Browsing by Author "Nayiga, Irene"

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    COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
    (Nature Publishing Group, 2024-02) Cummings, Matthew J; Bakamutumaho, Barnabas; Lutwama, Julius J; Owor, Nicholas; Che, Xiaoyu; Astorkia, Maider; Postler, Thomas S; Kayiwa, John; Kiconco, Jocelyn; Muwanga, Moses; Nsereko, Christopher; wamutwe, Emmanuel; Nayiga, Irene; Kyebambe, Stephen; Haumba, Mercy; Bosa, Henry Kyobe; Ocom, Felix; Watyaba, Benjamin; TKikaire, Bernard; Tomoiaga, Alin S; Kisaka, Stevens; Kiwanuka, Noah; Lipkin, W Ian; O'Donnell, Max R
    Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity. Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.
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    Detection of urine lipoarabinomannan is associated with proinflammatory innate immune activation, impaired host defense, and organ dysfunction in adults with severe HIV-associated tuberculosis in Uganda
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2023) Matthew, J. Cummings; Bakamutumaho, Barnabas; Komal, Jain; Adam Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Nayiga, Irene; Kyebambe, Stephen; Xiaoyu, Che; Stephen, Sameroff; Rafal, Tokarz; Wai, Wong; Thomas, S. Postler; Michelle, H. Larsen; W. Ian, Lipkin; Lutwama, Julius J.; Max, R. O’Donnell
    Background: The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB. Methods: We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results. Results: Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors. Conclusions: Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.
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    Prevalence of group a streptococcus pharyngeal carriage and clinical manifestations in school children aged 5–15 yrs in Wakiso District, Uganda
    (BMC Infectious Diseases, 2017) Nayiga, Irene; Okello, Emmy; Lwabi, Peter; Ndeezi, Grace
    Beta-hemolytic streptococci carrier rates in children living in low-income countries are high ranging from 10 to 50%. Although most of these children are asymptomatic, they are a reservoir and pose a risk of transmission. The aim of this study was to determine the prevalence of group a streptococcus pharyngeal carriage and clinical manifestations in school going children in Wakiso district, Uganda.A cross sectional study targeting children age 5–15 years in primary schools in one sub-county of Wakiso district was carried out. Three hundred and sixty-six children from five primary schools were enrolled and evaluated for group a streptococcus (GAS) carriage. A semi-structured questionnaire was used to collect data that included social demographics, school environment and clinical findings. For every enrolled child a throat swab was taken and cultured for GAS and blood was drawn for anti-streptolysin-O titres. Analysis of data was done using STATA.The prevalence of GAS carriage was 16%. The children with GAS positive cultures were mainly females. The factor associated with GAS carriage was the school location, with peri-urban schools more likely to have children with GAS compared to rural schools; AOR 2.48 (95% CI: 1.01 – 6.11), P = 0.049. There was no significant difference between the characteristic of children with GAS positive verses GAS negative throat swab cultures.There is a high prevalence of GAS pharyngeal carriage among children aged 5–15 years attending primary schools in Wakiso District, Uganda.
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    Prevalence of Group a Streptococcus Pharyngeal Carriage and Clinical Manifestations in School Children aged 5–15 yrs in Wakiso District, Uganda
    (BMC Infectious Diseases, 2017-04-05) Nayiga, Irene; Okello, Emmy; Lwabi, Peter; Ndeezi, Grace
    Beta-hemolytic streptococci carrier rates in children living in low-income countries are high ranging from 10 to 50%. Although most of these children are asymptomatic, they are a reservoir and pose a risk of transmission. The aim of this study was to determine the prevalence of group a streptococcus pharyngeal carriage and clinical manifestations in school going children in Wakiso district, Uganda. A cross sectional study targeting children age 5–15 years in primary schools in one sub-county of Wakiso district was carried out. Three hundred and sixty-six children from five primary schools were enrolled and evaluated for group a streptococcus (GAS) carriage. A semi-structured questionnaire was used to collect data that included social demographics, school environment and clinical findings. For every enrolled child a throat swab was taken and cultured for GAS and blood was drawn for anti-streptolysin-O titres. Analysis of data was done using STATA. The prevalence of GAS carriage was 16%. The children with GAS positive cultures were mainly females. The factor associated with GAS carriage was the school location, with peri-urban schools more likely to have children with GAS compared to rural schools; AOR 2.48 (95% CI: 1.01 – 6.11), P = 0.049. There was no significant difference between the characteristic of children with GAS positive verses GAS negative throat swab cultures. There is a high prevalence of GAS pharyngeal carriage among children aged 5–15 years attending primary schools in Wakiso District, Uganda.