Extending beyond the myeloid-mediated response, innate immunity pathways were identified as significantly differentiated, such as Toll-like receptor (TLR) signaling pathways (
z-score = 2) and interferon signaling (
z-score = 3.2) (Table S
3). The TLR signaling pathway was activated by up-regulation of CD14 (Log2(FC)1.64)), TLR3 (Log2(FC)1.94), and TLR4 (Log2(FC)1.49)) (Fig.
2, Tables S
2 and S
3). Genes that were upregulated in the interferon signaling pathways were IFI35 (Log2(FC)1.0), IFI6 (Log2(FC)2.0), IFIT1 (Log2(FC)2.8), IFIT3 (Log2(FC)3.3), IRF9 (Log2(FC)1.8), ISG15 (Log2(FC)4.2), MX1 (Log2(FC)2.9), OAS1 (Log2(FC)2.5), PSMB8 (Log2(FC)3.3), STAT1, (Log2(FC)1.9), and STAT2 (Log2(FC)1.4) (Tables S
2 and S
3). In line to what previously reported during acute SIV infection in the brain of rhesus macaques, the interferon signaling pathway was predicated to be activated even in absence of high expression of either IFNα or IFNγ genes (Roberts et al.
2004) (Fig.
2, Table S
3). Intensification of innate immune response was also indicated by several DEGs, such as C1QB (Log2(FC)2.0), C1QC (Log2(FC)2.3), and C3 (Log2(FC)1.5), involved in activation of complement and coagulation cascades (
z-score = 2). Such complement cascades work to enhance the phagocytosis, proteolysis, inflammation, and overall magnitude of immune action (Janeway CA Jr
2001). Complement system cascades have been linked to HIV-induced neurodegeneration in other research studies (Bruder et al.
2004; Speth et al.
2001) and to endothelial damage leading to reduced integrity of the blood-brain barrier (Orsini et al.
2014) (Fig.
2, Tables S
2 and S
3). This increased innate immune response led to consequent up-regulation of numerous genes within the neuroinflammation signaling pathway (
z-score = 3.6), likely establishing inflammation processes in the frontal cortex of the SIV-infected DV macaques (Table S
3). Neuroinflammation signaling pathway plays a key role in maintaining the homeostasis of CNS, functioning to remove damaging agents, such as SIV in this case, and clear injured neural tissues (Tohidpour et al.
2017). Excessive cell and tissue damage can ensue recruitment of microglia and enhancement of their activities, which exacerbates neuronal damage and ultimately results in chronic inflammation with necrosis of glial cells and neurons (Wang et al.
2015). Necroptosis is a regulated necrotic cell death pathway that defends against pathogen-mediated infections, morphologically characterized by the loss of cell plasma membrane and the swelling of organelles, particularly mitochondria. Compared with apoptosis, necroptosis generates more inflammation. Several death receptors promote necroptosis when activated, including tumor necrosis factor receptor TNFR1, Fas, TNFRSF10A, and TNFRSF10B—with up-regulation of its ligand TNFSF10 (Log2(FC)1.13)—as well as TLRs (Feoktistova and Leverkus
2015; Najafov et al.
2019) (Tables S
2 and S
3). Activation of pathways associated with interferon (
z-score = 3.2) and death receptor signaling (
z-score = 2.2) are likely to be associated with neuronal apoptosis, similarly to what reported for infection of neurotropic West Nile virus in the brain (Clarke et al.
2014) (Table S
3). Finally, neuronal damage was also suggested by up-regulation of PSMB8 (Log2(FC)3.3) and PSMB9 (Log2(FC)3.0), crucial for proteasome activity and regulation of protein turnover in neuronal synapses (Speese et al.
2003). PSMB8 and PSMB9 have been previously implicated in research studying SIVE-induced neuronal dysfunction (Gersten et al.
2009b) (Table S
3). Lastly, NCF1 produces superoxide anions causing increased oxidative stress, which is linked to nervous system damage (Starkov et al.
2004; Uzasci et al.
2013), and activation of STAT1 (Log2(FC)1.9) provides further evidence of response to oxidative stress (Olagnier et al.
2014) (Table S
3).