Vaccinia virus induces rapid necrosis in keratinocytes by a STAT3-dependent mechanism
Yong He1, Robert Fisher1, Soma Chowdhury1
1Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
Rationale:
Humans with a dominant negative mutation in STAT3 are susceptible to severe skin infections, suggesting an essential role for STAT3 signaling in defense against cutaneous pathogens.
Methods:
To focus on innate antiviral defenses in keratinocytes, we used a standard model of cutaneous infection of severe combined immunodeficient mice with the current smallpox vaccine, ACAM-2000. In parallel, early events post-infection with the smallpox vaccine ACAM-2000 were investigated in cultured keratinocytes of human and mouse origin.
Results:
Mice treated topically with a STAT3 inhibitor (Stattic) developed larger vaccinia lesions with higher virus titers and died more rapidly than untreated controls. Cultured human and murine keratinocytes infected with ACAM-2000 underwent rapid necrosis, but when treated with Stattic or with inhibitors of RIP1 kinase or caspase-1, they survived longer, produced higher titers of virus, and showed reduced activation of type I interferon responses and inflammatory cytokines release. Treatment with inhibitors of RIP1 kinase and STAT3, but not caspase-1, also reduced the inflammatory response of keratinocytes to TLR ligands. Vaccinia growth properties in Vero cells, which are known to be defective in some antiviral responses, were unaffected by inhibition of RIP1K, caspase-1, or STAT3.
Conclusions:
Our findings indicate that keratinocytes suppress the replication and spread of vaccinia virus by undergoing rapid programmed cell death, in a process requiring STAT3. These data offer a new framework for understanding susceptibility to skin infection in patients with STAT3 mutations. Interventions which promote prompt necroptosis/pyroptosis of infected keratinocytes may reduce risks associated with vaccination with live vaccinia virus.
Insights
STAT3 signaling is crucial for skin immunity against vaccinia virus. Keratinocytes use programmed cell death to limit viral spread, a process dependent on STAT3. This finding impacts understanding STAT3 mutations and vaccinia virus vaccination risks.
Area of Science:
- Immunology
- Dermatology
- Virology
Background:
- STAT3 mutations impair immunity to skin infections.
- STAT3 signaling plays a vital role in cutaneous pathogen defense.
Purpose of the Study:
- Investigate STAT3's role in keratinocyte innate antiviral defense.
- Examine early events in keratinocyte infection with vaccinia virus (ACAM-2000).
Main Methods:
- Used a mouse model of cutaneous vaccinia virus infection.
- Studied human and mouse keratinocytes infected with ACAM-2000.
- Utilized STAT3 inhibitor (Stattic) and other kinase inhibitors.
Main Results:
- STAT3 inhibition worsened vaccinia lesions and mortality in mice.
- Inhibiting STAT3, RIP1 kinase, or caspase-1 prolonged keratinocyte survival and increased viral titers.
- STAT3 and RIP1 kinase inhibition reduced keratinocyte inflammatory responses to TLR ligands.
Conclusions:
- Keratinocytes suppress vaccinia virus via STAT3-dependent programmed cell death.
- This clarifies skin infection susceptibility in STAT3 mutation patients.
- Promoting keratinocyte necroptosis/pyroptosis may mitigate vaccinia vaccination risks.
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