Samantha bunyavirus infection. Bunyaviruses are emerging due to

Samantha
Hover, Barnabas King, Bradley Hall, Eleni-Anna Loundras, Hussah Taqi, Janet
Daly, Mark Dallas, Chris Peers, Esther Schnettler, Clive McKimmie,
Alain Kohl, John N. Barr, and Jamel Mankouri

Author:
Saliha Ihsan

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Reviewer:
Graeme Cottrell                                                   

Introduction

Bunyaviruses are emerging pathogens transmitted
via arthropod vectors causing disease that is impacting healthcare, economics
and animal welfare globally. They cause lethal haemorrhagic fevers in infected
humans and can also infect plants and animals. There are currently no vaccines
or anti-viral treatments for bunyavirus infection. Bunyaviruses are
emerging due to the re-assortment of their genome between different species.
Bunyamwera virus (BUNV) is used as the model bunyavirus, as it shares some
biological characteristics with other family members. Ion channels are key
players in a range of cellular processes including the cell cycle. This study
aimed to demonstrate host cell potassium ion (K+) channels as
potential targets for the treatment of BUNV infection.

Experimental
Procedures

Firstly,
both human and vero cells were infected, and subjected to a range of tests.
Then the virus production was detected by the expression analysis of
bunyavirus-nucleoprotein using Western blot and immunofluorescence techniques.
A further assay was carried out in the presence of tetraethylammonium (TEA), a
known K+ channel
inhibitor, KCl and K2SO4, and the percentage of
infected cells present was detected. K2P
channel RT-PCR was used to generate more channel copies for testing with
different channel inhibitors. Lastly, statistical analysis was done on these
tests to check the significance of the data.

Results

The
addition of TEA, KCl and K2SO4 significantly reduced the
percentage of BUNV infected cells showing that K+ channels are required for BUNV
replication. Other tests showed that K+
channel dependence was conserved across vertebrate and invertebrate cell types
indicating that the channel is exploited by BUNV in all animals and therefore
making it a prime target for the treatment of BUNV infection. K+ channel dependence
was also specific to bunyavirus through testing with similar viruses. The
post-infection inhibition of BUNV infected cells using TEA showed that K+ channels are required
in the post-entry stage of infection.

The
specific K+
channel needed in BUNV infection was investigated using quinidine and quinine.
It showed that BUNV requires quinidine/quinine-sensitive host cell K+ channels. The K2P channels showed
sensitivity to quinidine/quinine and their role in the BUNV infection was
studied. Host cells were treated with different K2P specific channel inhibitors and the
results can be seen in figure 7D ii). Each channel inhibitor treatment caused a
significant decrease in the percentage of BUNV infected cells. Also, there was
no cytotoxicity experienced, and the K2P
channel inhibitors caused inhibition at micromolar concentrations which shows
the possibility of using these substances as potentially potent drugs for the
treatment of bunyavirus infection.

Conclusion

Overall,
the study has significantly improved our knowledge of the bunyavirus infection.
It bought up key points in using K2P
channels as potential targets for drugs, subject to human response. However,
the mechanism of K2P
channel activation in impeding the BUNV lifecycle is unknown. It is vital for
this to be researched further as understanding these mechanisms will be important
in producing safe and effective drugs.

Bibliography

Hover, S. et al. (2016) ‘Modulation
of potassium channels inhibits bunyavirus infection’, Journal of Biological
Chemistry, 291(7), pp. 3411–3422. doi: 10.1074/jbc.M115.692673.

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