Dr. David Meya successfully defended his PhD thesis on 29 April 2016 at the College of Health Sciences, Makerere University. His thesis entitled “ Immunopathogenesis of Immune Reconstitution Inflammatory Syndrome Secondary to Central Nervous System Infections in HIV-Infected Patients” was largely focused on HIV-infected individuals who present with Cryptococcal Meningitis (CM), receive adequate antifungal therapy, and upon initiating Antiretroviral Therapy present with the clinical syndrome referred to as Immune Reconstitution Inflammatory Syndrome or IRIS.

Immune Reconstitution Inflammatory Syndrome (IRIS) occurs in approximately 30% of patients with Cryptococcal Meningitis after ART initiation and has high associated mortality. The triggers for CM-IRIS and the specific immune axes involved remain unclear. In his thesis, he reviewed the current state of knowledge about CM-IRIS and presented results of studies that characterized cell phenotype and activation in cerebrospinal fluid (CSF), T cell responses to cryptococcal antigen and monocyte responses to Interferon-γ at diagnosis of CM and during CM-IRIS in peripheral blood.

The main Objective of his PhD work was to determine the role of T cell and monocyte responses in peripheral blood, and cellular trafficking into the CSF during Immune Reconstitution Inflammatory Syndrome following cryptococcal meningitis.

Using flow cytometry, Dr. Meya assessed in vitro T cell responses to the predominant cryptococcal capsular antigen Glucuronoxylomannan (GXM) and monocyte responses to IFN-γ (T cell signal) at CM diagnosis and during CM-IRIS compared with those in patients without IRIS (Controls) matched for ART duration. He quantified T cell memory, monocyte subsets, and their activation phenotypes and measured intracellular interleukin (IL)-2, IL-17, Interferon-γ (IFN-γ), IL-6 and TNF-α expression by flow cytometry and characterized the phenotype and activation of CSF cells.

He found that in CSF, there was an increasing frequency of CD4+ T cells, and a shift in monocyte phenotype from classical to an intermediate/pro-inflammatory phenotype that occurred at CM-IRIS. The CSF cellular responses were distinct from those in peripheral blood. He also observed lower frequencies of non-classical monocytes and a predominance of dual function IL-6- and TNF-α-producing monocytes in persons who developed CM-IRIS vs controls. Patients with CM-IRIS had aberrant T cell responses to GXM, with increased frequency of poly-functional IL-2- and IL-17- producing CD4+ T cells and IL-2- producing CD8+ T cells compared with controls.

Dr. Meya therefore concluded that polyfunctional innate (monocyte) and adaptive (CD4+ T cell) responses to Interferon-γ and GXM respectively, a distinct evolution of cell phenotype in the CSF and aberrant T cell responses to GXM contribute to the immunopathogenesis of CM-IRIS. These findings suggest that the cells of the innate immune axis play a role in the immunopathogenesis of cryptococcal IRIS and secondly, there is a characteristic compartment-specific immune signature (at the local site of inflammation, in the central nervous system) associated with this syndrome. These immune responses could be further studied by blockade of the IL-6 pathway as a potential therapeutic strategy for CM-IRIS.

The work for this PhD thesis was nested within a larger clinical trial, the NIH-funded COAT trial, for which Dr. Meya was the Ugandan Principal investigator. This clinical trial showed that early initiation of antiretroviral therapy before 4-5 weeks of antifungal therapy among patients with cryptococcal meningitis carries a mortality risk and thus led to revision of the WHO guidelines on the timing of ART following Cryptococcal meningitis.