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Published on: July 15, 2019
Viral interference during coinfection and sequential infection of enterovirus A71 and coxsackievirus A16
Hooi Yee Chang1, Kien Chai Ong2, Kartini Jasni3
1Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Malaysia.
Abstract:
Hand, foot and mouth disease (HFMD) is a common childhood infection caused by enteroviruses including enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16). These viruses often co-circulate, resulting in potential viral interference which could impact virus transmission, virulence, and EV-A71 vaccine effectiveness. Experimental evidence to support these findings is lacking. Epidemiology and seroprevalence data for EV-A71 and CVA16 reveal trends suggestive of viral interference between the two viruses. Coinfection with both EV-A71 and CVA16, or sequential infection of EV-A71 followed by CVA16, were performed in rhabdomyosarcoma (RD) cells and compared with single virus infection. In RD cells, coinfection did not affect virus replication while prior EV-A71 infection inhibited CVA16 replication at 24 h post-infection. BALB/c mice were infected with mouse-adapted EV-A71 (MP4), EV-A71 and CVA16 simultaneously or sequentially. In mice, coinfection reduced mortality (40 %) while prior EV-A71 infection reduced sequential MP4-induced (40 %) and CVA16-induced (20 %) mortality in contrast to 100 % mortality in single virus-infected mice. Coinfection reduced EV-A71 MP4 viral RNA in limbs and brains, triggering innate immune activation with altered interferon-stimulating genes (ISGs) and cytokine expression. Prior EV-A71 infection suppressed CVA16 replication in limbs and brains, caused limited histopathological changes and unchanged innate immune responses. Prior EV-A71 infection suppressed MP4 antigens as evidenced by histological findings and elevation of IFITM3, ISG15, RSAD2, interleukin (IL)-1β and IL-6 expressions. We have experimentally demonstrated viral interference between EV-A71 and CVA16 during coinfection and sequential infection. A coadministered or sequential EV-A71 and CVA16 vaccine could provide broad innate immune protection.
Insights
Viral interference between enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) was experimentally demonstrated. Prior EV-A71 infection protected mice against subsequent CVA16 infection, suggesting potential for combined vaccines.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by enteroviruses, notably enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16).
- These viruses frequently co-circulate, raising the possibility of viral interference impacting disease transmission, severity, and vaccine efficacy.
- Epidemiological data suggest potential interference between EV-A71 and CVA16, but experimental evidence is limited.
Purpose of the Study:
- To experimentally investigate viral interference between EV-A71 and CVA16 in cell culture and a mouse model.
- To assess the impact of coinfection and sequential infection on viral replication, mortality, and immune responses.
- To explore the potential for developing combined EV-A71 and CVA16 vaccines.
Main Methods:
- Coinfection and sequential infection experiments were conducted using rhabdomyosarcoma (RD) cells and BALB/c mice.
- Mice were infected with mouse-adapted EV-A71 (MP4) and/or CVA16, either simultaneously or sequentially.
- Outcomes measured included viral replication, mortality rates, viral RNA levels in tissues, histopathological changes, and innate immune gene/cytokine expression.
Main Results:
- In RD cells, prior EV-A71 infection inhibited CVA16 replication.
- In mice, coinfection reduced mortality, and prior EV-A71 infection significantly reduced mortality from subsequent EV-A71 or CVA16 infection compared to single infections.
- Coinfection altered innate immune responses in mice, while prior EV-A71 infection suppressed CVA16 replication and modulated specific immune gene expressions.
Conclusions:
- Experimental evidence confirms viral interference between EV-A71 and CVA16 during coinfection and sequential infection.
- Prior EV-A71 infection confers protection against subsequent CVA16 infection in a mouse model.
- A coadministered or sequential EV-A71 and CVA16 vaccine strategy could potentially offer broad innate immune protection against HFMD.
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