Immunological Responses to Seoul Orthohantavirus in Experimentally and Naturally Infected Brown Rats (Rattus norvegicus)

Yasuda, Shumpei P.; Shimizu, Kenta; Koma, Takaaki; Hoa, Nguyen Thuy; Le, Mai Quynh; Wei, Zhuoxing; Muthusinghe, Devinda S.; Lokupathirage, Sithumini M. W.; Hasebe, Futoshi; Yamashiro, Tetsu; Arikawa, Jiro; Yoshimatsu, Kumiko

doi:10.3390/v13040665

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…The detection of high viral RNA copy numbers in genome-positive rodent tissues suggests a high possibility of shedding viruses in their excreta. Yasuda et al reported that the Seoul orthohantavirus was excreted in feces when showing more than 10 5 genome copies/mg of lung tissues of R. norvegicus [ 43 ]. The Lanka virus and SA108 may pose elevated risks of human infections.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Rodent-Borne Orthohantaviruses in an Endemic Area of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Muthusinghe

Shimizu

Lokupathirage

et al. 2021

Viruses

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We reported the genetic evidence of circulating hantaviruses from small mammals captured in a chronic kidney disease of unknown etiology (CKDu) hotspot area of Sri Lanka. The high seroprevalence of anti-hantavirus antibodies against Thailand orthohantavirus (THAIV) has been reported among CKDu patients and rodents in Sri Lankan CKDu hotspots. We captured 116 small mammals from CKDu endemic regions in the Polonnaruwa District of Sri Lanka. Seven animals (five out of 11 Mus booduga and two out of 99 Rattus rattus) were PCR-positive for the hantavirus. A rat-borne sequence was grouped with a THAIV-like Anjozorobe virus. In contrast, Mus-borne sequences belonged to the THAIV lineage, suggesting a novel orthohantavirus species according to the phylogenetic analyses and whole-genome comparisons. Our genetic evidence indicates the presence of two THAIV-related viruses circulating in this CKDu endemic area, suggesting a basis for further investigations to identify the infectious virus in patients with CKDu and the CKDu induction mechanism of these viruses.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Rodent-Borne Orthohantaviruses in an Endemic Area of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Muthusinghe

Shimizu

Lokupathirage

et al. 2021

Viruses

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“…We hypothesize that later during acute infection in rats, the virus-induced endothelial PD-L1 increases to high levels to eliminate virus with minimal collateral vascular and tissue damage in the lungs. When virus is not entirely cleared, this results in persistent infection, as previously observed in naturally infected rats [ 50 ]. The association of severe HRFS cases with increased CD8 + T cell activity and initial failure to mount strong T cell responses early during acute infection, further confirms that the in rats observed PD-L1-mediated immunomodulatory mechanism is less efficient or less present in human patients, thereby failing to protect them from immunopathology [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 72%

Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells

Noack,

van den Hout,

Embregts

et al. 2024

PLoS Negl Trop Dis

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Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.

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“…Conversely, virus specific CD8+ T cells are also effective in recovery [ 24 ]. Suppression of CD8+ T cells is probably associated with the establishment of persistent infection [ 45 , 46 ]. Since KHF, especially KHF5, replicates faster in mouse tissues than prototype Hantaan virus strain 76–118, T-cell activations tending towards increasing inflammation rather than recovery.…”

Section: Discussionmentioning

confidence: 99%

Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome

Wei

Shimizu

Sarii

et al. 2022

Viruses

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Hantaan virus is the causative agent of hemorrhagic fever with renal syndrome (HFRS). The Hantaan virus strain, Korean hemorrhagic fever virus clone-5 (KHF5), causes weight loss and renal hemorrhage in laboratory mice. Clone-4 (KHF4), which has a single E417K amino acid change in its glycoprotein, is an avirulent variant. In this study, KHF4 and KHF5 were compared to evaluate pathological differences in mice in vitro and in vivo. The characteristics of the two glycoproteins were not significantly different in vitro. However, the virulent KHF5 strain targeted the lungs and caused pneumonia and edema in vivo. Both strains induced high infectivity levels in the liver and caused hepatitis; however, petechial hemorrhage and glycogen storage reduction were observed in KHF5-infected mice alone. Renal hemorrhage was observed using viral antigens in the tubular region of KHF5-infected mice. In addition, an increase in white blood cell levels and neutrophilia were found in KHF5-infected mice. Microarray analysis of liver cells showed that CD8+ T cell activation, acute-phase protein production, and neutrophil activation was induced by KHF5 infection. KHF5 infectivity was significantly increased in vivo and the histological and clinicopathological findings were similar to those in patients with HFRS.

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Immunological Responses to Seoul Orthohantavirus in Experimentally and Naturally Infected Brown Rats (Rattus norvegicus)

Cited by 6 publications

References 37 publications

Identification of Novel Rodent-Borne Orthohantaviruses in an Endemic Area of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Identification of Novel Rodent-Borne Orthohantaviruses in an Endemic Area of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells

Pathological Studies on Hantaan Virus-Infected Mice Simulating Severe Hemorrhagic Fever with Renal Syndrome

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