IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice.

Development of cerebral malaria (CM), a severe and fatal form of clinical Plasmodium falciparum infection, results from a damaging cascade of vascular, inflammatory, and immunological host responses that leads to brain injury. Progression to CM can be modified by host genetic factors. Our case-control study in Angolan children aimed at highlighting the role of IFN (α, ß) receptor 1 (IFNAR1) in progression to CM. We report a robust association between IFNAR1 and CM protection, as well as detailed studies showing analogous protection from experimental CM in Ifnar1(-/-) mice infected with P. berghei ANKA. We developed a novel cell-transfer protocol that enables spleen cell priming in the absence of disease. This led to the discovery that IFNAR1 expression in CD8(+) T cells is crucial and can abrogate resistance to experimental CM in Ifnar1(-/-) mice. Splenic CD8(+) T cells from Ifnar1(-/-) mice are functionally activated upon infection, yet are unable to mediate experimental CM development within the brain tissue. Our findings prove that IFNAR1 signaling unleashes CD8(+) T cell effector capacity, which is vital for CM, and raises the hypothesis that the cohesive role of IFNAR1 in both human and mouse CM operates through CD8(+) T cell triggering.

NOS2 variants reveal a dual genetic control of nitric oxide levels, susceptibility to Plasmodium infection, and cerebral malaria.

Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes.

COVID-19 vaccine effectiveness among healthcare workers: a hospital-based cohort study.

OBJECTIVES: Healthcare workers (HCWs) were the first to be prioritised for COVID-19 vaccination. This study aims to estimate the COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 symptomatic infection among HCWs in Portuguese hospitals. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: We analysed data from HCWs (all professional categories) from three central hospitals: one in the Lisbon and Tagus Valley region and two in the central region of mainland Portugal, between December 2020 and March 2022. VE against symptomatic SARS-CoV-2 infection was estimated as one minus the confounder adjusted HRs by Cox models considering age group, sex, self-reported chronic disease and occupational exposure to patients diagnosed with COVID-19 as adjustment variables. RESULTS: During the 15 months of follow-up, the 3034 HCWs contributed a total of 3054 person-years at risk, and 581 SARS-CoV-2 events occurred. Most participants were already vaccinated with a booster dose (n=2653, 87%), some are vaccinated with only the primary scheme (n=369, 12.6%) and a few remained unvaccinated (n=12, 0.4%) at the end of the study period. VE against symptomatic infection was 63.6% (95% CI 22.6% to 82.9%) for HCWs vaccinated with two doses and 55.9% (95% CI -1.3% to 80.8%) for HCWs vaccinated with one booster dose. Point estimate VE was higher for individuals with two doses taken between 14 days and 98 days (VE=71.9%; 95% CI 32.3% to 88.3%). CONCLUSION: This cohort study found a high COVID-19 VE against symptomatic SARS-CoV-2 infection in Portuguese HCWs after vaccination with one booster dose, even after Omicron variant occurrence. The small sample size, the high vaccine coverage, the very low number of unvaccinated individuals and the few events observed during the study period contributed to the low precision of the estimates.