Innate immune surveillance of the circulation: A review on the removal of circulating virions from the bloodstream

Abstract

Many viruses utilize the lymphohematogenous route for dissemination; however, they may not freely use this highway unchecked. The reticuloendothelial system (RES) is an innate defense system that surveys circulating blood, recognizing and capturing viral particles. Examination of the literature shows that the bulk of viral clearance is mediated by the liver; however, the precise mechanism(s) mediating viral vascular clearance vary between viruses and, in many cases, remains poorly defined. Herein, we summarize what is known regarding the recognition and capture of virions from the circulation prior to the generation of a specific antibody response. We also discuss the consequences of viral capture on viral pathogenesis and the fate of the captor cell. Finally, this understudied topic has implications beyond viral pathogenesis, including effects on arbovirus ecology and the application of virus-vectored gene therapies.

Fig 1. The liver sinusoid.

There are 2 key cell types located in the liver sinusoid that have been shown to contribute to viral vascular clearance. Although in vitro studies suggest that LSECs, which form the liver endothelium, interact with certain viruses (e.g., AdV), KCs, which are the liver’s main tissue-resident macrophages, are responsible for clearing diverse circulating viruses (e.g., CHIKV and AdV) in vivo. In addition, KCs are important in controlling pathogenesis of viruses like LCMV. This figure was created with BioRender.com. AdV, adenovirus; CHIKV, chikungunya virus; HA, hepatic artery; IFN, interferon; KC, Kupffer cell; LCMV, lymphocytic choriomeningitis virus; LSEC, liver sinusoidal endothelial cell; PRR, pathogen recognition receptor; PV, portal vein; VACV, vaccinia virus.

Fig 2. Macrophages of the spleen.

Splenic macrophages also participate in the capture of circulating virus particles. There are 3 major splenic macrophage populations (MMM, MZM, and RpM), and they localize to distinct regions of the spleen. These macrophage subsets can be identified by their localization and the indicated key cellular markers. While the mechanisms by which specific splenic macrophage populations mediate viral clearance are not well understood, they are critical in activating immune responses to circulating viruses. This figure was created with BioRender.com. MMM, marginal zone metallophilic macrophage; MZM, marginal zone macrophage; RpM, red pulp macrophage.

Fig 3. Mechanisms of viral capture.

The liver appears to be the main mediator of viral vascular clearance. However, the specific mechanisms of removing virions from the circulation is distinct and virus-specific. The removal of AdV particles is mainly performed by KCs; however, some of the receptors shown to interact with AdV can also be expressed by LSECs (SR-F1 and SR-A1). In addition to SRs (SR-F1, SR-A1, and SR-A6), nAb, and CRIg also promote clearance of AdV from the bloodstream. For arthritogenic alphaviruses (CHIKV, RRV, and ONNV), clearance is mediated specifically by SR-A6 (MARCO) and KCs. However, particles that have a single point mutation to replace a lysine residue on the E2 glycoprotein (K200X for CHIKV and ONNV; K251X for RRV) evade capture. For the flaviviruses DENV and WNV, the type of virion glycosylation present affects clearance mediated by MBL. Specifically, MBL binds the high-mannose glycosylated virus particles, but not virions decorated with complex glycosylation. However, MBL is not the only mediator of DENV and WNV clearance, and it is clear another, as-yet-unknown mechanism also exists. This figure was created with BioRender.com. AdV, adenovirus; CHIKV, chikungunya virus; DENV, dengue virus; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cell; MBL, mannose-binding lectin; nAb, natural antibodies; ONNV, o’nyong’nyong virus; RRV, Ross River virus; WNV, West Nile virus.