Browsing by Author "Calverley, Matthew David"

Now showing 1 - 1 of 1

The alveolar macrophage in pulmonary infection : a comparison of permissiveness to infection with an obligate and a facultative intracellular pathogen
(Montana State University - Bozeman, College of Agriculture, 2013) Calverley, Matthew David; Chairperson, Graduate Committee: Allen G. Harmsen; Allen G. Harmsen, Sara Erickson, and Amanda J. Read were co-authors of the article, 'Resident alveolar macrophages are susceptible to and permissive of Coxiella burnetii infection' in the journal 'PLoS ONE' which is contained within this thesis.; Robert A. Cramer and Allen G. Harmsen were co-authors of the article, 'The facultative intracellular pathogen Cryptococcus neoformans proliferates primarily extracellularly early in in vivo infection' submitted to the journal 'mBio' which is contained within this thesis.
The lung must mount an effective immune response to pathogenic challenge while controlling attendant tissue damage. Central to this co-ordination are the immunomodulatory effects exerted by the pulmonary environment on the local alveolar macrophages (AMs). Moreover, intracellular pathogens are known to exploit the host immune system. For this reason, we hypothesized that the resident AM would comprise a vulnerable population of cells capable of being exploited by intracellular pathogens. To test this hypothesis, we investigated the role of the AM during pulmonary infection with either the obligate intracellular bacterium Coxiella burnetii or the facultative intracellular fungus Cryptococcus neoformans. We showed [1] that resident AM are indeed the cell-type most susceptible to infection with C. burnetii. These resident AM remain infected up to twelve days, serving as a permissive niche that supports bacterial survival. Additionally, a subset of infected AMs underwent a characteristic phenotypic change in response to infection, resulting in an increased expression of surface integrin CD11b and continued expression of surface integrin CD11c. We conclude that C. burnetii is capable of exploiting the pulmonary environmental effects on the resident AM allowing for exploitation of the AM as a susceptible and permissive niche for infection. In the context of C. neoformans infection, we found that only a restricted population of C. neoformans replicated in AMs. The majority of C. neoformans that replicated in vivo did so extracellularly and the extent of extracellular replication exceeded intracellular replication of the yeast. In fact, the majority of intracellular fungal load in AMs at 48 hours post-infection was attributable to the uptake of extracellular C. neoformans from 24 to 48 hours post-infection. Thus, unlike C. burnetii, C. neoformans does not appear to exploit the pulmonary environmental effects on the resident AM during establishment of infection. Through the identification of the AM as a susceptible and permissive niche for C. burnetii infection and the finding that C. neoformans replicates primarily extracellularly during early pulmonary infection, we have both filled a deficiency in the previous knowledge base and set the stage for future studies into the induction of subsequent adaptive immune responses during these varied infections.