Viral Inhibition of host immune defenses
Many viruses have evolved mechanisms to protect themselves from host immune defenses. Among this group are the orthopoxviruses, whose members include smallpox virus, one of the deadliest of human viruses, and cowpox virus, the virus that Edward Jenner used to begin the eradication of smallpox.

One of the unusual features of theses viruses is their ability to interfere with elements of the first phase of the immune defense, the innate immune responses, including inflammatory responses. We are trying to determine how cowpox virus and related viruses achieve this inhibition, and how such virus-host interactions contribute to viral pathogenesis.

So far, we have found that cowpox virus inhibits inflammation by modifying the action of cytokines controlling inflammatory processes. It does this by:

1. preventing the synthesis of cytokines;
2. modifying cytokine-receptor interactions;
3. inhibiting cytokine-signaling pathways.

For example, among the ~200 proteins encoded by cowpox virus, we have identified 7 cytokine-response modifiers: CrmA, a caspase inhibitor (with anti-inflammatory and anti-apoptosis roles); and soluble secreted, receptors for IL-1, CC-chemokines, CD30L, and TNF (here not one viral receptor protein but three, CrmB, CrmC, and CrmD). Recently we have shown that several poxviruses interfere with the activation of NF-kB, a family of transcription factors central to the control of a variety of immune processes.