Viral infection pathogenesis is influenced by a complex interplay of viral genetic variation and host immune regulation. Changes in the viral genome can alter immune evasion, replication, and tissue tropism, while host genetic and molecular factors influence susceptibility and the intensity of inflammation. This dissertation focuses on the pathogenesis of two-different RNA- viruses, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and West Nile Virus (WNV) to elucidate how viral genetic variation and host immune regulation shape infection dynamics. Multiple mutations in SARS-CoV-2, known to cause neurological complications, have emerged worldwide as Variants of Concern (VoC). I compared the differential pathogenesis of SARS-CoV-2 variants in human Angiotensin Converting Enzyme 2 (ACE2) expressing (K18- hACE2) mice by analyzing clinical signs, survival pattern, and immune response following intranasal infection with B.1, B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), or B.1.1.529 (omicron) lineages or mouse-adapted SARS CoV-2 (MA10). B.1.1.7, B.1.351 and B.1.617.2 viruses were significantly more lethal and produced higher viral titers than the B.1 strain, whereas the B.1.1.529 variant caused milder disease, a high survival rate, and lower viral replication in lungs and brains. The transcription levels of cytokines and chemokines in the lungs of B.1- and B.1.1.529-infected mice were significantly lower compared to those challenged with other VoC. West Nile virus (WNV) is a flavivirus known to cause mild illness, encephalitis, and meningitis globally. These diseases are influenced by antiviral inflammatory responses. Here, I investigated the role of microRNA-155 (miR-155), a key regulator of innate and adaptive immune responses, in WNV infection using miR-155 knockout mice(miR-155−/−) and wild-type mice. Loss of miR-155 led to higher viral loads in the CNS and periphery, increased tissue damage, higher mortality, and dysregulated cytokine production. Alternatively, the wild-type mice showed limited viral replication and pathogenesis miR-155-dependent modulation of pro-inflammatory pathways. These findings indicate that host microRNA-induced immune regulation is critical for orchestrating an effective and controlled immune response during WNV infection. Together, my dissertation study provides new insights into host-virus interactions across multiple viral systems, demonstrating how viral evolution and host regulatory mechanisms collectively shape infection outcomes and disease severity.