Viral Infection and Dissemination Through the Lymphatic System

Many viruses induce viremia (virus in the blood) and disseminate throughout the body via the bloodstream from the initial infection site. However, viruses must often pass through the lymphatic system to reach the blood. The lymphatic system comprises a network of vessels distinct from blood vessels, along with interconnected lymph nodes (LNs). The complex network has become increasingly appreciated as a crucial host factor that contributes to both the spread and control of viral infections. Viruses can enter the lymphatics as free virions or along with migratory cells. Once virions arrive in the LN, sinus-resident macrophages remove infectious virus from the lymph. Depending on the virus, macrophages can eliminate infection or propagate the virus. A virus released from an LN is eventually deposited into the blood. This unique pathway highlights LNs as targets for viral infection control and for modulation of antiviral response development. Here, we review the lymphatic system and viruses that disseminate through this network. We discuss infection of the LN, the generation of adaptive antiviral immunity, and current knowledge of protection within the infected node. We conclude by sharing insights from ongoing efforts to optimize lymphatic targeting by vaccines and pharmaceuticals. Understanding the lymphatic system's role during viral infection enhances our knowledge of antiviral immunity and virus-host interactions and reveals potential targets for next-generation therapies.