Complex Roles of Neutrophils during Arboviral Infections

Abstract

Arboviruses are known to cause large-scale epidemics in many parts of the world. These arthropod-borne viruses are a large group consisting of viruses from a wide range of families. The ability of their vector to enhance viral pathogenesis and transmission makes the development of treatments against these viruses challenging. Neutrophils are generally the first leukocytes to be recruited to a site of infection, playing a major role in regulating inflammation and, as a result, viral replication and dissemination. However, the underlying mechanisms through which neutrophils control the progression of inflammation and disease remain to be fully understood. In this review, we highlight the major findings from recent years regarding the role of neutrophils during arboviral infections. We discuss the complex nature of neutrophils in mediating not only protection, but also augmenting disease pathology. Better understanding of neutrophil pathways involved in effective protection against arboviral infections can help identify potential targets for therapeutics.

Keywords: arboviruses; inflammation; mosquito; neutrophils; pathology.

Figure 1

Neutrophil-mediated viral replication and dissemination induced by mosquito saliva. During a blood meal, mosquito carrying an arbovirus injects the virus along with its salivary gland proteins below the skin of the host. There is a decrease in IL-8 levels in the serum correlating to lower number of circulating neutrophils and higher number in the skin. One of the proteins in the saliva, neutrophil-stimulating factor 1 (NeSt1), activates the neutrophils in the dermis, the deepest layer of the skin, which houses the immune cells. IL-1β is secreted by these inflammatory neutrophils to establish cutaneous response to the bite. Additionally, bite-associated monocyte/macrophage-attracting chemokines, CCL2, CCL7, CCL12, and CXCL2, are upregulated. The infiltrating monocytes and macrophages are permissive to infection enhancing viral replication and increasing the potential for systemic spread. The mosquito saliva also causes vascular permeabilization and mast cell degranulation in the skin recruiting dendritic cells to the bite site, contributing to the inflammation, and neutrophils to the draining lymph nodes.

Figure 2

Alphavirus infection-induced neutrophil recruitment and inflammation. Following footpad injection of mice with alphavirus, levels of neutrophil-attracting chemokines, CXCL1 and CXCL2, increase. These chemokines and CXCL10 recruit neutrophils, which release reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and other cytotoxic mediators through degranulation, promoting viral clearance. The infiltrating neutrophils can also be directly infected, triggering NET release in a ROS-dependent manner. Furthermore, monocytes/macrophages infiltrating the site of infection can be directly infected. On the other hand, alphaviral infections induce monocyte and neutrophil recruitment into the draining lymph node (dLN) that inhibit germinal center formation decreasing B cell maturation and neutralizing antibody (Ab) production. MyD88-IL-1R signaling promotes the accumulation of neutrophils in the dLN, while IFN-α inhibits this influx.