Widespread Circulation of Tick-Borne Viruses in Virginia-Evidence of Exposure to Heartland, Bourbon, and Powassan Viruses in Wildlife and Livestock.

Emerging tick-borne viruses such as Powassan virus (POWV), Bourbon virus (BRBV), and Heartland virus (HRTV), whilst rare, can cause severe health problems in humans. While limited clinical cases have been reported thus far in Virginia, the presence of tick-borne viruses poses a serious health threat, and the extent of their prevalence in Virginia is unknown. Here, we sought evidence of POWV, BRBV, and HRTV exposure in Virginia via a serological assessment of wildlife and livestock. Wildlife in Virginia were found to be seropositive against POWV (18%), BRBV (8%), and HRTV (5%), with western and northern regions of the state having a higher prevalence. Multiple wildlife species were shown to have been exposed to each virus examined. To a lesser extent, cattle also showed exposure to tick-borne viruses, with seroprevalences of 1%, 1.2%, and 8% detected in cattle against POWV, BRBV, and HRTV, respectively. Cross-reactivity against other known circulating mosquito-borne flaviviruses was ruled out. In conclusion, there is widespread exposure to tick-borne viruses in western and northern Virginia, with exposure to a diverse range of animal populations. Our study provides the first confirmation that HRTV is circulating in the Commonwealth. These findings strengthen the existing evidence of emerging tick-borne viruses in Virginia and highlight the need for public health vigilance to avoid tick bites.

Pathogenesis and virulence of Heartland virus.

Heartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease. Moreover, little is known about HRTV-host interactions, viral replication mechanisms, pathogenesis and virulence, further hampering the development of vaccines and antiviral interventions. Here, we aimed to provide a brief review of HRTV epidemiology, molecular biology, pathogenesis and virulence on the basis of published article data to better understand this virus and provide clues for further study.

Modeling Heartland virus disease in mice and therapeutic intervention with 4'-fluorouridine.

Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.

Heartland Virus Disease-An Underreported Emerging Infection.

First recognized 15 years ago, Heartland virus disease (Heartland) is a tickborne infection contracted from the transmission of Heartland virus (HRTV) through tick bites from the lone star tick (Amblyomma americanum) and potentially other tick species. Heartland symptoms include a fever <100.4 °F, lethargy, fatigue, headaches, myalgia, a loss of appetite, nausea, diarrhea, weight loss, arthralgia, leukopenia and thrombocytopenia. We reviewed the existing peer-reviewed literature for HRTV and Heartland to more completely characterize this rarely reported, recently discovered illness. The absence of ongoing serosurveys and targeted clinical and tickborne virus investigations specific to HRTV presence and Heartland likely contributes to infection underestimation. While HRTV transmission occurs in southern and midwestern states, the true range of this infection is likely larger than now understood. The disease's proliferation benefits from an expanded tick range due to rising climate temperatures favoring habitat expansion. We recommend HRTV disease be considered in the differential diagnosis for patients with a reported exposure to ticks in areas where HRTV has been previously identified. HRTV testing should be considered early for those matching the Heartland disease profile and nonresponsive to initial broad-spectrum antimicrobial treatment. Despite aggressive supportive therapy, patients deteriorating to sepsis early in the course of the disease have a very grim prognosis.

Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus.

Rift Valley fever is a zoonotic viral disease transmitted by mosquitoes, impacting both humans and livestock. Currently, there are no approved vaccines or antiviral treatments for humans. This study aimed to evaluate the in vitro efficacy of chemical compounds targeting the Gc fusion mechanism. These compounds were identified through virtual screening of millions of commercially available small molecules using a structure-based artificial intelligence bioactivity predictor. In our experiments, a pretreatment with small molecule compounds revealed that 3 out of 94 selected compounds effectively inhibited the replication of the Rift Valley fever virus MP-12 strain in Vero cells. As anticipated, these compounds did not impede viral RNA replication when administered three hours after infection. However, significant inhibition of viral RNA replication occurred upon viral entry when cells were pretreated with these small molecules. Furthermore, these compounds exhibited significant inhibition against Arumowot virus, another phlebovirus, while showing no antiviral effects on tick-borne bandaviruses. Our study validates AI-based virtual high throughput screening as a rational approach for identifying effective antiviral candidates for Rift Valley fever virus and other bunyaviruses.

Pathological and virological findings of type I interferon receptor knockout mice upon experimental infection with Heartland virus.

Heartland virus (HRTV) causes generalized symptoms, severe shock, and multiple organ failure. We previously reported that interferon-α/ß receptor knockout (IFNAR-/-) mice infected intraperitoneally with 1 × 107 tissue culture-infective dose (TCID50) of HRTV died, while those subcutaneously infected with the same dose of HRTV did not. The pathophysiology of IFNAR-/- mice infected with HRTV and the mechanism underlying the difference in disease severity, which depends on HRTV infection route, were analyzed in this study. The liver, spleen, mesenteric and axillary lymph nodes, and gastrointestinal tract of intraperitoneally (I.P.) infected mice had pathological changes; however, subcutaneously (S.C.) infected mice only had pathological changes in the axillary lymph node and gastrointestinal tract. HRTV RNA levels in the mesenteric lymph node, lung, liver, spleen, kidney, stomach, intestine, and blood were significantly higher in I.P. infected mice than those in S.C. infected mice. Chemokine ligand-1 (CXCL-1), tumor necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, and IL-10 levels in plasma of I.P. infected mice were higher than those of S.C. infected mice. These results indicated that high levels of viral RNA and the induction of inflammatory responses in HRTV-infected IFNAR-/- mice may be associated with disease severity.

Heartland virus: a novel and emerging tick-borne encephalitis / Virus Heartland: una nueva y emergente encefalitis transmitida por garrapatas

Heartland virus (HRTV) is a Bunyaviridae, phlebovirus that it has recently emerged as the causative agent of human disease characterized by thrombocytopenia and leukopenia in the United States and China. It seems to be the HRTV has been also reported in China, Japan and Korea. Recently the first fatal case of HRTV disease in an 80-year-old Tennessee resident was reported (1)