Related Experiment Video
Updated: Jul 29, 2025
Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection
Abstract:
SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responses in-vivo are not well defined. CoVs possess single-stranded RNA (ssRNA) genome that is abundantly produced during infection and stimulates both antiviral interferon (IFN) and inflammatory cytokine/ chemokine responses. Therefore, in this study, using wild-type control and TLR7 deficient BALB/c mice infected with a mouse-adapted SARS-COV-2 (MA-CoV-2), we evaluated the role of TLR7 signaling in MA-CoV-2-induced antiviral and inflammatory responses and disease outcome. We show that TLR7-deficient mice are more susceptible to MA-CoV-2 infection as compared to infected control mice. Further evaluation of MA-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral type I (IFNα/β) and type III (IFNλ) IFNs, IFN stimulated genes (ISGs, ISG15 and CXCL10), and several pro-inflammatory cytokines/chemokines in TLR7 deficient compared to control mice. Reduced lung IFN/ISG levels and increased morbidity/mortality in TLR7 deficient mice correlated with high lung viral titer. Detailed examination of total cells from MA-CoV-2 infected lungs showed high neutrophil count in TLR7 deficient mice compared to control mice. Additionally, blocking TLR7 activity post-MA-CoV-2 infection using a specific inhibitor also enhanced disease severity. In summary, our results conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite robust inflammatory response, TLR7-mediated IFN/ISG responses likely protect the host from lethal disease. Given similar outcomes in control and TLR7 deficient humans and mice, these results show that MA-CoV-2 infected mice serve as excellent model to study COVID-19.
Insights
Toll-like receptor 7 (TLR7) signaling is protective against SARS-CoV-2 infection. TLR7 deficiency increases susceptibility to severe pneumonia by impairing antiviral responses and increasing viral load.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- SARS-CoV-2 infection can cause fatal pneumonia due to impaired antiviral responses and excessive inflammation.
- The specific pattern recognition receptors responsible for effective antiviral and lethal inflammatory responses in vivo are not fully understood.
- Single-stranded RNA (ssRNA) from coronaviruses stimulates both antiviral interferon and inflammatory responses.
Purpose of the Study:
- To investigate the role of Toll-like receptor 7 (TLR7) signaling in antiviral and inflammatory responses to mouse-adapted SARS-CoV-2 (MA-CoV-2) infection.
- To determine the impact of TLR7 signaling on disease outcome in a mouse model of COVID-19.
Main Methods:
- Utilized wild-type and TLR7-deficient BALB/c mice infected with MA-CoV-2.
- Analyzed mRNA levels of type I and III interferons (IFNs), IFN-stimulated genes (ISGs), and cytokines/chemokines in lung tissue.
- Assessed lung viral titers, immune cell populations (neutrophils), morbidity, and mortality.
- Investigated the effect of TLR7 inhibition on disease severity post-infection.
Main Results:
- TLR7-deficient mice exhibited increased susceptibility to MA-CoV-2 infection compared to control mice.
- Reduced mRNA levels of IFNs, ISGs (ISG15, CXCL10), and pro-inflammatory mediators were observed in the lungs of TLR7-deficient mice.
- Lower IFN/ISG levels in TLR7-deficient mice correlated with higher lung viral titers, increased neutrophil counts, and enhanced morbidity/mortality.
- Blocking TLR7 activity post-infection exacerbated disease severity.
Conclusions:
- TLR7 signaling plays a crucial protective role during SARS-CoV-2 infection.
- TLR7-mediated interferon and ISG responses are critical for controlling viral replication and preventing lethal disease, despite potentially robust inflammatory signals.
- MA-CoV-2 infected mice, particularly TLR7-deficient models, serve as a valuable tool for studying COVID-19 pathogenesis and host responses.
