We discovered that M. tuberculosis (Mtb) infection causes apoptosis of primary human alveolar macrophages (AMphi) in vitro by a tumor necrosis factor-alpha death signaling pathway. Apoptotic AMphi are present in bronchoalveolar lavage of tuberculosis (TB) patients and in TB lung biopsies. We found that virulent Mtb strains downregulate apoptosis of host AMphi, and we have shown that apoptosis is linked to microbicidal processing. Based on these observations, we hypothesize that lung Mphi apoptosis constitutes a newly recognized mechanism of innate immunity in TB. TB is a major co-infection in AIDS, contributing to increased morbidity and mortality. With declining adaptive immunity in AIDS, the relative importance of innate immunity may be augmented. Our research plan proposes novel use of the murine aerosol TB model to define the role of lung Mphi apoptosis in disease susceptibility and resistance in vivo.
The specific aims address three key issues: 1, we will characterize the kinetics and distribution of lung Mphi apoptosis following aerosol Mtb infection; 2, we will examine the relationship between lung Mphi apoptosis and host resistance in experiments comparing Mtb strains of high and low virulence, common inbred mouse strains that are innately susceptible or resistant to TB, wildtype and knockout mice with targeted deletion of genes regulating apoptosis, and Mtb transduced to express apoptosis regulating genes; 3, we will evaluate the impact of lung Mphi apoptosis on cytokine expression and the pattern of leukocyte recruitment to the lung in TB, and it's contribution to the development of delayed type hypersensitivity. These studies will provide a detailed analysis of early events in murine TB, and will be the first to fully characterize lung Mphi apoptosis in vivo and to define it's contribution to the integrated host response to infection. Our model may reflect a mechanism broadly involved in the defense against a variety of other intracellular pathogens (such as Legionella) of immediate relevance to the HIV-infected host.
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| Riendeau, Carrie J; Kornfeld, Hardy (2003) THP-1 cell apoptosis in response to Mycobacterial infection. Infect Immun 71:254-9 |
| Keane, J; Shurtleff, B; Kornfeld, H (2002) TNF-dependent BALB/c murine macrophage apoptosis following Mycobacterium tuberculosis infection inhibits bacillary growth in an IFN-gamma independent manner. Tuberculosis (Edinb) 82:55-61 |
