Large DNA viruses defend against hostile assault executed by the host immune system by producing an array of gene products that systematically sabotage key components of the inflammatory response. Poxviruses target many of the primary mediators of innate immunity including interferons, tumor necrosis factors, interleukins, complement, and chemokines. Poxviruses also manipulate a variety of intracellular signal transduction pathways such as the apoptotic response. Many of the poxvirus genes that disrupt these pathways have been hijacked directly from the host immune system, while others have demonstrated no clear resemblance to any known host genes. Nonetheless, the immunological targets and the diversity of strategies used by poxviruses to disrupt these host pathways have provided important insights into diverse aspects of immunology, virology, and inflammation. Furthermore, because of their anti-inflammatory nature, many of these poxvirus proteins hold promise as potential therapeutic agents for acute or chronic inflammatory conditions.

The nuclear factor-κB (NF-κB) family of transcription factors plays a central part in orchestrating the innate and adaptive immune response against invading microbial pathogens. Successful pathogens have acquired multiple mechanisms to control the signalling pathways that regulate the NF-κB cascade, and they can collectively target every aspect of the NF-κB signalling pathway. This Review focuses on the different strategies used by viruses, bacteria and parasites to manipulate NF-κB functions. The essential role of NF-κB family members in protection against viruses, bacteria and parasites has been established by the observation that knocking down (ablating) the expression of any of the NF-κB components or blocking their signalling function increases host susceptibility to diverse microbial pathogens. Viruses are obligate intracellular parasites and frequently either activate or inhibit the NF-κB signalling pathway during different phases of their life cycle. So, a delicate balance must be maintained between activation and inhibition of the NF-κB pathway. Some viruses uniquely activate NF-κB to promote viral replication and to control virus-induced cellular apoptosis. Viruses usually activate or suppress the NF-κB signalling pathway by modulating the function of multiple signalling receptors, adaptor molecules, cellular kinases, and cellular NF-κB inhibitors or regulators, and also by direct interaction with the NF-κB subunits themselves. Virus-encoded proteins can also sometimes modulate the transcriptional activity of activated NF-κB after translocation to the nucleus. Bacteria and parasites can activate or inhibit the NF-κB signalling pathway, depending on the host cellular status that most benefits the pathogen. Bacteria-derived molecules can modulate NF-κB by targeting the same pathway components and stages as are targeted by viruses. Sometimes, bacteria and parasites can hijack crucial NF-κB signalling molecules and re-appropriate them for exploitation during the pathogen's own replication cycle. Although virus- and bacteria-derived molecules are remarkably diverse in structure, they often target operationally common NF-κB signalling molecules for modulation. Interestingly, a single pathogen often encodes multiple proteins to modulate the NF-κB signalling pathway at different steps, which affirms the key importance of the NF-κB pathway in combating diverse invading microbial pathogens.