Abstract
Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.
Highlights
Numerous viruses relevant to human and animal health utilize a lympho-hematogenous route of dissemination whereby they penetrate their hosts though disruptions of epithelial surfaces such as the skin, spread to the draining lymph node via afferent lymphatics, and become systemic by disseminating to the blood through efferent lymphatics [1]
We demonstrated that the cytosolic pathogen recognition receptor (PRR) cGAS in hematopoietic cells but not in parenchymal cells is required for protection against ectromelia virus, the archetype for viruses that spread through the lympho-hematogenous route
We show that cGAS deficiency can be bypassed by local administration of cyclic-GMP-AMP by inducing IFN-I only in the skin and in the presence of virus
Summary
Numerous viruses relevant to human and animal health utilize a lympho-hematogenous route of dissemination whereby they penetrate their hosts though disruptions of epithelial surfaces such as the skin, spread to the draining lymph node (dLN) via afferent lymphatics, and become systemic by disseminating to the blood through efferent lymphatics [1]. Our understanding of how the host innate immune system mechanistically induces protective resistance to the virus during lympho-hematogenous dissemination is incomplete. Ectromelia virus (ECTV), a member of the Orthopoxvirus genus of large, closely-related DNA viruses and the causative agent of mousepox (the mouse homolog of human smallpox) is the archetype used to study lympho-hematogenous dissemination [1,2,3,4]. C57BL/6(B6) mice are resistant to mousepox, but B6 mice deficient in the IFN-I receptor (IFNAR) subunit IFNAR1 have very high levels of viral replication, dissemination and succumb to mousepox [8,9,10]. EVM166 inactivates mouse IFNα but not IFNβ suggesting that only IFNα is critical for resistance to mousepox [9]
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