A lethal model of disseminated dengue virus type 1 infection in AG129 mice

Milligan, Gregg N.; Sarathy, Vanessa V.; White, Mellodee; Greenberg, M. Banks; Campbell, Gerald A.; Pyles, Richard B.; Barrett, Alan D.T.; Bourne, Nigel

doi:10.1099/jgv.0.000923

Cited by 30 publications

(38 citation statements)

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“…Pathologic changes included splenomegaly with immune reactivity and hepatic focal necrosis. Also, we established similar AG129 models using low passage DENV-4 703-4, DENV-4 TVP-376, and DENV-1 WP/74 infection that develop hallmarks of dengue infection in humans 13 – 15 . Therefore acute, severe, lethal mouse models are available for the four DENVs.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a murine model of non-lethal, symptomatic dengue virus infection

Sarathy

White

Li³

et al. 2018

Sci Rep

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The mosquito-borne disease dengue is caused by four serologically- and genetically-related viruses, termed DENV-1 to DENV-4. Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/β/γ receptors). Recently, our group established lethal AG129 mouse infection models of DENV-1, DENV-3, and DENV-4 using human isolates. Here we compare a non-lethal, disseminated model of DENV-3 infection using strain D83-144 to that of the lethal outcome following infection by strain C0360/94. Both strains belong to DENV-3 genotype II and differ by only 13 amino acids. Intraperitoneal inoculation of AG129 mice with strain D83-144 led to clinical signs of dengue infection, such as cytokine induction, thrombocytopenia, and systemic infection. However, C0360/94 infection led to features of severe human dengue, including coagulopathy and lethal outcome, whereas D83-144 infection does not. This study is the first to investigate a low passage, non-mouse lethal strain in AG129 mice and demonstrates that D83-144 infection induces milder features of human dengue than those induced by lethal C0360/94 infection. The results suggest that the AG129 mouse model has applications to investigate factors associated with mild or severe disease.

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Section: Introductionmentioning

confidence: 99%

Characterization of a murine model of non-lethal, symptomatic dengue virus infection

Sarathy

White

Li³

et al. 2018

Sci Rep

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“…Of In relation to the hepatic tissue damage reported in humans infected by DENV, most studies have demonstrated some common characteristics of the livers infected with this virus, especially highlighting the presence of necrosis and microvesicular steatosis [12,15,24] . The presence of necrosis is a common finding among studies in both humans and in models of mice infected by DENV and YFV [2,12,15,22,25,26] . Histopathological evidence suggests that severe forms of DENV are determined by the presence of hepatocellular necrosis, usually delimited to zones I and II of hepatic acini [27] .…”

Section: Resultsmentioning

confidence: 99%

Dengue Virus and Yellow Fever Virus Damage the Liver: A Systematic Review About the Histopathological Profiles

Costa

Moita

Alves

et al. 2019

Journal of Gastroenterology and Hepatology Research

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available in the literature on the main histopathological alterations in the liver after infection by DENV and YFV. For so, a literature search was conducted in the PubMed and ScienceDirect databases for the selection of articles published between 2005 and 2018 with relevance on the subject under study. The search resulted in the selection of 20 articles, of which 15 assessed the histopathological alterations in the liver after infection by DENV and 5 evaluated liver tissue damage after YFV infection. All studies demonstrated the presence of the main tissue abnormalities typical of dengue and yellow fever infection, showing a greater severity of hepatic damage related to YF infection. The main histopathological alterations in the liver after infection by these arboviruses have been demonstrated, however, the knowledge regarding some tissue damage in the liver is limited. There is, therefore, the need for further studies to clarify the pathogenesis of the arboviruses under study and the role in the progression and severity of the lesions, especially related to liver damage.

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“…Additionally, IRF5 is required for controlling R. parkeri and viral infection (Carlin et al, 2017; Proenca-Modena et al, 2016; Thackray et al, 2014). Lastly, as with R. parkeri , many viruses have increased lethality in Ifnar -/- Ifngr -/- mice (Milligan et al, 2017; Rossi et al, 2016), suggesting a non-redundant protective role for IFN-I and IFN-γ in both types of infection. These similarities are not true for facultative cytosolic bacterial pathogens such as L. monocytogenes, for which IFN-γ is significantly more protective than IFN-I (Rayamajhi et al, 2010).…”

Section: Discussionmentioning

confidence: 95%

Inflammasome-mediated antagonism of type I interferon enhancesRickettsiapathogenesis

Burke

Engström

Chavez

et al. 2019

Preprint

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10Inflammasomes and interferons constitute two critical arms of innate immunity. Most facultative bacterial 11 pathogens that inhabit the host cell cytosol avoid activating inflammasomes and are often resistant to 12 killing by type I interferon (IFN-I). We report that the human pathogen Rickettsia parkeri, an obligate 13 intracellular pathogen that resides in the cytosol, is sensitive to IFN-I. The mechanism of IFN-I-14 dependent restriction requires the transcription factor IRF5, which upregulates anti-rickettsial factors 15 including guanylate-binding proteins and iNOS. However, R. parkeri curtails cGAS-dependent IFN-I 16 production by causing caspase-11-dependent pyroptosis. In vivo, inflammasome activation antagonizes 17 IFN-I production, enhancing R. parkeri abundance in the spleen. Mice lacking either IFN-I or IFN-g 18 signaling are resistant to infection, but mice lacking both rapidly succumb, revealing that both interferons 19 are required to control R. parkeri. This study illuminates how an obligate cytosolic pathogen exploits the 20 intrinsic trade-off between cell death and cytokine production to escape killing by innate immunity. 21 22 Highlights 23 • Rickettsia killed by GBPs activates caspase-11 and GSDMD, promoting pyroptosis 24 • Rickettsia exploits pyroptosis to avoid cGAS-dependent type I interferon 25 • IRF5, GBPs, and iNOS contribute to controlling R. parkeri infection 26 • Ifnar -/-Ifngr -/mice succumb to infection, uncovering a mouse model to study R. parkeri 27 28 Keywords 29 Inflammasome; type I interferon; IFN-g; Rickettsia parkeri; IRF5; guanylate-binding proteins; GBP2; 30 GBP5; caspase-11; cGAS 31 32 33 34 35 36 42 cytosol (Brubaker et al., 2015; McNab et al., 2015; Wallet et al., 2016). However, less well understood 43 are the innate immune responses to obligate intracellular bacterial pathogens. Spotted fever group 44 (SFG) Rickettsia spp. are tick-borne pathogens that cause spotted fever diseases worldwide (Walker 45 and Ismail, 2008). As obligate intracellular bacteria that replicate exclusively in the host cell cytosol, 46 SFG Rickettsia spp. must continually interface with host innate immune sensors. Therefore, they 47 presumably have evolved sophisticated mechanisms to avoid or even exploit innate immune responses.48 Following infection and subsequent detection of pathogen associated molecular patterns 49 (PAMPS) by host cell sensors (Takeuchi and Akira, 2010), cytokines including type I interferon (IFN-I) 50 are upregulated. For example, the detection of cytosolic DNA by cyclic GMP-AMP synthase (cGAS) 51 results in activation of the downstream adaptor stimulator of IFN genes (STING) and transcription 52 factors including IFN regulatory factor 3 (IRF3) to upregulate IFN-I expression and secretion (Sun et al., 53 2013). Binding of IFN-I to the interferon-a/b receptor (IFNAR) then activates a signaling cascade that 54 upregulates the expression of hundreds of interferon-stimulated genes (ISGs), mobilizing the cytosol to 55 an antimicrobial state (MacMicking, 2012; Meunier and Bro...

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A lethal model of disseminated dengue virus type 1 infection in AG129 mice

Cited by 30 publications

References 30 publications

Characterization of a murine model of non-lethal, symptomatic dengue virus infection

Characterization of a murine model of non-lethal, symptomatic dengue virus infection

Dengue Virus and Yellow Fever Virus Damage the Liver: A Systematic Review About the Histopathological Profiles

Inflammasome-mediated antagonism of type I interferon enhancesRickettsiapathogenesis

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