Influenza A virus (IAV) is considered one of the main threats that causes
contagious respiratory disease in humans. Each year it threatens the human population
with epidemics and pandemics. Limited anti-Influenza drugs are available that target viral
proteins. The Influenza virus can mutate rapidly and can quickly develop resistance
against available drugs. Therefore, developing novel host-targeted therapeutics effective
against different IAVs may be very beneficial.
Influenza virus is an intracellular parasite that uses host cell system to favour its
replication process and evade host cell defense system. The Influenza A viral nonstructural
protein 1(NS1) is a multifunctional protein that is expressed to high levels in
infected cells; thus, interacting proteins may be ideal targets for drug development. In this
study nine broadly cross-reactive anti-NS1 monoclonal antibodies (mAbs) were
generated, characterized and used to co-immunoprecipitate IAV NS1 and its interacting
host proteins. 183 proteins were consistently identified in this NS1 interactome study.
Importantly, most proteins clustered into different cellular pathways, biological processes
and molecular functions, such as mRNA splicing, gene expression, processing of capped
intron-containing pre-mRNA and nucleoside, nucleotide and nucleic acid metabolism.
Among these, 124 proteins detected in my study represent novel NS1-interacting targets
not previously identified. RNAi screening then identified 11 NS1-interacting host factors
as vital for IAV replication. From RNAi screening two NS1-interacting candidates,
NUMA1 and PRPF19 were chosen for further analysis. IAV production was dramatically
reduced in NUMA1 knockdown (KD) cells. Although viral transcription and translation
were not inhibited, transport of viral structural proteins to the cytoplasmic membrane was obstructed during maturation steps in NUMA1 KD cells. IAV maturation was also
inhibited and new virion production was significantly reduced in PRPF19 KD cells.
Overall, a list of novel NS1-interacting host factors were identified utilizing some
broadly cross reactive anti-NS1 mAbs in my study, and 11 of them were required for
IAV replication. Further research on these new proteins may discover new targets for
anti-Influenza drug development. / May 2017
| Identifer | oai:union.ndltd.org:MANITOBA/oai:mspace.lib.umanitoba.ca:1993/32159 |
| Date | 21 March 2017 |
| Creators | Rahim, Md Niaz |
| Contributors | Coombs, Kevin (Medical Microbiology and Infectious Diseases), Mai, Sabine (Physiology and Pathophysiology) Yao, Xiaojian (Medical Microbiology and Infectious Diseases) Frappier, Lori (University of Toronto) |
| Source Sets | University of Manitoba Canada |
| Detected Language | English |
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