The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses.

The vaccinia virus (VACV) strain Western Reserve C16 protein has been characterized and its effects on virus replication and virulence have been determined. The C16L gene is present in the inverted terminal repeat and so is one of the few VACV genes that are diploid. The C16 protein is highly conserved between different VACV strains, and also in the orthopoxviruses variola virus, ectromelia virus, horsepox virus and cowpox virus. C16 is a 37.5 kDa protein, which is expressed early during infection and localizes to the cell nucleus and cytoplasm of infected and transfected cells. The loss of the C16L gene had no effect on virus growth kinetics but did reduce plaque size slightly. Furthermore, the virulence of a virus lacking C16L (vΔC16) was reduced in a murine intranasal model compared with control viruses and there were reduced virus titres from 4 days post-infection. In the absence of C16, the recruitment of inflammatory cells in the lung and bronchoalveolar lavage was increased early after infection (day 3) and more CD4+ and CD8+ T cells expressed the CD69 activation marker. Conversely, late after infection with vΔC16 (day 10) there were fewer T cells remaining, indicating more rapid clearance of infection. Collectively, these data indicate that C16 diminishes the immune response and is an intracellular immunomodulator.

Postoperative pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by PG at surgical incisions. It is often misdiagnosed as wound infection, and pathergy may complicate wound debridement. From September 1, 2013, through November 30, 2013, a literature search was conducted of articles published from January 1, 1978, through December 31, 2012. We referenced PubMed, MEDLINE, and Mayo Clinic Libraries using the keywords pyoderma gangrenosum, postoperative pyoderma gangrenosum, postsurgical pyoderma gangrenosum, superficial granulomatous pyoderma, pathergic pyoderma, and pyoderma gangrenosum associated with surgery, incision, breast, and wound dehiscence. In addition, all titles from PubMed with the words pyoderma gangrenosum were reviewed manually for postoperative cases. Of 136 patients, 90 (66%) did not have associated systemic diseases. If a comorbidity was present, hematologic disorders were most common. In addition, 29% (28) of women had predisposing disease vs 53% (19) of men. Women had more frequent breast involvement (P<.001); chest involvement was more common in men (P=.005). Girls and women aged 13 to 64 years had more frequent breast involvement (P=.01). Sites were distributed equally for men regardless of age (P=.40). Antibiotic drug therapy was begun and debridement occurred in 90% (110 of 122 treated patients) and 73% (90 of 123 available patients), respectively. Postoperative PG has less association with systemic disease than its nonpostoperative counterpart. Antibiotic drug therapy is routinely initiated. Affected sites are often debrided, causing additional wound breakdown. Early diagnosis may prevent complications.

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PVB results in decreased opioid use and decreased need for postoperative antiemetic medication in patients undergoing mastectomy. The greatest benefit is seen in patients undergoing bilateral mastectomy with immediate breast reconstruction.