Pathogenesis study of enterovirus 71 infection in rhesus monkeys

Abstract

Enterovirus 71 (EV71), a major pathogen that is responsible for causing hand-foot-and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. HFMD that is caused by EV71 is usually characterized by vesicular lesions on the skin and oral mucosa and high morbidity rates in children; additionally, occasional fatal cases have been reported involving brainstem encephalitis and myelitis associated with cardiopulmonary collapse. Although viral pathogenesis in humans is unclear, previous animal studies have indicated that EV71, inoculated via various routes, is capable of targeting and injuring the central nervous system (CNS). We report here the pathogenic process of systemic EV71 infection in rhesus monkeys after inoculation via intracerebral, intravenous, respiratory and digestive routes. Infection with EV71 via these routes resulted in different rates of targeting to and injury of the CNS. Intracerebral inoculation resulted in pulmonary edema and hemorrhage, along with impairment of neurons. However, intravenous and respiratory inoculations resulted in a direct infection of the CNS, accompanied by obvious inflammation of lung tissue, as shown by impairment of the alveoli structure and massive cellular infiltration around the terminal bronchioles and small vessels. These pathological changes were associated with a peak of viremia and dynamic viral distribution in organs over time in the infected monkeys. Our results suggest that the rhesus monkey model may be used to study not only the basic pathogenesis of EV71 viral infections, but also to examine clinical features, such as neurological lesions, in the CNS and pathological changes in associated organs.

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

“…The ability to further our knowledge of EV71 and to develop effective prophylactic and therapeutic approaches has been severely hampered by the lack of a relevant animal model, a deficit resulting from the limited species tropism of EV71. Experimental infection of rhesus and cynomolgus monkeys has been reported, but their use is limited for ethical and economical reasons (6,15,17,41). Furthermore, EV71-infected monkeys do not develop any typical neurological complications, including flaccid paralysis and ataxia, while only 10% of infected animals develop clinical symptoms, which is in agreement with reports of human patients but impractical at the experimental level.…”

Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon

“…Moreover, the presence of EV71 in the blood of wild-type mice, but not miR146a À / À mice, at 3 d.p.i. indicated that viremia occurred only in wild-type mice and that miR-146a knockdown restricted the spread of EV71 [49][50][51] . These data implied that a systemic EV71 infection occurred in wild-type mice but not in miR-146a À / À and IFIT1 (n ¼ 3) (g) in mEV71-infected wild-type or miR-146a À / À mice (mouse tissue samples pooling, n ¼ 4).…”

“…The mice were infected with mEV71 through the natural oral route, and the clinical signs, including paralysis, loss of body weight, mortality and even pulmonary edema, were similar to those in human beings 4,[8][9][10][47][48][49][50][51] . However, certain pathological observations in the EV71 infection mouse model were not clinically confirmed in human beings.…”

Dynamic Constitution of the Pathogens Inducing Encephalitis in Hand, Foot and Mouth Disease in Kunming, 2009–2011

“…In recent years, hand, foot and mouth disease (HFMD) has emerged as one of the major epidemic communicable diseases in children in Asian-Pacific countries (1)(2)(3)(4)(5). It manifests as vesicles on the hands, feet, and mouth; herpangina and other cold-like symptoms, and it is occasionally associated with severe encephalitis and cerebromeningitis, which pose a major threat to patients (6)(7)(8)(9).…”