1. Microglia are the principle immune cells of the central nervous system (CNS) and play a key role in host defense against invading pathogens. However, much like macrophages to which these cells are related, microglia may play a far more sinister role by amplifying the effects of inflammation leading to damage in the CNS. Deleterious inflammatory reactions mediated by microglia include such chronic conditions as cerebral malaria, HIV infection of the nervous system, and multiple sclerosis. Much study has been devoted to the study of microglial involvement in these conditions, but despite this work the nature of the stimuli that initiate and exacerbate the inflammatory activities of microglia remains a mystery. The neuropeptide, substance P, is the most abundant neurokinin within the CNS. Importantly, substance P has been implicated in a wide variety of inflammatory events where it is recognized to augment immune responses. While it is well known that substance P plays a significant role in the development of inflammatory responses, the ability of substance P to influence the function of resident immune cells of the brain remains obscure. Our central hypothesis is that substance P released by peripheral CNS cells augments the initiation of microglia and astrocyte-mediated immune responses against pathogens or immunogens by increasing pro-inflammatory monokine production, decreasing anti-inflammatory cytokine production, increasing expression of co-stimulatory molecules and increasing class II MHC expression.

2. The initiation of immune responses in bone infections, such as osteomyelitis, is not well understood even though such infections are difficult to treat and recurrent infections often occur. In collaboration with Dr. Michael Hudson, we have investigated the ability of osteoblasts to initiate an immune response following infection with Staphylococcus aureus. Results of these studies suggest an unappreciated ability of osteoblasts to contribute to an inflammatory response following such infection. Such responses could be protective and limit infection, however we are also exploring the possibility that activated osteoblasts may contribute to the inflammation and bone destruction associated with Staphylococcus infections.

3. Gender has long been known to be a contributory factor in the incidence and progression of disorders associated with immune system dysregulation. More recently, evidence has accumulated that gender may also play an important role in infectious disease susceptibility. In general, females generate more robust and potentially protective humoral and cell-mediated immune responses following antigenic challenge than their male counterparts. In contrast, males have frequently been observed to mount more aggressive and damaging inflammatory immune responses to microbial stimuli. In collaboration with Dr. Yvette Huet-Hudson, we have recently begun to investgate the molecular mechanisms underlying gender-based differences observed in conditions such as bacterial sepsis. We have shown that male and female-derived macrophages differ significantly in their level of expression of critical host pattern recognition receptors for gram-negative bacteria derived LPS.