Ngara, M. | Search bioRxiv

bioRxiv2025

Plasmodium falciparum subverts neutrophil function via host miR-451a loaded extracellular vesicles driving bacterial superinfection susceptibility

Malaria caused by Plasmodium falciparum (Pf) compromise innate immunity, yet the underlying mechanisms remain elusive. The immune dysregulation caused by the parasite may lead to bacterial superinfections and increase mortality. We reveal that Pf exploits extracellular vesicles (EVs) secreted by infected red blood cells (iRBC-EVs) to deliver host-derived miR451a to human neutrophils, impairing their antimicrobial defences. Neutrophil phagocytosis of iRBC-EVs suppresses reactive oxygen species (ROS) production and compromised microbicidal activity against Salmonella typhimurium. Microfluidic assays show that miR451a transfer significantly disrupts neutrophil chemotaxis and swarming upon microbial challenge. Transcriptomic profiling indicates that EVs and miR451a reprogram neutrophil gene expression, notably upregulating ferroptosis-related genes, suggesting a role in further impairing immune responses. We have uncovered a novel mechanism of iRBC-EVs-induced neutrophil immune suppression and provide insights into increased susceptibility to bacterial superinfections in malaria. These findings have implications for therapeutic strategies aimed at mitigating bacterial superinfections and sepsis in malaria-endemic regions.

immunology↗

bioRxiv2021

Molecular relationships between SARS-CoV-2 Spike protein and LIFR, a pneumonia protective IL-6 family cytokine

The fine-tuned control of immune responses is attained by pairs of activating and inhibitory signaling receptors which modulate the quality and magnitude of immune responses. Some viruses exploit these pathways to enter host cells as well as interfere with immune responses. Here, we report that the SARS-CoV-1/2 Spike proteins (S) contain a potential inhibitory tyrosine- based immunoreceptor motif (ITIM) with the D614G variant occurring within this motif. Through an in silico screen of ITIM-containing human proteins, we find that the S-located ITIM is closely related to a previously reported ITIM in the cytoplasmic tail of the human Leukemia Inhibitory Factor Receptor (LIFR), a pneumonia protective IL-6 family cytokine receptor. To infer potential functional interactions between SARS-CoV-2 infection and LIFR expression, we performed single-cell transcriptome analysis of public datasets of lung tissues from healthy individuals and COVID-19 patients. We show that transcripts of LIFR and its ligand LIF are highly expressed in SARS-CoV-2 susceptible lung cells from mild and severe COVID-19 patients but not in healthy individuals. In addition, the human endogenous retroviral envelope gene (ERVW-1) encoding a fusogenic protein of the same functional class as the S protein, is induced in SARS-CoV-2 susceptible cell subpopulations in COVID-19 patients with no detectable expression in healthy individuals. We also report that pulmonary epithelial cells express transcripts of several immunoreceptors including the ITIM-containing antibody receptor FCGR2B which is detectable in healthy and severe COVID-19 cases but not in mild cases. These results suggest that molecular dysregulation of ITIM-mediated inhibitory signaling by the SARS-CoV-2 S protein may play a role in COVID-19 immunopathology.

genomics↗