the most severely affected cases. Prospective clinical or epidemiological studies of congenital LCMV infection have not been conducted. The fact that LCMV is not one of the infectious agents for which infants with a suspected congenital infection are routinely evaluated further limits information regarding the incidence and spectrum of LCMV-induced teratogenicity. Therefore, congenital LCMV infection might produce a spectrum of pathologic effects ranging from minimal to severe [11
]. The high prevalence of infected mice and of sero-positive postnatal humans suggest that congenital LCMV infection is an underdiagnosed disease and that the virus is responsible for more cases of congenital neurologic and vision dysfunction than has previously been recognized [6
Transplacental infection of the fetus is the basis for most cases of congenital LCMV infection, presumably during maternal viremia [5
]. In some cases, the fetus may acquire LCMV during the intrapartum period [14
]. Within the human fetus, the brain is the principal target of LCMV infection and the most important site of pathology [8
]. Mitotically active neuronal precursors are particularly vulnerable to LCMV infection and an important site of LCMV replication [5
]. Microencephaly, periventricular calcifications, gyral dysplasia, cerebellar hypoplasia, and focal cerebral destruction are common pathologic effects of congenital LCMV infection [11
]. These pathologic changes reflect both the viral tropism for replicating neuroblasts and disrupted brain development induced by loss or dysfunction of immature or replicating neurons [5
]. The mechanism by which LCMV damages the fetal human brain is unknown. LCMV is not a cytolytic virus in most cell types, including neurons. Thus, unlike herpes and several other pathogens that directly damage the brain by killing host brain cells [1
], LCMV neuroteratogenicity must have some other underlying pathogenesis [30
Progress toward understanding the pathogenesis of most perinatal infections is limited by the absence of animal models that mirror human disease. However, this is not the case for congenital LCMV infection. Neonatal rats infected with LCMV develop virtually all of the neuropathological abnormalities observed in infected humans [29
], including, but not limited to encephalomalacia (), disrupted neuronal migration (), and periventricular infection (). Most strikingly, the rat model of LCMV illustrates the complex interactions among timing of infection relative to animal age, cellular tropism, and the host immune response in determining acute disease and ultimate outcome [30
LCMV Infection Induces Focal Destructive Lesions within the Developing Brains of Humans and Rats
LCMV Infection Disrupts Neuronal Migration in the Developing Brain of Humans and Rats
Congenital LCMV Infection of Humans Induces Periventricular Calcifications
In the rat model, rat pups receive intracerebral injections of LCMV during the neonatal period [30
]. Postnatal rat pups model human congenital LCMV infection because the rat brain is immature at the time of birth, relative to the human brain [33
]. Thus, in terms of brain development, the first two postnatal weeks in the rat mimic the second half of human gestation [34
The neonatal rat model of congenital LCMV infection was pioneered by Monjan and coworkers during the 1970s and early 1980s. They discovered that LCMV induces a distinct pattern of infection in which certain neuronal populations are infected, while others are spared [31
]. They further found that the virus can induce retinopathy [35
], cerebellar destruction [32
], disrupted neurotransmission [36
], and altered behavior [37
]. In addition, they found that much of the pathology induced by LCMV is immune-mediated [38
]. This finding of an important role for the immune system in LCMV infection of the neonatal rat complemented the many landmark studies by others over the past 70 years, in which immunologists and virologists have utilized LCMV to gain a deeper understanding of immunology and immunopathology [39
]. Recently, interest in the neonatal rat model of LCMV infection has been re-ignited, as the importance of human congenital LCMV infection and the value of the rat model system for studying that infection have become clear.