Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover

Subudhi, Sonu; Rapin, Noreen; Misra, Vikram

The unique features of bats, whereby they tolerate viral infections without excessive inflammation while suppressing viral replication, leads to the obvious question: What is so special about bats? The answer to this has been linked to the evolution of the ability to fly. The increased rate of metabolism accompanying flight would lead to higher levels of oxygen-free radicals [32, 33] . This makes bats more prone to generating damaged DNA [34] . As mounting an immune response is energetically expensive [35] and would be detrimental, bats probably evolved mechanisms to suppress activation of immune response due to damaged DNA generated via flight, thereby leading to reduced inflammation. This would also explain why bats of certain species live longer than expected given their high metabolism and small size [36] . In bats the evolutionary suppression of inflammation and consequent susceptibility to virus infection is counteracted by constitutive expression of innate immune genes or novel genes to target viruses as described earlier. This model has been depicted in in Figure 1 . Development of flight necessitated the evolution of bats with the ability to modulate the consequences of increased metabolic activity by suppressing inflammation (left). Inflammation was suppressed by dampening the activation of DNA sensors, such as STING, and reducing levels of inflammatory cytokines, such as TNFα (center). These traits were positively selected but a reduced inflammatory response made it advantageous for virus replication (lower right). Increased susceptibility of cells to virus replication was compensated by selection of more effective antiviral measures, such as higher constitutive expression of Interferons or unique ISG expressions (upper right). (Abbreviations used: cGAS-cyclic GMP-AMP synthase, GTP-Guanosine triphosphate, cGMP-cyclic guanosine monophosphate, STING-stimulator of interferon genes, TBK1-TANK binding kinase 1, IRF3interferon regulatory transcription factor 3, cRel, TNFα-tumor necrosis factor α, RNase-Lribonuclease L).