Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever

Remy, Melissa M; Mehmet, Sahin; Flatz, Lukas; Regen, Tommy; Xu, Liangliang; Kreutzfeldt, Mario; Fallet, Bénédict; Doras, Camille; Rieger, Toni; Bestmann, Lukas; Hanisch, Uwe‐Karsten; Kaufmann, Beat A.; Merkler, Doron; Pinschewer, Daniel D.

doi:10.1016/j.chom.2017.07.008

Cited by 15 publications

(10 citation statements)

References 70 publications

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“…Other models of LCMV-induced pathogenesis have implicated lung injury, platelet loss, cytokine storm, and IFNg- induced nitric oxide and shock (Baccala et al, 2014; Christiaansen et al, 2017; Oldstone et al, 1993, 2018; Puglielli et al, 1999; Remy et al, 2017; Schnell et al, 2012). Similar to our findings with B6.PL mice, NZB, NZO, and FVB strains of mice show thrombocytopenia, vascular permeability, soaring inflammatory cytokine expression, and lethality following LCMV-Clone13 (Baccala et al, 2014; Oldstone et al, 1993, 2018; Puglielli et al, 1999; Schnell et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Locus in Mice that Regulates the Collateral Damage and Lethality of Virus Infection

et al. 2019

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SUMMARY Arenaviruses can cause severe hemorrhagic disease in humans, which can progress to organ failure and death. The underlying mechanisms causing lethality and person-to-person variation in outcome remain incompletely explained. Herein, we characterize a mouse model that recapitulates many features of pathogenesis observed in humans with arenavirus-induced hemorrhagic disease, including thrombocytopenia, severe vascular leakage, lung edema, and lethality. The susceptibility of congenic B6.PL mice to lymphocytic choriomeningitis virus (LCMV) infection is associated with increased antiviral T cell responses in B6.PL mice compared with C57BL/6 mice and is T cell dependent. Pathogenesis imparted by the causative locus is inherited in a semi-dominant manner in F1 crosses. The locus includes PL-derived sequence variants in both poorly annotated genes and genes known to contribute to immune responses. This model can be used to further interrogate how limited genetic differences in the host can remarkably alter the disease course of viral infection.

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Section: Discussionmentioning

confidence: 99%

Identification of a Locus in Mice that Regulates the Collateral Damage and Lethality of Virus Infection

et al. 2019

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“…Indeed, several laboratories have used LCMV to develop surrogate animal models for LF (reviewed in [19]). For example, the LCMV (WE strain) can cause a disease in rhesus macaques [20] and HHD mice [21] that reproduces certain aspects of LASV pathogenesis such as vascular leakage. However, the requirement of a BSL-3 biosecurity and biosafety to work with LCMV (WE strain) limits its use.…”

Section: Introductionmentioning

confidence: 99%

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

et al. 2020

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Arenaviruses, such as Lassa virus (LASV), can cause severe and fatal hemorrhagic fevers (e.g., Lassa fever, LF) in humans with no vaccines or therapeutics. Research on arenavirus-induced hemorrhagic fevers (AHFs) has been hampered by the highly virulent nature of these viral pathogens, which require high biocontainment laboratory, and the lack of an immune-competent small animal model that can recapitulate AHF disease and pathological features. Guinea pig infected with Pichinde virus (PICV), an arenavirus that does not cause disease in humans, has been established as a convenient surrogate animal model for AHFs as it can be handled in a conventional laboratory. The PICV strain P18, derived from sequential passaging of the virus 18 times in strain 13 inbred guinea pigs, causes severe febrile illness in guinea pigs that is reminiscent of lethal LF in humans. As inbred guinea pigs are not readily available and are difficult to maintain, outbred Hartley guinea pigs have been used but they show a high degree of disease heterogeneity upon virulent P18 PICV infection. Here, we describe an improved outbred guineapig infection model using recombinant rP18 PICV generated by reverse genetics technique followed by plaque purification, which consistently shows >90% mortality and virulent infection. Comprehensive virological, histopathological, and immunohistochemical analyses of the rP18virus infected animals show similar features of human LASV infection. Our data demonstrate that this improved animal model can serve as a safe, affordable, and convenient surrogate small animal model for studying human LF pathogenesis and for evaluating efficacy of preventative or therapeutic approaches.

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“…Interferon‐γ manipulated multiple functions to modulate innate and adaptive immune response against pathogen infections . Evidence demonstrated a critical role of IFN‐γ in mediating vasculature reprogramming and that IFN‐γ produced by CD4 T helper cells altered vascular permeability to indulge antibody through blood‐nerve barrier .…”

Section: Discussionmentioning

confidence: 99%

Interferon‐γ facilitated adjuvant‐induced arthritis at early stage

Zhang

et al. 2019

Scand J Immunol

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Background and aim: Interferon-γ (IFN-γ) is a versatile cytokine which broadly involves in the inflammatory diseases, mediating both immune activation and tolerance. Here, we aimed to investigate the role of IFN-γ in the initiation of adjuvant-induced arthritis (AIA). Methods and Results:In an AIA mice model, increasing IFN-γ mRNA was observed at day 3 and peaked on day 7. At day 3, the majority of IFN-γ-producing cells were located around vessels observed by immunofluorescent staining. Recombinant IFN-γ or anti-IFN-γ antibody was injected into the AIA paw on day 2 to study the outcome of AIA. The recipients of IFN-γ showed increased synovial inflammation, whereas anti-IFN-γ antibody injection repressed the expansion of inflammatory cells. As the percentages of blood monocytes were approximately equivalent, we hypothesized that IFN-γ might impact the access of innate leucocytes from blood to expand local inflammation at this stage. Analysis of tissue CD31 and vascular cell adhesion molecule-1 (VCAM-1) expressions suggested a positive effect of these factors in the development of inflammation, and IFN-γ affected the VCAM-1 expression. To further verify this idea, mice regionally injected with IFN-γ were systematically administrated with anti-VCAM-1 antibody during AIA induction. The IFN-γ expression was inhibited, and the development of AIA was partly abolished in these mice regardless of regional IFN-γ injection. Conclusion: These data suggested that IFN-γ might be critical for the expansion of AIA at early stage through helping inflammatory cell access.

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Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever

Cited by 15 publications

References 70 publications

Identification of a Locus in Mice that Regulates the Collateral Damage and Lethality of Virus Infection

Identification of a Locus in Mice that Regulates the Collateral Damage and Lethality of Virus Infection

Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever

Interferon‐γ facilitated adjuvant‐induced arthritis at early stage

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