Dynamics of human B and T cell adaptive immune responses to Kyasanur Forest disease virus infection

Devadiga, Santhosha; McElroy, Anita K.; Prabhu, Suresh; Arunkumar, Govindakarnavar

doi:10.1038/s41598-020-72205-1

Cited by 11 publications

(10 citation statements)

References 16 publications

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“…While monocytes/macrophages are known targets of flavivirus infections, the consequences of potential B cell infection or antigen positivity is not described. A recent report of human infection with KFDV showed decreased levels of activated B cells in the acute phase of illness [ 40 ]. The association of virus and B cells in the PTMs could provide mechanism for this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…The current vaccine for KFDV is a formalin-inactivated virus preparation that requires multiple boosters and has limited efficacy. Unfortunately, patients who received the KFDV vaccine may still develop viremia and clinical illness after KFDV infection [ 40 , 57 , 58 ]. While the TBEV vaccine elicits cross-neutralizing antibodies that may protect against KFDV and AHFV [ 59 ], the TBEV vaccine is not approved for prevention of disease caused by these hemorrhagic TBFVs.…”

Section: Discussionmentioning

confidence: 99%

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A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis

et al. 2021

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Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis

et al. 2021

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“…While monocytes/macrophages are known targets of flavivirus infections, the consequences of potential B cell infection or antigen positivity is not described. A recent report of human infection with KFDV showed decreased levels of activated B cells in the acute phase of illness (34). The association of virus and B cells in the PTMs could provide mechanism for this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…The current vaccine for KFDV is a formalin-inactivated virus preparation that requires multiple boosters and has limited efficacy. Unfortunately, patients who received the KFDV vaccine may still develop viremia and clinical illness after KFDV infection (34, 46, 47). No vaccine has been approved for prevention of disease caused by AHFV.…”

Section: Discussionmentioning

confidence: 99%

A pigtailed macaque model for Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus

Feldmann

McNally

et al. 2021

Preprint

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Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models for KFDV do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs such as epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.Author SummaryKyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic disease virus (AHFV) are tick-borne flaviviruses that cause viral hemorrhagic fevers in India and the Arabian Peninsula, respectively. Bonnet macaques and black-faced langurs are susceptible to KFDV infection, but these animals do not experience hemorrhagic signs as seen in human cases with KFDV. This work characterizes for the first time experimental infection of KFDV and AHFV in pigtailed macaques (PTMs). Infected PTMs can develop moderate to severe disease that mirrors many aspects of human disease, including some hemorrhagic signs. Together these data describe the PTM model for KFDV and AHFV as a valuable tool for future work to study viral pathogenesis and for assessing the efficacy of vaccines and antivirals.

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“…Previous report on KFDV immune response has suggested to target both T cell and B cells mediated immune response for successful KFDV vaccine development 18 . Here, we have applied few immune informatic tools to identify the epitope which elicit both cellular and humoral immune responses.…”

Section: Discussionmentioning

confidence: 99%

In-Silico Design of Envelope based Multi-epitope Vaccine Candidate Against Kyasanur Forest Disease Virus

Arumugam

2021

Preprint

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Kyasanur Forest Disease Virus (KFDV) causing common tick-borne hemorrhagic fever in south India, there is no approved anti-viral or efficacious vaccine against this disease. Recent KFDV spread into new geographic locations gives urgent call for development of new vaccine and drugs. In this study, we adapted in-silico approach to design multi-epitope subunit vaccine for KFDV. Conserved regions of KFDV envelope protein sequences reported during 1962 to 2016 were identified. Eight different immuno-informatics tools were employed to predict the linear B-cell and T-cell epitopes, high scored and/or multi-immunogenic epitopes were linked together and obtained two vaccine candidates (VC1 and VC2). Obtained vaccine candidates were found to be non-allergic and had good antigenic properties, also gives the cross-protection against to Alkhurma Hemorrhagic Fever virus (AHFV). The 3D structures of vaccine candidates were built and validated. Docking of vaccine candidates with toll-like receptor-8 (TLR-8) was performed by Hex 8.0 and Cluspro, highest binding energy observed between VC2 and TLR8. JCAT sever confirmed cloning efficiency of both vaccine constructs and in-silico cloning into pET30a (+) vector by SnapGene suggests successful translation of vaccine constructs. In this study, multi-epitope vaccine candidates were designed and validated, it paves the way for up-coming vaccine and diagnostic kit development.

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Dynamics of human B and T cell adaptive immune responses to Kyasanur Forest disease virus infection

Cited by 11 publications

References 16 publications

A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis

A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis

A pigtailed macaque model for Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus

In-Silico Design of Envelope based Multi-epitope Vaccine Candidate Against Kyasanur Forest Disease Virus

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