Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

Klingström, Jonas; Smed‐Sörensen, Anna; Maleki, Kimia T.; Solà-Riera, Carles; Ahlm, Clas; Björkström, Niklas K.; Ljunggren, Hans‐Gustaf

doi:10.1111/joim.12876

Cited by 47 publications

(42 citation statements)

References 115 publications

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“…This outcome may therefore also represent a universal rodent host response to orthohantaviruses. The absence of proinflammatory responses, correlating with asymptomatic infections in our non-reservoir host mouse model, strengthens the evidence that hantavirus disease is driven by inflammation [9,61]. Importantly, we observed no differences in viral load or tissue dissemination between WT and Mavs -/mice, indicating that other immune signaling pathways are involved in type I IFN production and viral control in vivo.…”

Section: Plos Pathogenssupporting

confidence: 85%

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

et al. 2020

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Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.

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Section: Plos Pathogenssupporting

confidence: 85%

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

et al. 2020

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“…At the same time, hantavirus infection triggers a massive activation of cytotoxic lymphocytes, which should serve to eradicate infected cells. However, despite high levels of activated NK cells and CD8 T cells in hantavirus-infected patients (Bjö rkströ m et al, 2011;Kilpatrick et al, 2004;Lindgren et al, 2011;Van Epps et al, 2002), analyses of autopsies from deceased patients have revealed that infected endothelial cells are intact (Zaki et al, 1995), and others have also reported not observing clear cytopathic effects on infected endothelial cells (Safronetz et al, 2014;Klingströ m et al, 2019;Vaheri et al, 2013). These observations suggested the possibility that hantaviruses could inhibit cytotoxic lymphocyte-mediated killing, likely contributing to the observed high levels of infected cells in patients.…”

Section: Discussionmentioning

confidence: 99%

Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

et al. 2019

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“…Well controlled human studies have shown that hantavirus infections cause aberrant activation of both innate and adaptive immunity (5–8). A potent antiviral IgG-response is associated with protection from severe disease during both HPS and HFRS (9–12) and passive transfer of serum antibodies could reduce case fatality rate in a small cohort of HPS patients (13).…”

Section: Introductionmentioning

confidence: 99%

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

Kerkman

Dernstedt

Tadala

et al. 2019

Preprint

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Human hantavirus infections can cause hemorrhagic fever with renal syndrome (HFRS), major signs of the disease being thrombocytopenia and transient kidney dysfunction. By a comprehensive and longitudinal study of circulating B cells, we demonstrate that these two pathologies associate with distinct effects on the humoral immune system during HFRS. Low thrombocyte counts strongly associated with an abnormal frequency of plasmablasts in circulation, whereas kidney dysfunction was indicative of an accumulation of CD27 -B cells and plasmablasts. Finally, we provide evidence that high levels of extracellular ATP in circulation during HFRS correlates with shedding of surface CD27 on B cells via a metallomatrix proteinase-8-mediated mechanism. Since extracellular ATP is known to regulate kidney function, our study reveals a link between kidney dysfunction and the generation of CD27 -IgD -B cells, and a potential molecular target for treatment of the symptomatic phase of HFRS. Dobrava, Seol and Puumala (PUUV) strains, where PUUV is endemic to Scandinavia. To date, no efficacious treatment or vaccination regimen exists to protect against severe hantavirus infections.Well controlled human studies have shown that hantavirus infections cause aberrant activation of both innate and adaptive immunity (5)(6)(7)(8). A potent antiviral IgG-response is associated with protection from severe disease during both HPS and HFRS (9-12) and passive transfer of serum antibodies could reduce case fatality rate in a small cohort of HPS patients (13). These findings clearly demonstrate that activation of the humoral immune system and subsequent elicitation of antiviral antibodies play a central role in the control of viremia and/or pathogenesis during hantavirus infections.A recent study of HPS demonstrated that very high levels of plasmablasts (PBs) and CD27 -IgD -B cells were detected in circulation of patients (14). The rapid and extensive PB-response is similar to that reported during acute dengue virus infection and contrasts to the comparably moderate levels of PBs that are found in circulation during influenza infection or after influenza vaccination (15). An expansion of the CD27 -IgD -B cell subset has previously been shown for numerous inflammatory and infectious diseases, as well as during ageing and cancer (16-21), yet their functional role in humoral immunity remains undetermined. The CD27 -IgD -B cells resemble memory B cells, have isotype switched and hypermutated B cell receptors and therefore likely originate from T cell-dependent germinal center reactions in secondary lymphoid organs (16, 20). In systemic lupus erythematosus (SLE), an expanded population of CD27 -IgD -B cells was associated with the manifestation of nephritis in patients (16). This suggests that their detection in blood may be linked to reduced kidney function, but the cause for their expansion remains to be determined.During HFRS-causing hantavirus infections, reduced kidney function occurs independently of the induced thrombocytopenia (22, 23). We therefor...

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Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

Cited by 47 publications

References 115 publications

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

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Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

Cited by 47 publications

References 115 publications

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication

Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

The generation of plasma cells and CD27−IgD−B cells during Hantavirus infection are associated with distinct pathological findings

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The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings