Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice

Khanolkar, Aaruni; Hartwig, Stacey M.; Haag, Brayton A.; Meyerholz, David K.; Harty, John T.; Varga, Steven M.

doi:10.1128/jvi.01857-08

Cited by 60 publications

(89 citation statements)

References 48 publications

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“…In addition to mouse-adapted SARS-CoV, we evaluated the susceptibility of murine ATI-like and ATII cells for infection by a murine coronavirus, MHV-1. MHV-1 infects the respiratory tract and causes disease with a wide range of severities, depending upon the genetic line of mice (De Albuquerque et al, 2006;Khanolkar et al, 2009). Upon intranasal inoculation with MHV-1, BALB/cJ mice exhibit some of the pathological characteristics of SARS in humans, including pulmonary congestion, alveolar and interstitial inflammation, and hyaline membranes.…”

Section: Discussionmentioning

confidence: 99%

“…MHV-1 is a murine coronavirus that causes severe disease and pathology in the lungs of specific genetic lines of mice (De Albuquerque et al, 2006;Khanolkar et al, 2009). The pathology of MHV-1 infection in A/J mice resembles that seen in fatal SARS cases, thus MHV-1 is studied as a model of SARS pulmonary pathogenesis (De Albuquerque et al, 2006).…”

Section: Mhv-1 Replicates In Primary Murine Cultures With An Ati or Amentioning

confidence: 99%

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Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses

2013

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Severe respiratory viral infections are associated with spread to the alveoli of the lungs. There are multiple murine models of severe respiratory viral infections that have been used to identify viral and host factors that contribute to disease severity. Primary cultures of murine alveolar epithelial cells provide a robust in vitro model to perform mechanistic studies that can be correlated with in vivo studies to identify cell type-specific factors that contribute to pathology within the alveoli of the lung during viral infection. In this study, we established an in vitro model to compare the responses of type I (ATI) and type II (ATII) alveolar epithelial cells to infection by respiratory viruses used in murine models: mouse-adapted severe acute respiratory syndrome-associated coronavirus (SARS-CoV, v2163), murine coronavirus MHV-1, and influenza A (H1N1) virus, strain PR8. Murine alveolar cells cultured to maintain an ATII cell phenotype, determined by expression of LBP180, were susceptible to infection by all three viruses. In contrast, ATII cells that were cultured to trans-differentiate into an ATI-like cell phenotype were susceptible to MHV-1 and PR8, but not mouse-adapted SARS-CoV. Epithelial cells produce cytokines in response to viral infections, thereby activating immune responses. Thus, virus-induced cytokine expression was quantified in ATI and ATII cells. Both cell types had increased expression of IL-1β mRNA upon viral infection, though at different levels. While MHV-1 and PR8 induced expression of a number of shared cytokines in ATI cells, there were several cytokines whose expression was induced uniquely by MHV-1 infection. In summary, ATI and ATII cells exhibited differential susceptibilities and cytokine responses to infection by respiratory viruses. This in vitro model will be critical for future studies to determine the roles of these specialized cell types in the pathogenesis of respiratory viral infection.

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Section: Discussionmentioning

confidence: 99%

Section: Mhv-1 Replicates In Primary Murine Cultures With An Ati or Amentioning

confidence: 99%

Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses

2013

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“…1 (MHV-1) infection, indicating that TLR-4 plays an important role in respiratory CoV pathogenesis (Khanolkar et al, 2009). In this study, we hypothesized whether intranasal infection of TLR-4 -/mice with mouse-adapted SARS-CoV would result in an acute respiratory disease with a higher lethality.…”

Section: Treatmentmentioning

confidence: 99%

“…Khanolkar et al reported that C3H/HeJ mice harboring a natural mutation in the gene that encodes Toll-like receptor 4 (TLR4) that disrupts its normal function exhibited the enhanced morbidity and mortality following i.n. mouse hepatitis virus strain 1 (MHV-1) infection, indicating that TLR-4 plays an important role in respiratory CoV pathogenesis (Khanolkar et al, 2009). In the current study, we hypothesized that intranasal infection of TLR4 -/-mice with mouse-adapted SARS-CoV would result in an acute respiratory disease with a higher lethality.…”

Section: Evaluating Therapeutic Dosing Regimens Of Treating Sars-cov mentioning

confidence: 99%

Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model

et al. 2017

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Hiltonol, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol is considered for possible clinical use.

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“…On the surface of cells, TLR1, TLR2, TLR4, and TLR6 have been implicated in the recognition of PAMPs from other viruses (Figure 3a), while the endosomal receptors TLR3, TLR7, TLR8, and TLR9 detect viral nucleic acid PAMPs (Figure 3b). TLR4 recognizes viral glycoproteins of RSV, is expressed on the surface of lung epithelium, is a potential entry co-factor for respiratory viruses, and has been identified as a protective host factor against MHV-1 in a respiratory model of SARS disease [47][48][49]. Transcription of TLRs increased in mice following infection with MA15-SARS-CoV and in human dendritic cells infected with SARS-CoV [50 ,51].…”

Section: Toll-like Receptor Signalingmentioning

confidence: 99%

SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon

Totura

Baric

2012

Current Opinion in Virology

384

437

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SARS-CoV is a pathogenic coronavirus that emerged from a zoonotic reservoir, leading to global dissemination of the virus. The association SARS-CoV with aberrant cytokine, chemokine, and Interferon Stimulated Gene (ISG) responses in patients provided evidence that SARS-CoV pathogenesis is at least partially controlled by innate immune signaling. Utilizing models for SARS-CoV infection, key components of innate immune signaling pathways have been identified as protective factors against SARS-CoV disease, including STAT1 and MyD88. Gene transcription signatures unique to SARS-CoV disease states have been identified, but host factors that regulate exacerbated disease phenotypes still remain largely undetermined. SARS-CoV encodes several proteins that modulate innate immune signaling through the antagonism of the induction of Interferon and by avoidance of ISG effector functions.

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Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice

Cited by 60 publications

References 48 publications

Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses

Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses

Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model

SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon

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