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Enterovirus 71 directly infects human natural killer cells and induces cell apoptosis

Enterovirus 71 (EV71) belongs to the Enterovirus genus of the family Picornaviridae and

is the major causative agent of hand, foot and mouth disease (HFMD). Although clinical

manifestations of HFMD are usually mild and self-limiting, severe HFMD patients suffer

from a diverse array of neurological diseases and sometimes these diseases are fatal.

HFMD usually occurs in young children and gradually becomes a new threaten in Asia.

Unfortunately, effective EV71 vaccine is not available to date and alternative treatments

are still in debate. This is partially due to the lack of understanding of EV71 pathogenesis

and host immune responses against EV71.



Natural killer (NK) cells are key effector cells in host antiviral activities by directly killing

viral-infected cells and producing cytokines and chemokines, especially in early phase of

viral infection. After enteroviruses infection, NK cells were one of the most abundant cell

types in the inflammatory infiltrate, and appeared to limit both enteroviruses replication

and virus-induced disease in experimental mice model. However, role of human NK cells

during EV71 infection, especially the direct interaction between EV71 and human NK

cells, was not studied extensively. Clinical observation manifested that patients with severe

EV71 infection have marked diminished NK cells in peripheral blood. Therefore we

hypothesized that EV71 might directly target human NK cells as one of its immunoevasion

strategies.



Here, we demonstrated for the first time that fresh primary human NK cells were

susceptible to EV71 infection. By flow cytometry and florescence microscope, EV71

capsid protein VP1 was able to be detected in viral-infected NK cells as soon as 6 hours

after infection and peaked at 24 hour after infection. In the same time, EV71 viral RNA

was detected by quantitative RT-PCR and the viral copies increased from 6 hour onwards

to peak at 12 hours after infection. We further demonstrated the infectious entry of EV71

in human NK cells was depended on clathrin-mediated endocytosis. Next, we illustrated

that EV71 infection could trigger NK cells apoptosis as evidenced by increased Annexin

V+, PI+, and activated caspase 3+ cells in EV71-treated NK cells. We further proved that

the cytotoxicity of NK cells was inhibited by EV71 infection and this inhibition might not

be related with down-regulation of NKp46, but may be related to the increased apoptosis.

In conclusion, our data suggested that EV71 might directly target and kill NK cells as a

strategy to evade human innate immunity, which might facilitate virus replication,

transmission and then contribute to viral-related pathogenesis. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Identiferoai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/208428
Date January 2011
CreatorsLiang, Huyi, 梁湖沂
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Source SetsHong Kong University Theses
LanguageEnglish
Detected LanguageEnglish
TypePG_Thesis
RightsCreative Commons: Attribution 3.0 Hong Kong License, The author retains all proprietary rights, (such as patent rights) and the right to use in future works.
RelationHKU Theses Online (HKUTO)

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