INNATE IMMUNITY IN ENCEPHALITIC BUNYAVIRUS INFECTION: OVERCOMING NEURONAL VULNERABILITY
Immunology and Infectious Disease
Several arthropod-borne bunyaviruses cause encephalitic disease in humans, primarily infecting neurons in the brain. Two of the most prominent examples are Rift valley fever virus (RVFV), and La Crosse virus (LACV). These viruses may preferentially infect neurons due to dampened neuronal innate immune responses. Innate immunity, including the antiviral interferon (IFN) and inflammatory NF-κB pathways, coordinates host responses to pathogens. It is unclear whether neurons are able to detect RVFV and LACV and mount an effective antiviral response, as neurons have likely adapted to minimize pathogenic inflammation in the brain. Studying the capacity of neurons to detect bunyavirus infection and generate antiviral responses will reveal the vulnerabilities of these essential cells, and may suggest novel therapeutic targets. Transcriptomic studies were used to evaluate the response of infected or IFN stimulated primary rat cortical neurons. Microscopy, qPCR, and plaque assays were used in infectivity assays to test the antiviral function of IFNs or other immune ligands. Primary neurons were able to detect infection with RVFV, LACV, or California encephalitis virus (CEV), and induced inflammatory responses biased towards NF-κB signaling. Neurons also responded to IFNβ stimulation, and transcribed well-known interferon stimulated genes. Despite this, type-I IFN-treated neurons were not protected from RVFV or LACV infection. CEV was inhibited. Thus, IFNβ activates antiviral gene expression in neurons, but RVFV and LACV evade this response. To identify immune ligands that antagonize RVFV, neurons were treated with 75 ligands before RVFV infection. The lipopeptide Pam3CSK4 decreased RVFV and LACV infection in neurons and the mouse brain by blocking viral fusion. Additionally, two beta glucans were antiviral specifically in neurons, and likely decreased viral entry. These data clarify the mechanisms of neuronal vulnerability to bunyavirus infection, and show that innate IFNα/β responses are insufficient to protect these essential cells. Exogenous ligands such as Pam3CSK4 may have a use as antiviral agents in cases of bunyavirus encephalitis. Studying the regulation and functions of immunity in the brain may ameliorate viral encephalitis caused by emerging and re-emerging pathogens.