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With the increasing incidence of tick-borne viral diseases (TBVDs) year by year, more and more emerging pathogenic tick-borne viruses (TBVs) that can infect animals and humans are beginning to attract attention. TBVs comprise a large number of viruses with different genetic characteristics, some of which can be classified into established families or genera, while many virus sequences have distant phylogenetic relationships with known viruses and cannot be classified. Currently, TBVs are divided into two orders, nine families, at least 12 genera, and other unclassified members, with Bunyaviridae and Flaviviridae containing the most TBV members. With the further development of high-throughput sequencing technology in recent years, an increasing number of bunyaviruses have been identified. The Bunyaviridae family has gradually developed from the initial 5 viral genera into the current 12 viral families of the order Bunyavirales. The SFTSV, which was initially classified as part of the genus Phlebovirus, has now been reclassified as part of the genus Banyangvirus, and serves as the type species of this genus.
Heartland virus (HRTV) was first identified in two critically ill patients in Missouri, USA. Whole-genome sequencing revealed that HRTV is similar to SFTSV, both belonging to the genus Banyangvirus, marking the first discovery of a Banyangvirus causing severe human disease in the United States. Phylogenetic analysis shows that HRTV and SFTSV belong to the same clade. Clinical symptoms in the two patients were similar to those in patients with SFTSV infection: fever, fatigue, loss of appetite, diarrhea, leukopenia, and thrombocytopenia. Similar to SFTSV and GTV, the HRTV genome is divided into three segments: S, M and L. The S segment of HRTV encodes two proteins, NP and NSs; NP is the most important immunogen. The M segment encodes the glycoprotein, the major target of neutralizing immune responses and the mediator of HRTV interaction with host cell receptors. The HRTV L segment encodes RNA-dependent RNA polymerase (RdRP) which is directly involved in transcription and replication of the viral genome.
All bunyaviruses have a similar genome organization. They have segmented negative-sense or ambisense RNA genomes that are composed of three segments: L, M, and S. The L segment encodes RdRp that directly involved in viral genome transcription. The M segment encodes structural glycoproteins Gn and Gc. They are responsible for binding to host cell receptors, and are the main targets of neutralizing antibodies. The S segment uses an ambisense coding strategy to express nucleocapsid protein (N) and non-structural protein NSs. The NSs protein can suppress host innate immune responses during orthobunyavirus infection, promoting viral replication. In various pathogenic bunyaviruses (including HRTV), the NSs protein is considered a key virulence factor that may participate in viral pathogenesis. Animal experiments have found that the primary immune response against HRTV targets the N protein, but since the N protein is not on the viral surface, this immune response cannot neutralize the virus.
Figure 1. Schematic diagram of the HRTV virion and genome organization
(Source: Feng K, et al. 2024)
Bunyaviruses use a cap-snatching mechanism for viral mRNA transcription. In this step, the viral RNA polymerase also "borrows" short capped primers from host mRNAs. Using the L protein, the viral mRNA is transcribed. Cap-snatching is a three-step process where the viral RdRp binds to the 5' methylated cap structure of host mRNA, the viral endonuclease cleaves the host mRNA a few nucleotides downstream from the cap, and the capped RNA fragment is used as a primer by RdRp to synthesize viral mRNA.
In the United States, most HRTV cases are reported from the Midwest and South, where the distribution of A. americanum coincides. In laboratory experiments, the lone star tick (A. americanum) was found to be the major vector. Lone star tick larvae and nymphs can become infected after immersion in viral suspensions and are able to transmit HRTV by transstadial transmission, nonviremic transmission, vertical transmission and horizontal transmission. The virus is known to be acquired by Lone star tick larvae by feeding on viremic hosts (infected white-tailed deer or raccoon). Transstadial transmission of the virus (larvae→nymph→adult) to blood-feeding nymphs and adults has also been shown. Laboratory experiments have confirmed that the virus can be transmitted vertically within ticks (transovarial transmission) as well as through co-feeding transmission (when infected and uninfected ticks feeding on the same host simultaneously). Nymph bites are the primary route of human infection, with peak activity occurring during spring and summer. Notably, the Asian longhorned tick (Haemaphysalis longicornis) has also been shown to transmit HRTV under laboratory conditions, making it a potential new vector for HRTV.
Figure 2. Proposed transmission model for the Heartland virus
(Source: Brault AC, et al. 2018)
Serological evidence has indicated that numerous domestic and wild animals including white-tailed deer, raccoons, horses, dogs, opossums, moose, and coyotes are possible reservoir hosts for HRTV because HRTV-specific neutralizing antibodies have been found in these animals. White-tailed deer and raccoons in particular are thought to be important hosts for virus maintenance and amplification due to their high population densities and frequent exposure to ticks. In contrast, experimental infections have shown that although many hosts, including white-tailed deer, raccoons, and goats are seropositive, there is no evidence of clinically relevant viremia and disease in these animals, except for immunodeficient hosts such as mice deficient in type I interferon signaling. This discrepancy in findings has led to the hypothesis that vertical transmission in ticks and co-feeding may be the primary driver of the enzootic cycle of the virus, and that the vertebrate hosts may simply serve as an "ecological bridge" that facilitates tick infection through repeated blood meals, but do not represent amplification hosts.
The viral infection is sensed by the host cell PRRs (RIG-I-like receptors and Toll-like receptors). PRRs initiate the downstream signalling pathways that recruit the crucial kinases such as TBK1 and IKKε to phosphorylate the transcription factors like IRF3 and NF-κB. The activated transcription factors move to the nucleus, and initiate the expression of type I and III interferons and pro-inflammatory cytokines. The secreted interferons bind to their cell-surface receptors, and trigger the activation of STAT1 and STAT2 to form ISGF3 complex. ISGF3 moves to the nucleus and induces the expression of ISGs. The ISGs may then act to inhibit viral infection at various steps.
Screening studies have identified several host antiviral factors that block viral replication, including MOV10 and MxA. MOV10 is robustly induced early during Banyangvirus (e.g., SFTSV, HRTV) infection, and MOV10 inhibits viral replication by binding to the nucleoprotein, thereby preventing the formation of the viral ribonucleoprotein (RNP) complex. MxA is an antiviral protein that directly binds viral NP, thereby blocking NP interaction with the RdRp and inhibiting viral replication.
The non-structural protein NSs of HRTV is an important virulence factor that effectively counteracts host interferon responses. Experiments have shown that HRTV NSs protein can target and inhibit STAT2, blocking type I and III interferon signaling pathways. Unlike SFTSV NSs, HRTV NSs primarily blocks STAT2 nuclear translocation, but during viral infection it can also suppress STAT1 activation and nuclear translocation. HRTV NSs can also bind to TBK1, blocking the TBK1-IRF3 interaction, inhibiting IRF3 phosphorylation and nuclear translocation, thereby blocking IFN-β production. HRTV NSs protein has the potential to induce pro-viral autophagy. Studies had shown that infection by SFTSV could induce autophagy. SFTSV NSs protein expression could promote the conversion of autophagy-related protein LC3-I to LC3-II, a marker of active autophagy. Mechanistically, SFTSV NSs protein bound to mTOR protein and sequestered it in inclusion bodies, thereby attenuating mTOR's inhibition of ULK1, which activates ULK1 to induce autophagy, thus facilitating SFTSV infection. Through the SFTSV reverse genetic minigenome system, research has found that autophagy can promote SFTSV replication and propagation because autophagy enhances the activity of RNP. In the same study, it was discovered that HRTV NSs protein can also target mTOR through protein-protein interactions. Subsequent studies demonstrated that HRTV NSs protein suppresses ULK1 phosphorylation at Ser 757 and induces LC3-I to LC3-II conversion, suggesting that HRTV may also control autophagy by a similar mechanism to support its own replication. However, the details of HRTV NSs regulation of host autophagy still require further investigation. All these events contribute to an impaired host antiviral signaling. As a result, virus can replicate without much hindrance and cause the disease. Animals that are deficient in the interferon system are highly sensitive to HRTV infection and develop severe pathology, suggesting that the interferon system and downstream ISGs (e.g., MOV10) have significant antiviral effects during HRTV infection.
Figure 3. The model of HRTV NSs interfering with host antiviral responses as a virulence factor
(Source: Feng K, et al. 2024)
The incubation period ranges from a few days to 2 weeks after a tick bite. The disease has an acute onset. The main symptoms are high fever, persistent headache, marked fatigue, muscle pain, joint pain, and gastrointestinal symptoms. Rash is rare, although patients may have a localized rash at the site of the tick bite. Clinical findings in some patients include confusion or altered mental status. Cerebrospinal fluid analysis from 2 patients did not show evidence of acute inflammation and was not suggestive of encephalitis or meningitis.
The most common laboratory abnormalities are hematologic abnormalities, elevated AST/ALT, and mild hyponatremia. Severe illness with multi-organ involvement can be associated with coagulopathy, a massive elevation of creatine kinase, acute kidney injury and metabolic acidosis. Histopathologic examination has revealed a generalized viral infiltration of the heart, liver, spleen and lung, as well as a systemic inflammatory response. Secondary hemophagocytic lymphohistiocytosis, a syndrome in which macrophages, having become over-stimulated, phagocytose blood cells and cause progressive blood cell depletion, has also been reported. Mortality is high in elderly males with comorbidities, with deaths most commonly attributable to respiratory failure or multi-organ failure.
Currently, there is no known antiviral therapy available to treat HRTV infection. Management of acute illness mainly relies on supportive care. Antipyretics and analgesics may be used to treat fever and pain. In severe cases, ventilator support, vasopressors, blood products, or dialysis may be necessary.
References
| Target | Cat. No. | Product Name | Host | Isotype | Application | |
| HRTV Glycoprotein 1 | DPAB-L20527 | Anti-Heartland virus Glycoprotein 1 Polyclonal antibody | Rabbit | IgG | ELISA | Inquiry |
| DPAB-DC4308 | Anti-Heartland virus G1 protein Polyclonal antibody | Rabbit | IgG | ELISA | Inquiry | |
| HRTV Glycoprotein 2 | DPAB-L20528 | Anti-Heartland virus Glycoprotein 2 Polyclonal antibody | Rabbit | IgG | ELISA | Inquiry |
| DPAB-DC4309 | Anti-Heartland virus G2 protein Polyclonal antibody | Rabbit | IgG | ELISA | Inquiry |
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| HRTV Glycoprotein 1 | CDBP5527 | HRTV GLYCOPROTEIN blocking peptide | N/A | Unconjugated | IB | Inquiry |
| DAG-WT3568 | Recombinant Heartland virus Glycoprotein G1 [His] | HEK293 cells | His | WB, ELISA, Immunogen | Inquiry | |
| HRTV Glycoprotein 2 | CDBP5528 | HRTV GLYCOPROTEIN blocking peptide | N/A | Unconjugated | IB | Inquiry |
| DAG-WT3569 | Recombinant Heartland virus Glycoprotein G2 [His] | HEK293 cells | His | WB, ELISA, Immunogen | Inquiry | |
| HRTV | DAG-WT3562 | Recombinant Heartland virus Nucleoprotein [His] | E. coli | His | WB, ELISA, Immunogen | Inquiry |
| DAG-WT3563 | Recombinant Heartland virus Nucleoprotein [His] | HEK293 cells | His | WB, ELISA, Immunogen | Inquiry | |
| DAG-WT3564 | Recombinant Heartland virus NS protein [His] | E. coli | His | WB, ELISA, Immunogen | Inquiry |
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