Immune Cell Targets of Infection at the Tick-Skin Interface during Powassan Virus Transmission

Abstract

Powassan virus (POWV) is a tick-borne flavivirus that can result in a severe neuroinvasive disease with 50% of survivors displaying long-term neurological sequelae. Human POWV cases have been documented in Canada, the United States, and Russia. Although the number of reported POWV human cases has increased in the past fifteen years, POWV remains one of the less studied human pathogenic flaviviruses. Ixodes ticks are the vectors for POWV, and the virus is transmitted to a host’s skin very early during the tick feeding process. Central to the successful transmission of a tick-borne pathogen are complex interactions between the host immune response and early tick-mediated immunomodulation, all of which initially occur at the skin interface. In our prior work, we examined the cutaneous immune gene expression during the early stages of POWV-infected Ixodes scapularis feeding. The present study serves to further investigate the skin interface by identifying early cell targets of infection at the POWV-infected tick feeding site. An in vivo infection model consisting of POWV-infected ticks feeding on mice for short durations was used in this study. Skin biopsies from the tick feeding sites were harvested at various early time points, enabling us to examine the skin histopathology and detect POWV viral antigen in immune cells present at the tick feeding site. The histopathology from the present study demonstrates that neutrophil and mononuclear cell infiltrates are recruited earlier to the feeding site of a POWV-infected tick versus an uninfected tick. This is the first report demonstrating that macrophages and fibroblasts contain POWV antigens, which suggests that they are early cellular targets of infection at the tick feeding site. These data provide key insights towards defining the complex interactions between the host immune response and early tick-mediated immunomodulation.

Heartland virus infection in hamsters deficient in type I interferon signaling: Protracted disease course ameliorated by favipiravir

“…In tissues where lesions were present, severity was scored on a scale of 0–4 with 0 indicating no lesions and 4 indicating severe lesions. Spleen, liver, kidney, heart, lymph node and intestine from the moribund HRTV-infected hamster and a sham-infected control were also processed for IHC following standard protocols (Hermance et al, 2016; Santos et al, 2016). The presence of HRTV antigen was detected in the fixed tissues using a mouse monoclonal antibody against the nucleoprotein (Calvert and Brault, 2015).…”

Tick-Borne Encephalitis Virus Infection Alters the Sialome of Ixodes ricinus Ticks During the Earliest Stages of Feeding

“…Of particular concern is tick-borne encephalitis virus (TBEV), a flavivirus endemic to Europe and northern Asia which is vectored by Ixodes ricinus in Europe and Ixodes persulcatus in parts of Eastern Europe and Asiatic Russia. Upon TBEV-infected tick feeding, the virus initially replicates in host skin fibroblasts (Hermance et al, 2016) and macrophages (Labuda et al, 1996). The virus is then transported by these macrophages to the draining lymph nodes, where it replicates before entering the blood and progressing to the remainder of the body.…”

“…In addition to creating a favorable microenvironment to acquire blood, the immunomodulatory functions of tick salivary molecules have been demonstrated to facilitate pathogen transmission. Tick saliva initially alters the inflammatory state of the inoculation site by altering the expression of cytokines to increase neutrophil and monocyte (Hermance et al, 2016) influx. This results in an inflammatory environment that is conducive to viral invasion and macrophagedriven replication and dissemination (Labuda et al, 1996;Hermance et al, 2016).…”

“…Tick saliva initially alters the inflammatory state of the inoculation site by altering the expression of cytokines to increase neutrophil and monocyte (Hermance et al, 2016) influx. This results in an inflammatory environment that is conducive to viral invasion and macrophagedriven replication and dissemination (Labuda et al, 1996;Hermance et al, 2016). Elements of the tick saliva can also alter the behavior of dendritic cells to increase the replication of TBEV, in turn accelerating viral dissemination through the lymphatic system (Fialova et al, 2010;Lieskovska et al, 2018).…”

“…It is also plausible that the infection and replication of viruses in tick salivary glands induce alterations that enhance the transmission properties of tick saliva. For example, in contrast to uninfected ticks, the presence of POWV has been shown to increase skin inflammation during tick feeding (Hermance et al, 2016), which in turn increased the influx of macrophages and may potentially accelerate early viral infection and dissemination through the lymphatic system.…”