Ref Robbins 8/e p184;9/e p186-188The principal barriers between hosts and their environ- ment are the epithelia of the skin and the gastrointestinal and respiratory tracts. Infectious microbes usually enter through these routes and attempt to colonize the hosts. The mechanisms of innate immunity operate at every step in a microbe's attempt to invade. At the site of entry, epithelia serve as physical barriers to infections and eliminate microbes through production of peptide antibiotics and the actions of intraepithelial lymphocytes. If microbes are able to survive and traverse these epithelia, they encounter phagocytes, including neutrophils, which are rapidly recruited from the blood into tissues, and macrophages, which live in tissues under epithelia. The function of these phagocytic cells is to ingest microbes and destroy them by producing microbicidal substances. In response to recogni- tion of microbes, phagocytes, DCs, and many other cell types secrete proteins called cytokines (described later), which promote inflammation and microbial killing and enhance protective immune responses. Cells use several receptors to sense microbes; foremost among these are the Toll-like receptors (TLRs), so named because of homology with the Drosophila Toll protein, that recognize bacterial and viral components (Chapter 2). NK cells kill virus- infected cells and produce the macrophage-activating cyto- kine IFN-g. If the microbes enter the blood, many plasma proteins, including the proteins of the complement system, recognize the microbes and are activated, and their products kill microbes and coat (opsonize) the microbes for phagocytosis. In addition to combating infections, innate immune responses stimulate subsequent adaptive immu- nity, providing signals that are essential for initiating the responses of antigen-specific T and B lymphocytes.