Search bioRxiv⌕ Search

Biology subjects

Lukande, R.

Publications and source records attributed to Lukande, R..

2 recordsLinked to original sources

Human postmortem studies reveal tissue-specific differences amongst TB-patient groups

If we are to break new grounds in TB research, we need to have a complete understanding of what is occurring at the site of infection in humans. Postmortem studies give us an opportunity to compare TB-involved and -uninvolved tissues, in both diseased and non-diseased individuals. We examined the feasibility of carrying out a postmortem study in Mulago and Kiruddu National Referral Hospitals in Uganda, to determine whether we could use immune cells collected postmortem for immunological studies. We report that we can consent the Next-of-Kin, perform postmortem procedures and process tissues within 8 hours of death, and that immune cells remain viable and functional up to 14 hours after death. We found subtle differences in T cell subsets within TB groups. We found a depletion of the CD4 CD69+CD103+ T cell subset in the lungs and BAL, which was associated with HIV, and that the CD8 CD69+CD103- T cell subset was depleted in BAL only, and was associated with TB. Our data show overall changes Tissue Resident Memory T cells within, and between, TB-infected and TB-uninfected human lungs. SummaryO_LICoroner led postmortem studies are possible in Uganda, samples processed within 8 hours from death C_LIO_LICells from samples collected postmortem are viable and functional C_LIO_LIHIV associated depletion of CD4 CD69+/CD103+ T cell subset in lungs and BAL C_LIO_LICD8 CD69+/CD103- depletion in BAL associated with TB C_LI

immunology↗

Microglia protect fungi against copper starvation and promote brain infection

Microglia provide protection against a range of brain infections, but how these glial cells respond to fungi is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal brain infections in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, microglia supported cryptococcal fungal brain infection. We show that microglia become hosts for intracellular fungal growth and are a site in which the fungus accesses the restricted micronutrient copper. We developed a reporter fungal strain to track copper starvation responses by the fungus and found that yeast were protected from copper starvation within microglia. Lastly, we show that stimulation of microglia with IFN{gamma} causes restriction of phagosomal copper to intracellular fungi. These data provide a mechanistic explanation for why microglia depletion has a therapeutic effect in the context of this life-threatening fungal infection and is one of the few examples of microglia acting to promote infection. Our data demonstrate how tissue-resident phagocytes can support cryptococcal infections by acting as intracellular reservoirs and sites of microbial nutrient acquisition, and how these mechanisms may be blocked by IFN{gamma} immunotherapy.

immunology↗