Impairment of neutrophil function contributes to increased morbidity and mortality in HIV-1 and Mycobacterium tuberculosis co-infection

Patients infected with HIV-1 have an increased susceptibility to secondary microbial infections and this is further exacerbated by co-infection with M ycobacterium tuberculosis. Polymorphonuclear neutrophils (PMN), Important e ffector cells in the host's immune response to bacterial and fungal infecti ons, mediate their killing by either oxidative or non-oxidative mechanisms. Here we provide an overview of a suite of studies that we have conducted t hat address the integrity of PMN function in healthy individuals (normal do nor (ND) group), HIV-1 seropositive patients (HIV), patients with pulmonary tuberculosis (TB), and HIV-1 seropositive individuals with concurrent pulm onary TB (HIV/TB). This was monitored by measuring PMN capacity to phagocyt ose E. coli, to produce reactive oxygen intermediates (oxidative burst) in response to E. coli as agonist, and to degranulate and migrate in response to interleukin-8 (IL-8). When compared to the ND group, phagocytosis and ox idative burst were significantly depressed in the TB and HIV/TB groups, whe reas in the HIV group phagocytosis was enhanced. In the HIV and HIV/TB grou ps, degranulation showed a reciprocal IL-8 dose-response when compared with the ND and TB groups. Chemotaxis of PMN and the mobilization of intracellu lar calcium monitored in response to IL-8 were also shown to be decreased i n a group of HIV/TB patients when compared to healthy controls. Furthermore , these diminished functions were associated with reduced CXCR1 (IL-BRA) an d CXCR1 (IL-8RB) expression on PMN from HIV/TB patients. Taken together, pa tients in the HIV/TB group showed the greatest impairment of PMN function, consistent with clinical findings of increased susceptibility to secondary Infections compared to patients infected with HIV-1 alone.