Neutrophil Recruitment and Participation in Severe Diseases Caused by Flavivirus Infection

Abstract

Neutrophils are first-line responders to infections and are recruited to target tissues through the action of chemoattractant molecules, such as chemokines. Neutrophils are crucial for the control of bacterial and fungal infections, but their role in the context of viral infections has been understudied. Flaviviruses are important human viral pathogens transmitted by arthropods. Infection with a flavivirus may result in a variety of complex disease manifestations, including hemorrhagic fever, encephalitis or congenital malformations. Our understanding of flaviviral diseases is incomplete, and so is the role of neutrophils in such diseases. Here we present a comprehensive overview on the participation of neutrophils in severe disease forms evolving from flavivirus infection, focusing on the role of chemokines and their receptors as main drivers of neutrophil function. Neutrophil activation during viral infection was shown to interfere in viral replication through effector functions, but the resulting inflammation is significant and may be detrimental to the host. For congenital infections in humans, neutrophil recruitment mediated by CXCL8 would be catastrophic. Evidence suggests that control of neutrophil recruitment to flavivirus-infected tissues may reduce immunopathology in experimental models and patients, with minimal loss to viral clearance. Further investigation on the roles of neutrophils in flaviviral infections may reveal unappreciated functions of this leukocyte population while increasing our understanding of flaviviral disease pathogenesis in its multiple forms.

Keywords: encephalitis; flavivirus; hemorrhagic fever; neutrophils; pregnancy.

Figure 1

Involvement of neutrophils in hemorrhagic fever and shock induced by flavivirus infections. (a) Viruses such as DENV or YFV (yellow viral particles) are transmitted to human hosts through an infected mosquito bite. (b) Local inflammation results in the recruitment of neutrophils to the infected site. (c) Activated neutrophils amplify inflammation secreting IL-1β. Subsequent activation and recruitment of mononuclear phagocytic leukocytes, target cells in flavivirus infections, promotes viral replication and dissemination of infection. (d) Severe disease takes place as high levels of proinflammatory cytokines are produced, including those participating in neutrophil recruitment and activation, and result in systemic inflammation and multiorgan failure. (e) Levels of ROS and MPO-DNA complexes correlate with disease severity. Green dots—Neutrophil chemoattractants; Purple dots—IL-1β.

Figure 2

Involvement of neutrophils in flavivirus-induced encephalitis. (a) Encephalitic flavivirus such as WNV, JEV, SLEV, MVEV or TBEV (blue viral particles) are transmitted to vertebrate hosts through a mosquito or tick bite, reach resident mononuclear phagocytes in the skin and later disseminate to lymph nodes. (b) Neurotropic flaviviruses cross the blood–brain barrier through uncertain mechanisms, infecting cells in the CNS. (c) Infected neurons and activated glial cells release neutrophil-attracting chemokines in the CNS, initiating the development of encephalitis or meningoencephalitis. (d) Circulating neutrophils and other leukocytes are recruited to the CNS, resulting in CSF pleocytosis often observed in patients and consolidating the onset of severe disease. (e) High levels of CXC chemokines in the brain and CSF contribute to neutrophil activation and trigger neutrophil effector functions in situ, which may contribute to tissue damage, sequelae or death. Green dots—CXC chemokines.

Figure 3

ZIKV congenital infection and the probable participation of neutrophils in CZS. (a) High levels of CXCL8 are found in the serum of pregnant women infected with ZIKV (blue/red viral particles). (b) ZIKV is able to trespass the placental barrier, the persistence of the infection leads to an imbalance on Type-I and Type-III IFN responses, which may lead to tissue damage. (c) Amniotic fluid from CZS pregnancies present high levels of neutrophil-chemoattractants and proinflammatory cytokines and ZIKV-infected human umbilical vein endothelial cells are sources of CXCL1. (d) Recruited neutrophils respond to pathogenic activation of Type-I IFN responses in patients. (e) ZIKV may infect fetal tissues, inducing a proinflammatory environment that promotes neuronal damage and the onset of CZS. Green dots—CXC chemokines; Yellow dots—IFNs.