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Abstract
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.
Highlights
Vaccination against smallpox has long provided investigators with a simple way to study host responses to infection, by directly examining the spread of vaccinia virus in the skin
We examine the role of STAT3 signaling in the response to smallpox vaccination, and show for the first time that it plays an essential role in the rapid programmed necrosis of keratinocytes induced by vaccinia virus
severe combined immunodeficient (SCID) mice scarified at the base of the tail with ACAM-2000 develop an ulcer which gradually expands over 5–6 weeks (Figure 1A)
Summary
Vaccination against smallpox has long provided investigators with a simple way to study host responses to infection, by directly examining the spread of vaccinia virus in the skin. The failure of keratinocytes to provide an effective antiviral barrier appears to underlie the extensive infections which may occur when persons with skin disorders ranging from atopic dermatitis to burns and acne are vaccinated against smallpox [1]. One innate defect which was not known in the era of universal smallpox vaccination is the dominant negative mutation in the STAT3 gene responsible for hyper-IgE (‘‘Job’s’’) syndrome, which is characterized by a chronic eczema-like skin condition and enhanced susceptibility to cutaneous bacterial and viral infections, observed from days after birth and continuing throughout life [2]. There are no specific accounts of smallpox vaccine complications in hyper-IgE syndrome patients, but it seems likely that, as in naturally occurring herpesvirus and varicella infections, a defect in STAT3 signaling would permit extensive spread of vaccinia virus [3,4]. Defining a protective role of STAT3 in the response to infection might lead to the development of novel countermeasures against vaccinia and other pathogens
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