Zika: Investigating the link between Zika virus infection and neurological disease in ex vivo and in vivo models
Lead Research Organisation:
University of Liverpool
Department Name: UNLISTED
Abstract
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Technical Summary
The link between Zika virus (ZIKV) infection and neurological disease is not established, and
this proposal will seek to investigate this link using both in vivo models and ex vivo human
tissue. Reports have demonstrated the presence of ZIKV in the brain and placenta of babies
born to women who were infected during pregnancy (Mlakar et al. 2016), but these case
studies remain limited. The complete viral genome has also been recovered from the foetal
brain. Importantly, there seems to be different outcomes of infection in Brazil compared to
cases from the Pacific Islands, South-East Asia, and African. Although the focus has been on
the potential link with microcephaly, ZIKV has also been implicated in other neurological
complications such as Guillain-Barre syndrome (Oehler et al. 2014), with evidence of virus in
the spinal fluid (Brasil et al, under review, Lancet). Development of microcephaly and ZIKVassociated
neurological disease has been associated with the host response through
inflammation and autophagy. Classically Koch’s postulates have not been fully established
for virus infection of humans. Over the past year we have optimised the virus production set
up for ZIKV (see accompanying figure), and also developed a novel mouse model that has
been infected with different isolates. In this proposal, we will use the mouse model to
investigate whether different ZIKV isolates cause neurological disease. This will be correlated
with infection of primary human tissues representing the proposed route of infection: skin,
blood and neuronal tissues in the foetus and adult.
this proposal will seek to investigate this link using both in vivo models and ex vivo human
tissue. Reports have demonstrated the presence of ZIKV in the brain and placenta of babies
born to women who were infected during pregnancy (Mlakar et al. 2016), but these case
studies remain limited. The complete viral genome has also been recovered from the foetal
brain. Importantly, there seems to be different outcomes of infection in Brazil compared to
cases from the Pacific Islands, South-East Asia, and African. Although the focus has been on
the potential link with microcephaly, ZIKV has also been implicated in other neurological
complications such as Guillain-Barre syndrome (Oehler et al. 2014), with evidence of virus in
the spinal fluid (Brasil et al, under review, Lancet). Development of microcephaly and ZIKVassociated
neurological disease has been associated with the host response through
inflammation and autophagy. Classically Koch’s postulates have not been fully established
for virus infection of humans. Over the past year we have optimised the virus production set
up for ZIKV (see accompanying figure), and also developed a novel mouse model that has
been infected with different isolates. In this proposal, we will use the mouse model to
investigate whether different ZIKV isolates cause neurological disease. This will be correlated
with infection of primary human tissues representing the proposed route of infection: skin,
blood and neuronal tissues in the foetus and adult.
Organisations
Publications
| Title | Infection in fhuman blood monocytes nd macrophages |
| Description | development of an in vitro infection protocol and method to infect Zika virus into human monocytes and monocytes-derived macrophages |
| Type Of Material | Model of mechanisms or symptoms - in vitro |
| Provided To Others? | No |
| Impact | characterising how primary ex vivo human blood monocytes and macrophages responded to ZIKV infection. RNA-sequencing (RNA-seq) was used to identify and quantify the abundance of host messenger RNA (mRNA) abundance profiles. These were used to map the host response to ZIKV infection in the two different ex vivo cell types. The observations were also supported by analysis of tissue from an infected human patient and independent validation using alternative approaches. The data also gave an insight into the potential adaptation of the virus during replication in these cells. This study is the first large-scale investigation into the host cellular response to ZIKV infection in biological relevant cells. |
| Description | Health Protection Research Unit in Emerging and Zoonotic Infections |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | Health Protection Research Unit in Emerging and Zoonotic Infections. Workshop on Molecular and immunological approaches to high consequence infections |
| Year(s) Of Engagement Activity | 2016 |
| Description | Seminar at Catholic University of Leuven, Belgium in 9 Jun 2016 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited speaker for seminar hosted by the Rega Institute, Catholic University of Leuven. Met with various researchers working in the field of antiviral molecules against arbovirsues such as Zika virus |
| Year(s) Of Engagement Activity | 2016 |
| Description | Seminar at te Northwestern A and M University in Yang Ling, China on 20 Feb 2017 |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Working group of virologists and immunologists on RNA viruses |
| Year(s) Of Engagement Activity | 2017 |