PATHOGENIC ROLE OF CD8+ T CELLS IN MALARIA-ASSOCIATED ACUTE LUNG INJURY IN MICE

Ph.DDOCTOR OF PHILOSOPHY (SOM

Cytoadherence properties of Plasmodium knowlesi-infected erythrocytes

Plasmodium knowlesi is responsible for zoonotic malaria infections that are potentially fatal. While the severe pathology of falciparum malaria is associated with cytoadherence phenomena by Plasmodium falciparum-infected erythrocytes (IRBC), information regarding cytoadherence properties of P. knowlesi-IRBC remained scarce. Here, we characterized the cytoadherence properties of RBC infected with the laboratory-adapted P. knowlesi A1-H.1 strain. We found that late-stage IRBC formed rosettes in a human serum-dependent manner, and rosettes hampered IRBC phagocytosis. IRBC did not adhere much to unexposed (unstimulated) human endothelial cell lines derived from the brain (hCMEC/D3), lungs (HPMEC), and kidneys (HRGEC). However, after being "primed" with P. knowlesi culture supernatant, the IRBC-endothelial cytoadherence rate increased in HPMEC and HRGEC, but not in hCMEC/D3 cells. Both endothelial cytoadherence and rosetting phenomena were abrogated by treatment of P. knowlesi-IRBC with trypsin. We also found that different receptors were involved in IRBC cytoadherence to different types of endothelial cells. Although some of the host receptors were shared by both P. falciparum- and P. knowlesi-IRBC, the availability of glycoconjugates on the receptors might influence the capacity of P. knowlesi-IRBC to cytoadhere to these receptors.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Published versionW-CL, SN, and LR were supported by core funding from A ∗ STAR. W-CL was funded by the Open Fund-Young Individual Research Grant (OF-YIRG NMRC/OFYIRG/0070/2018). LR was funded by A∗ STAR grant (JCO-DP BMSI/15-800006-SIGN) and Singapore Ministry of Education AcRF Tier 3 grant (MOE2019- T3-1-007). SN was also supported by a postgraduate scholarship from the Yong Loo Lin School of Medicine, NUS

Experimental models to study the pathogenesis of malaria-associated acute respiratory distress syndrome

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is increasingly gaining recognition as a severe malaria complication because of poor prognostic outcomes, high lethality rate, and limited therapeutic interventions. Unfortunately, invasive clinical studies are challenging to conduct and yields insufficient mechanistic insights. These limitations have led to the development of suitable MA-ARDS experimental mouse models. In patients and mice, MA-ARDS is characterized by edematous lung, along with marked infiltration of inflammatory cells and damage of the alveolar-capillary barriers. Although, the pathogenic pathways have yet to be fully understood, the use of different experimental mouse models is fundamental in the identification of mediators of pulmonary vascular damage. In this review, we discuss the current knowledge on endothelial activation, leukocyte recruitment, leukocyte induced-endothelial dysfunction, and other important findings, to better understand the pathogenesis pathways leading to endothelial pulmonary barrier lesions and increased vascular permeability. We also discuss how the advances in imaging techniques can contribute to a better understanding of the lung lesions induced during MA-ARDS, and how it could aid to monitor MA-ARDS severity.Agency for Science, Technology and Research (A*STAR)Nanyang Technological UniversityPublished versionCC was financially supported by 2018/24470-0 grant from the São Paulo Research Foundation (FAPESP). JD was supported by Coordination for the Improvement of higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nıvel Superior: CAPES, Brazil) fellowship. SE was supported ́ by 2020/03163-1 from the São Paulo Research Foundation (FAPESP) and 304033/2021-9 from National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cientıfí co e Tecnológico: CNPq, Brazil). LR was supported by Agency for Science, Technology and Research (A*STAR) to a core grant to A*STAR ID labs and a Starting University grant from the Lee Kong Chian School of Medicine, Nanyang Technology University. SN was supported by a postgraduate scholarship from the Yong Loo Lin School of Medicine, National University of Singapore

Malaria abrogates O'nyong-nyong virus pathologies by restricting virus infection in nonimmune cells

O’nyongnyong virus (ONNV) is a re-emerging alphavirus previously known to be transmitted by main malaria vectors, thus suggesting the possibility of coinfections with arboviruses in co-endemic areas. However, the pathological outcomes of such infections remain unknown. Using murine coinfection models, we demonstrated that a preexisting blood-stage Plasmodium infection suppresses ONNV-induced pathologies. We further showed that suppression of viremia and virus dissemination are dependent on Plasmodium-induced IFNγ and are associated with reduced infection of CD45(−) cells at the site of virus inoculation. We further proved that treatment with IFNγ or plasma samples from Plasmodium vivax–infected patients containing IFNγ are able to restrict ONNV infection in human fibroblast, synoviocyte, skeletal muscle, and endothelial cell lines. Mechanistically, the role of IFNγ in restricting ONNV infection was confirmed in in vitro infection assays through the generation of an IFNγ receptor 1 α chain (IFNγR1)–deficient cell line

Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants