Cellular immune activation in cerebrospinal fluid from ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome.

BACKGROUND: Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. METHODS: We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). RESULTS: At diagnosis, highly activated CD8(+) T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4(+) T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. CONCLUSIONS: After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4(+) T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS.

Career development for infection and immunity research in Uganda: a decade of experience from the Makerere University - Uganda Virus Research Institute research and training programme.

Background: The Makerere University/Uganda Virus Research Institute (UVRI) Centre of Excellence for Infection & Immunity Research and Training (MUII) is a collaborative programme supporting excellence in Infection and Immunity (I&I) research in Uganda. Set up in 2008, MUII aims to produce internationally competitive Ugandan and East African I&I research leaders, and develop human and infrastructural resources to support research and training excellence. We undertook an internal evaluation of MUII's achievements, challenges and lessons learned between 08-2008 and 12-2019, to inform programmes seeking to build Africa's health research expertise. Methods: Quantitative data were abstracted from programme annual reports. Qualitative data were obtained in 03-04/2019: a cross-sectional evaluation was undertaken among a purposefully selected representative sample of 27 trainees and two programme staff. Qualitative data was analysed according to pre-determined themes of achievements, challenges, lessons learned and recommendations for improvement. Results: By 12-2019, MUII had supported 68 fellowships at master's-level and above (50% female: 23 Masters, 27 PhD, 15 post-doctoral, three group-leaders) and over 1,000 internships. Fellows reported career advancement, mentorship by experts, and improved research skills and outputs. Fellows have published over 300 papers, secured grants worth over £20m, established over 40 international collaborations, and taken on research and academic leadership positions in the country. Key lessons were: i) Efficient administration provides a conducive environment for high quality research; ii) Institutions need supportive policies for procurement, including provisions for purchases of specific biological research reagents from international manufacturers; iii) Strong international and multi-disciplinary collaboration provides a critical mass of expertise to mentor researchers in development; and iv) Mentorship catalyses young scientists to progress from graduate trainees to productive academic researchers, relevant to society's most pressing health challenges. Conclusions: Sustainable academic productivity can be achieved through efficient operational support, global collaboration and mentorship to provide solutions to Africa's health challenges.