Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

Abstract

Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. Infection can cause severe neurological, cardiac, and respiratory problems in children under the age of 5. Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host–viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions.

Immune responses against enterovirus A71 infection: Implications for vaccine success

“…Pattern recognition receptor (PRR) sensing against the pathogen‐associated molecular patterns (PAMPs) will activate the transcription of genes involved in inflammatory cytokine responses. A few comprehensive papers have described the innate signalling of enteroviruses and EV‐A71 . The term cytokine storm is used to describe the excessive secretion of inflammatory cytokines that results in massive tissue damage.…”

“…A few comprehensive papers have described the innate signalling of enteroviruses and EV-A71. [103][104][105][106][107] The term cytokine storm is used to describe the excessive secretion of inflammatory cytokines that results in massive tissue damage.…”

TREM-1 activation is a key regulator in driving severe pathogenesis of enterovirus 71 infection

“…Outbreaks of HFMD are caused by human enterovirus group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus 71 (EV71) (1, 4, 5). While often benign and self-limiting (2), the disease can cause cardiopulmonary and neurological complications such as myocarditis, brainstem encephalitis, aseptic meningitis, and neurogenic pulmonary edema, which can be fatal (6, 7). The severe manifestations of HFMD are often associated with cases of EV71 infections, rather than coxsackievirus A16 (8).…”

“…First isolated in California, USA, in 1969 (11), the virus is transmitted via the oral-fecal route, saliva and respiratory secretions (12). Based on the sequence analysis of VP1 gene, the virus can be broadly categorized into six genogroups: A, B, C, D, E and F (7, 10, 13). Whereas genogroup A contains the Californian prototype virus BrCr, genogroups B and C consist of various strains, and are further categorized into sub-genogroups B0-B5 and C1-C5 (10).…”

“…Whereas genogroup A contains the Californian prototype virus BrCr, genogroups B and C consist of various strains, and are further categorized into sub-genogroups B0-B5 and C1-C5 (10). B and C genogroups are globally distributed, whereas D, and E and F are limited to India and Africa respectively (7, 10). After the almost total eradication of poliovirus, EV71 is now noted as one of the most prevalent neurotropic enteroviruses, and is especially endemic in the Asia-Pacific region (14–17).…”