Browsing by Author "Kisaka, Stevens"

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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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    Epidemiology and preclinical management of dog bites among humans in Wakiso and Kampala districts, Uganda: Implications for prevention of dog bites and rabies
    (PloS one, 2020) Kisaka, Stevens; Makumbi, Fredrick E.; Majalija, Samuel; Bangirana, Alexander
    In rabies endemic areas, appropriate management of dog bites is critical in human rabies prevention. Victims must immediately wash bite wound for 15 minutes with water, soap, and a disinfectant before seeking medical care. This study investigated the epidemiology of dog bites and the determinants of compliance to these pre-clinical guidelines requirements among dog bite victims from high rabies-burden areas of Wakiso and Kampala, Uganda. An explanatory sequential mixed-methods study design was used. Quantitative data were collected from 376 dog-bite patients at two healthcare facilities. Qualitative data were also collected through 13 in-depth interviews with patients, healthcare workers, herbalists, and veterinarians. Qualitative data were analyzed using a deductive thematic approach. Generalized linear models were used to determine factors associated with compliance. Nearly half (190, 51%) of the patients were from Wakiso District and 293 (77.9%) had grade II wounds. Most of the wounds (171, 45.5%) were on the legs. Two-thirds of the bites occurred in public places. Only 70 (19%) of the bite patients had complied with pre-clinical guidelines. Nearly half of the patients had applied substances that were not recommended e.g. herbs (47/193), antiseptics (46/193), “black stone” (25/193), and unknown creams (10/193). Factors negatively associated with compliance included: being aged 15 years or older, adjPR = 0.70 (0.47–0.92) and knowing the dog owner, adjPR = 0.65 (0.36–0.93). However, attainment of secondary or higher education, adjPR = 1.76 (1.24–3.79), being in employment, adjPR = 1.48 (1.09–2.31), perception that the dog was sick, adjPR = 1.47 (1.02–2.72) and knowledge about the dog’s subsequent victim(s) adjPR = 0.35 (0.17–0.70) were positively associated with compliance. High occurrence of dog bites in public places by free-roaming dogs suggests the need for deliberate promotion of responsible dog ownership. Additionally, targeted health education may be required to improve the low compliance to pre-clinical guidelines.