Page 20 - Avian Virology: Current Research and Future Trends

Avian Influenza Virus | 13

al., 2015; Xu et al., 2015). Knowledge about the function of NLRs antigen presenting cell surface, where will be engaged by T-cell
in chicken is still limited. However, up-regulation of NLRC5 has for the activation of the adaptive immune response (reviewed in
been described in chickens infected with HPAI H5N1, probably Abbas et al., 2012b; Juul-Madsen et al., 2014; Kaspers and Kaiser,
inducing activation of NF-κB and downstream pro-inflammatory 2014).
molecules (Ranaware et al., 2016). There is evidence suggesting Influenza-induced interferon proteins are linked to the activa-
that NLRC5 functions as its mammalian orthologue in activating tion of a number of cellular genes, one of the most prominent
transcription factor NF-κB and subsequent expression of type I being protein kinase R (PKR) encoding double-stranded RNA
IFN and pro-inflammatory cytokines (Lian et al., 2012; Chang activated protein kinase. Activation of PKR induces phosphoryla-
et al., 2015). tion of the alpha subunit of eukaryotic initiation factor 2 (eIF2a),
Production of pro-inflammatory cytokines and chemokines which in turn leads to translational arrest and pro-apoptotic sig-
leads to inflammation and recruitment of leucocytes to site of nalling (Takizawa et al., 1996; Gale and Katze, 1998). Influenza
infection. Expression and release of IFNs results in activation of virus is able to inhibit PKR kinase activity indirectly through the
the Jak/STAT pathway, which in turn leads to the formation of the action of the NS1 protein or facilitating its binding to another
IFN stimulated gene factor 3 (ISGF3). ISGF3 is translocated into cellular component p58IPK (Melville et al., 1997). Connected to
the nucleus and initiates transcription of IFN stimulated genes the PKR pathway, the protein kinase C (PKC) is a large family of
(ISGs). Some of the products are involved in preventing fusion serine/threonine kinases enzymes upstream of the RAF kinase,
between viral envelop and host cell membrane (IFITM), vRNA which is involved in the activation of the RAF/MEK/ERK path-
degradation (OAS), inhibition of viral replication by sequestering way (Gaur et al., 2011). Influenza virus HA protein binding to
specific nucleic acids (IFIT), and by decreasing cellular and viral sialic acid on the cell surface activates PKC, which is indispen-
protein synthesis (PKR) (Balachandran et al., 2000; Silverman, sable for viral entry, whereas intracellular HA overexpression
2007; Brass et al., 2009; Schulz et al., 2010; Pichlmair et al., 2011; induces ERK signalling which through MAPK/ERK pathway is
Smith et al., 2015). Upon activation of the signalling cascades, important for efficient export of nuclear RNPs (Arora and Gasse,
the infected cells enter into an antiviral state consisting on the 1998; Root et al., 2000; Gaur et al., 2011).
continuous expression of cytokines, chemokines and surface Overexpression of key viral proteins, specifically HA, NP and
molecules. Macrophages, dendritic cells (DC), heterophils, and M1 appear to be responsible for the biphasic activation of the
natural killer (NK) cells are recruited at the site of infection in NF-κB: early and late activations have been associated with infec-
the attempts to limit spread of the IAV infection. Macrophages tion and viral replication respectively (Pahl and Baeuerle, 1995;
and DCs are some of the first cells to recognize and respond to Julkunen et al., 2001; Ludwig et al., 2003; Nimmerjahn et al.,
IAV infection. It has been shown that some strains of IAV can pro- 2004; Gaur et al., 2011). As a result, the host immune response
ductively replicate in macrophages of avian species and mammals elicits the production of IFN, which, again, is also antagonized by
(Van Campen et al., 1989; Lyon and Hinshaw, 1991; Powe and the viral non-structural protein NS1 of influenza virus (Mibayashi
Castleman, 2009; Kasloff and Weingartl, 2016). However, not all et al., 2007). The NS1 viral protein also activates the PI3K/Akt
the strains are able to replicate on those cell types. Once at the site pathway to support the virus efficient replication and propagation
of infection, macrophages, heterophils, and DCs engulf invading (Neri et al., 2002; Ehrhardt et al., 2006; Hale et al., 2006, 2008a;
pathogens and apoptotic/necrotic cells as well. Macrophages Mibayashi et al., 2007; Zhirnov and Klenk, 2007). PI3K is a
that have engulfed pathogens, express a NK activating ligand at family of enzymes that play a critical role in regulation of essential
the surface that is recognized by the NK cell. Upon engagement cellular functions including cell survival, proliferation, and dif-
of ligand and receptor, the macrophages release IL-12, and this ferentiation. Influenza virus, like many other viruses, alter this
stimulates IFNγ production (Jak/STAT pathway) and release pathway to prevent apoptosis by inhibiting proapoptotic factors
from NK cells. The IFNγ activates macrophages to destroy the such as Bcl-2-associated death promoters (BAD) and caspase-9.
engulfed antigen. In addition, NK cells eliminate host infected This is accomplished by the NS1 viral protein binding to the SH2
cells. Viral infection down-regulates expression of MHC I, domain of the p85 subunit during the later stages of replication,
inhibiting expression of self antigen on the infected cell. In conse- following activation of the PI3K which leads to suppression of
quence, the activating receptor on the NK cell binds to its ligand cell death (Neri et al., 2002; Vanhaesebroeck et al., 2005; Zhirnov
on the target cell, which in turn induces release of perforin (to and Klenk, 2007).
disrupt the plasma membrane) and granzymes thus inducing cell The Mitogen activated protein kinase (MAPK or MAP
death by apoptosis. This mechanism contributes on controlling kinase) are eukaryotic proteins involved in the conversion of
disease spread by eliminating reservoir cells. A study performed cellular responses to a diverse array of stimuli, such as mitogens,
to investigate the role of chicken NK cells during LPAI and HPAI osmotic stress, heat shock and proinflammatory cytokines. They
infections, showed that NK activation was enhanced during LPAI regulate cell functions including proliferation, gene expression,
infection and diminished during HPAI infection, correlating with differentiation, mitosis, cell survival, and apoptosis (Gaur et al.,
the pathogenicity observed (Jansen et al., 2013). On the other 2011). Interestingly, influenza virus infection also activates all
hand, macrophages, but mainly DCs, will process the engulfed the 4 major subgroups of the MAPK family: extracellular signal-
pathogens into small peptides. The small peptides are translo- regulated kinases (ERKs), ERK5/Big MAP kinase 1(BMK1),
cated into the endoplasmic reticulum and where bind the MHC I the p38 MAPK, and c-jun N-terminal or stress-activated protein
or II. MHC I and/or II are then transported and expressed on the kinases (JNK/SAPK) (Kujime et al., 2000; Ludwig et al., 2003).