Viral Infection and Dissemination Through the Lymphatic System

Abstract

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.

Keywords: B cell activation; NK cell; T cell activation; antigen presentation; cytokine; dendritic cell; lymph node; lymph-borne virus; monocyte; sinus macrophage.

Figure 1

The lymphatic system captures viruses that drain from the tissue. Free virions, or infected or viral antigen-carrying migratory cells (such as dendritic cells), enter lymphatic vessels near the initial site of infection (such as the skin). Lymph fluid unidirectionally flows through lymphatic vessels, eventually flowing into lymph node sinuses lined by lymphatic endothelial cells (LECs). Incoming virions can be captured by subcapsular sinus macrophages (SSMs) and medullary sinus macrophages (MSMs). Any uncaptured virus flows out of the lymph node through the efferent lymphatic vessel.

Figure 2

Strategies to maximize delivery of lymph-borne vaccines and therapeutics. (1) Antigen, vaccines, or antigen-presenting cells can be directly injected into a lymph node for enhanced antigen delivery and adaptive immune response development. (2) When administered in peripheral tissues, antigens and vaccines can be optimized for entry into lymphatic vessels with particle sizes of 10–200 nm, hydrophilicity, and a neutral or negative charge. (3) Antigens and vaccines can be optimized for antigen-presenting cell (APC) capture in peripheral tissues with particle sizes of 100–1000 nm, spherical shapes, hydrophobicity, and a positive charge. Vaccine-bearing APCs can migrate to draining lymph nodes for antigen relay and presentation.