Mammalian Host Responses to Proinflammatory Stimuli by Microbial Pathogens

The complex interplay between infectious agents and host defenses in both the innate and adaptive compartments of the immune system determines the outcome of host-pathogen interactions. Bacteria use virulence strategies to invade biological barriers, but active processes of host epithelial cells may also contribute to the endocytosis of microbial particles. To focus on the latter, the uptake of fixed bacterial particles by the inflamed intestinal epithelium was modeled in vitro by Caco-2BBe cells conditioned with TNF-&alpha and an agonist antibody to the lymphtoxin-&beta receptor. Staphylococcus and Yersinia were readily endocytosed, compared with scant uptake of the enteric and pulmonary pathogens Shigella , Salmonella, and Klebsiella. Endocytosed S. aureus, but not Yersinia, was often associated with cytoplasmic claudin-4 vesicles, suggesting that cytokine treatment upregulated at least two distinct endocytic pathways. Treatment induced epithelial redistribution of &beta1 integrin; consistent with this effect, &beta1 integrin blockade reduced uptake of bacterial particles in epithelial layers. Together, these data indicate that cells of the inflamed mucosa selectively enhance endocytic sampling of bacteria from the lumen, perhaps as a mechanism for enhancing the antigen-specific repertoire of the mucosal lymphocyte population. Other biological barriers to infection form a bulwark between immune cells in circulation and tissues at high risk for damage secondary to inflammation; these include the brain and eye. Infection of these tissues with the intracellular protozoan parasite Toxoplasma gondiiinduces a proinflammatory adaptive response. This is accompanied in the brain by the emergence of localized extracellular fiberlike networks along which parasite-specific T cells migrate. To identify molecules associated with tissue remodeling in the infected brain, matrix metalloprotease transcripts were measured. Substantial post-infection upregulation of MMP-8 and MMP-10 together with their endogenous inhibitor TIMP-1 was observed. Intracellular staining of brain mononuclear cells showed MMP-8 and -10 to be expressed by CD4+ and CD8+ cells; these populations, along with CNS-resident microglia and astrocytes, upregulated TIMP-1 during chronic infection. T. gondii burden was significantly reduced in the brains of TIMP-1 null animals. Together, these findings identify a role for specific MMPs and TIMP-1 in matrix remodeling and pathogen clearance associated with migration of brain-infiltrating leukocytes during Toxoplasma infection